Estetrol for use in the treatment of female sexual arousal disorder

Abstract

The present invention relates to a therapy for Female Sexual Arousal Disorder (FSAD), to the associated compositions, dosage units, and packaging units. Particularly, the present invention concerns the use of a composition comprising from about 14 mg to about 25 mg of an estetrol component for treating FSAD. The composition achieves favourable effects on subjects diagnosed to have FSAD based on self reporting questionnaires.

Description

[0001] ESTETROL FOR USE IN THE TREATMENT OF FEMALE SEXUAL AROUSAL DISORDER

[0002] FIELD OF THE INVENTION

[0003] The present invention broadly relates to the field of medicine, and more particularly to hormone treatments for subjects suffering from female sexual arousal disorder. Specifically, the invention relates to a composition comprising an estetrol component for treating female sexual arousal disorder.

[0004] BACKGROUND OF THE INVENTION

[0005] In popularizing media, distinct medical conditions relating to reduced or absent female sexual desire, sexual arousal, and pain during sexual activities are commonly indicated by the term Female Sexual Dysfunction (FSD). However, from a medical classification perspective, the term FSD is actually considered to encompass a group of at least four distinguishable disorders: Hypoactive Sexual Desire Disorder (HSDD) characterized by a reduced or absent interest in sexual activity; Female Sexual Arousal Disorder (FSAD) characterized by an inability to attain or maintain sexual excitement; Female Orgasmic Disorder (FOD) characterized by the difficulty to attain orgasm despite sufficient arousal; and sexual pain disorder characterized by pain during sexual activity. In all the dysfunctions, women must also experience personal distress in order to meet the criteria for a diagnosis. In one classification system, the DSM-5, FSAD and HSDD have been combined into one disorder, Female Sexual Interest / Arousal Disorder (FSIAD).

[0006] The condition FSIAD was included for the first time in the 2013 publication of the Diagnostic and Statistical Manual of Mental Disorders version 5 (DSM-5) and was received critically by experts within the field, who raised several concerns when comparing FSAD diagnostic criteria with the criteria present in the earlier DSM-IV-TR of FSAD and HSDD (Thomas and Gurevich, Feminism & Psychology, 2021, DOI: 10.1177 / 0959353521989536 and Clayton et al., Journal of Sexual Medicine, 2012, DOI: 10.1111 / j.1743-6109.2012.02850.x). Due to the complete and thorough stratification of HSDD and FSAD, experts in the field continue to use the diagnostic criteria of DSM-IV-TR for investigating FSAD or HSDD specifically, which remain to be considered two different indications by said experts. It would indeed be counterproductive to combine the two disorders, to make individual criteria for the disorders more stringent or to require more such criteria for a diagnosis because such disorders tend to be distinct in presentation, in treatability with currently available therapies, and in logical approaches to be tested to improve therapy (Clayton et al., Journal of Sexual Medicine, 2012, DOI: 10.1111 / j.1743- 6109.2012.02850.x). Further, the FDA 2016 guidance was published to assist sponsors in developing dmgs for the treatment of low sexual interest, desire, and / or arousal in women. The guidance focuses on conditions of low sexual interest, desire, and / or arousal that cause marked distress or interpersonal difficulty in women, including female sexual interest / arousal disorder (FSIAD), hypoactive sexual desire disorder (HSDD), and female sexual arousal disorder (FSAD).

[0007] According to DSM IV-TR, FSAD is to be diagnosed upon fulfilment of the following three criteria:

[0008] A. Persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement. B. The disturbance causes marked distress or interpersonal difficulty.

[0009] C. The sexual dysfunction is not better accounted for by another Axis I disorder (except another Sexual Dysfunction) and is not due exclusively to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.

[0010] There is currently no approved treatment for Female Sexual Arousal Disorder (FSAD). Sildenafil, a popular product to treat erectile dysfunction, has recently been formulated into a topical cream and is being studied for the treatment of FSAD in a premenopausal population of women with FSAD (Dare Bioscience, Phase 2b RESPOND study). Most commonly, women affected by FSAD resort to psychological treatments such as cognitive behavioural therapy and / or couples sex therapy. In addition, earlier studies investigating female sexual problems did not contain all information required to diagnose FSAD, as said studies did not inquire about distress or level of stimulation. In addition, several reports incorrectly use terms such as “libido” and “sexual arousal” interchangeably, while from a clinical, diagnostic and treatment perspective, these terms have a very distinct meaning. Indeed, libido refers to a general baseline interest in sexual activities (i.e. desire, sexual appetite), while arousal, specifically genital arousal, refers to the genital physiological response to sexual stimuli.

[0011] Given that FSAD has a profound adverse effect on the quality of life of a women, either by decreased psychological well-being and the loss of what the WHO considers a basic human right of sexual health, or the relationship consequences of sexual difficulties, there is a need to develop effective therapies.

[0012] SUMMARY OF THE INVENTION

[0013] By conducting rigorous diagnostic interviews, subjects suffering from FSAD could be studied in a highly specific manner by the inventors, whereas prior studies included women who were suffering from complaints such as persistent or recurrent deficient (or absent) sexual fantasies and desires for sexual activity. Those play a role in HSDD. However, in order to diagnose FSDs such as HSDD and FSAD, the additional criterion that the disorder causes significant distress or interpersonal difficulties must also be met. In the present study performed by the inventors, participants are diagnosed by an expert interview in accordance with the Diagnostic and Statistical Manual of Mental Disorders 4th edition-text revision (DSM-IV-TR) for FSAD. In addition, participants must have a total score at screening on the Female Sexual Distress Scale-Desire / ArousaFOrgasm (FSDS-DAO) > 18 and a score on the FSDS-DAO-Item 14 > 3. A particular focus point was the reporting of sexually related distress as a clear and reliable measure of clinical impact. High distress scores indicated that the subjects have indeed FSAD and required treatment. Through extensive experimentation and analysis, the inventors have found unexpectedly that estetrol components such as estetrol are effective in treating FSAD.

[0014] The invention therefore provides in the following aspects:

[0015] Aspect 1. A composition comprising about 14 mg to about 25 mg of an estetrol component, for use in treating female sexual arousal disorder (FSAD) and wherein preferably said composition is administered once daily.

[0016] Aspect 2. Use of a composition for the manufacturing of a medicament for treating FSAD, wherein said composition comprises from about 14 mg to about 25 mg of an estetrol component and wherein preferably said composition is administered once daily. Aspect 3. Use of a composition comprising an estetrol component for treating FSAD, wherein said composition comprises from about 14 mg to about 25 mg of an estetrol component and wherein preferably said composition is administered once daily.

[0017] Aspect 4. A method of treating FSAD in a subject, wherein said method comprises the step of administering once daily a composition comprising from about 14 mg to about 25 mg of an estetrol component.

[0018] Aspect 5. The composition for use according to aspect 1, the use according to aspects 2 or 3, or the method according to aspect 4, wherein the composition comprises from about 15 to about 25 mg of the estetrol component.

[0019] Aspect 6. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the estetrol component is estetrol monohydrate.

[0020] Aspect 7. The composition for use, the use, or the method according to 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 (i.e. a dosage unit for oral ingestion).

[0021] Aspect 8. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the subject is a female menopausal, perimenopausal, or post-menopausal subject.

[0022] Aspect 9. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the subject is a hysterectomized subject.

[0023] Aspect 10. The composition for use, the use, or the method according to the preceding aspect, wherein the hysterectomized subject is a bilateral salpingo-oophorectomy (BSO) subject.

[0024] Aspect 11. The composition for use, the use, or the method according to any one of the preceding aspects, characterized by an improvement of one or more of the following parameters after 12 weeks:

[0025] - sexual distress assessed by Female Sexual Distress Scalc-Dcsirc / Arousal / Orgasm (FSDS-DAO) total score or percentage of Satisfying Sexual Events (SSE) as preferably captured in an arousal diary;

[0026] - sexual function assessed by Sexual Function Questionnaire (SFQ-28) total score;

[0027] - sexual function assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) sexual function and satisfaction measures (SexFS) or assessed by PROMIS SexFS- customized;

[0028] - Patient Global Impression of Change (PGIC) at week 12;

[0029] - severity of sexual arousal disorder as assessed by Patient Global Impression of Severity (PGIS).

[0030] Aspect 12. The composition for use, the use, or the method according to any one of the preceding aspects, characterized by an improved sexual arousal as assessed by FSDS-DAO item 14, preferably characterized by an improved sexual arousal as assessed by FSDS-DAO item 14 after 12 weeks compared to baseline.

[0031] Aspect 13. The composition for use, the use, or the method according to the preceding aspect, wherein sexual arousal as assessed by FSDS-DAO item 14 after 12 weeks compared to baseline is improved by at least about 10%, preferably at least about 25%, more preferably at least about 50%. Aspect 14. The composition for use, the use, or the method according to aspect 12, wherein the score of sexual arousal as assessed by FSDS-DAO item 14 after 12 weeks compared to baseline is improved by at least 1, preferably by at least 2, more preferably by at least 3, most preferably by 4.

[0032] Aspect 15. The composition for use, the use, or the method according to any one of the preceding aspects, characterized by an increase in percentage of Satisfying Sexual Events (SSE) of at least about 10%, preferably at least about 20%, preferably at least about 30%, preferably at least about 40%, preferably at least about 50%, preferably at least about 60%, preferably at least about 70%, preferably at least about 80%, more preferably at least about 90%, most preferably at least about 100%.

[0033] Aspect 16. The composition for use, the use, or the method according to any one of the preceding aspects, characterized by an improved arousal-sensation domain as assessed by SFQ-28 questions 6 to 9, preferably characterized by an improved arousal-sensation domain as assessed by SFQ-28 questions 6 to 9 after 12 weeks compared to baseline.

[0034] Aspect 17. The composition for use, the use, or the method according to the preceding aspect, wherein the arousalsensation domain as assessed by SFQ-28 questions 6 to 9 after 12 weeks compared to baseline is improved by at least about 10%, preferably by at least about 25%, more preferably by at least about 50%.

[0035] Aspect 18. The composition for use, the use, or the method according to aspect 16, wherein the arousal-sensation domain assessed by SFQ-28 questions 6 to 9 is improved by a positive change in the response to one or more of said questions 6 to 9, preferably wherein the arousal-sensation domain assessed by SFQ-28 is improved by a positive change in the response to question 6, 7, 8, 9, or any combination thereof.

[0036] Aspect 19. The composition for use, the use, or the method according to any one of the preceding aspects, characterized by an improved arousal and lubrication as assessed by PROMIS sexual function and satisfaction measures (SexFS) or PROMIS SexFS - customized, preferably characterized by an improved arousal and lubrication as assessed by PROMIS SexFS after 12 weeks compared to baseline.

[0037] Aspect 20. The composition for use, the use, or the method according to the preceding aspect, wherein the arousal and lubrication as assessed by PROMIS SexFS or PROMIS SexFS cutomized after 12 weeks compared to baseline is improved by at least about 10%, preferably at least about 25%, more preferably at least about 50%.

[0038] Aspect 21. The composition for use, the use, or the method according to any one of the preceding aspects, characterized by an improved arousal and lubrication as assessed by PROMIS SexFS or PROMIS SexFS cutomized item ID SFACT201, SFACT202, SFACT203, SFACT204, SFACT205, SFACT206, SFACT207, SFACT208, SFACT209, SFACT210, SFACT212, SFACT213, SFACT214, SFACT215, or any combination thereof.

[0039] Aspect 22. The composition for use, the use, or the method according to any one of the preceding aspects, characterized by an improvement in sexual arousal as assessed by a PGIC scale at week 12, preferably characterized by an improvement in sexual arousal as assessed by an improvement in sexual arousal on a 7-point Likert scale at week 12. Aspect 23. The composition for use, the use, or the method according to the preceding aspect, characterized by an improvement in sexual arousal as indicated on a 7-point Likert scale of at least 1 point, preferably at least 2 points, preferably at least 3 points, preferably at least 4 points, preferably at least 5 points, preferably at least 6 points, more preferably by 7 points at week 12.

[0040] Aspect 24. The composition for use, the use, or the method according to any one of the preceding aspects, characterized by a decrease in severity of sexual arousal dysfunction as assessed by a PGIS scale, preferably characterized by a decrease in severity of sexual arousal dysfunction as assessed on a 7-point Likert scale.

[0041] Aspect 25. The composition for use, the use, or the method according to the preceding aspect, characterized by a decrease in severity of sexual arousal dysfunction as indicated on a 7-point Likert scale of at least 1 point, preferably at least 2 points, preferably at least 3 points, preferably at least 4 points, preferably at least 5 points, preferably at least 6 points, more preferably by 7 points.

[0042] Aspect 26. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the subject has been diagnosed to have FSAD, preferably wherein the subject has been diagnosed to have FSAD according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition-text revision (DSM IV-TR) criteria for the diagnosis of FSAD:

[0043] A. persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement;

[0044] B. the disturbance causes marked distress or interpersonal difficulty;

[0045] C. the sexual dysfunction is not better accounted for by another Axis I disorder and is not due exclusively to the direct physiological effects of a or a general medical condition.

[0046] Aspect 27. The composition for use, the use, or the method according to the preceding aspect, wherein criterion C. is understood to not exclude the diagnosis of sexual dysfunctions when modifiable contributory factors and / or causes are identified.

[0047] Aspect 28. The composition for use, the use, or the method according to the preceding aspect, wherein the modifiable contributory factors / causes are physiological causes selected from menopause, genitourinary syndrome of menopause (GSM), or the combination thereof.

[0048] Aspect 29. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the subject is characterized by a total score at screening on the FSDS-DAO > 18 and a score on the FSDS-DAO- Item 14 > 3.

[0049] Aspect 30. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the FSAD is Female Cognitive Arousal Disorder (FCAD) or Female Genital Arousal Disorder (FGAD).

[0050] Aspect 31. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the subject is affected by at least one distinct female sexual disorder in addition to FSAD, preferably wherein the subject is affected by at least one distinct female sexual disorder in addition to FSAD wherein said disorder is selected from the group consisting of: hypoactive sexual desire disorder (HSDD), female orgasmic disorder, and / or dyspareunia.

[0051] Aspect 32. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the subject is characterized by a recent decline in sexual function, preferably a decline in sexual function in the past year, more preferably a decline in sexual function in the past 6 months, most preferably a decline in sexual function in the past 2 months.

[0052] Aspect 33. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the composition comprises from about 15 mg to about 25 mg of an estetrol component and wherein said composition is administered once daily, preferably wherein the composition comprises from about 15 mg to about 25 mg of estetrol monohydrate and wherein said composition is administered once daily.

[0053] Aspect 34. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the composition comprises from about 15 mg to about 20 of an estetrol component and said composition is administered once daily, preferably wherein the composition comprises from about 15 mg to about 20 mg of estetrol monohydrate and wherein said composition is administered once daily.

[0054] Aspect 35. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the composition comprises about 15 mg of an estetrol component and wherein said composition is administered once daily, preferably wherein the composition comprises about 15 mg of estetrol monohydrate and wherein said composition is administered once daily.

[0055] Aspect 36. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the composition comprises about 20 mg of an estetrol component and wherein said composition is administered once daily, preferably wherein the composition comprises about 20 mg of estetrol monohydrate and wherein said composition is administered once daily.

[0056] Aspect 37. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the composition further comprises a progestogenic component.

[0057] Aspect 38. The composition for use, the use, or the method according to aspect 37, wherein the progestogenic component is selected from the group consisting of: progesterone, drospirenone, norethisterone, norethisteroneacetate (NETA), dydrogesterone, levonorgestrel (LNG), etonogestrel, norgestrel, nomegestrol, nomegestrol- acetate (NOMAC), trimegestone, nestorone, dydrogesterone, gestodene, desogestrel, norgestimate, cyproterone acetate, dienogest, and chlormadinone.

[0058] Aspect 39. The composition for use, the use, or the method according to aspect 37 or 38, wherein said progestogenic component is selected from the group comprising drospirenone, progesterone, or dydrogesterone.

[0059] Aspect 40. The composition for use, the use, or the method according to any one of aspects 37 to 39, wherein the progestogenic component is drospirenone, preferably of 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 wherein said progestogenic component is administered in an amount equivalent to from about 0.25 mg to about 10 mg of drospirenone, preferably in an amount equivalent to from about 1 mg to about 4 mg of drospirenone, more preferably in an amount equivalent to about 3 mg drospirenone.

[0060] Aspect 41. The composition for use, the use, or the method according to any one of aspects 37 to 39, wherein the progestogenic component is progesterone, preferably from about 25 mg to about 300 mg of progesterone, more preferably about 100 mg to about 200 mg of progesterone, or wherein said progestogenic component is administered in an amount equivalent to from about 25 mg to about 300 mg of progesterone, preferably in an amount equivalent to from about 100 mg to about 200 mg.

[0061] Aspect 42. The composition for use, the use, or the method according to any one of aspects 37 to 39, wherein the progestogenic component is dydrogesterone, preferably of from about 1 mg to about 20 mg dydrogesterone, more preferably from about 5 mg to about 10 mg dydrogesterone, or wherein said progestogenic component is administered in an amount equivalent to from about 1 mg to about 20 mg dydrogesterone, preferably in an amount equivalent to from about 5 mg to about 10 mg dydrogesterone.

[0062] Aspect 43. The composition for use, the use, or the method according to any one of aspects 1 to 36, wherein the composition further comprises bazedoxifene.

[0063] Aspect 44. The composition for use, the use, or the method according to any one of aspects 1 to 36, wherein the estetrol component is the single (i.e. only) pharmaceutically active ingredient in the composition.

[0064] Aspect 45. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the composition is formulated to correspond to a daily dosage unit.

[0065] Aspect 46. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the composition is formulated to correspond to an oral dosage unit, preferably an oral dosage unit that is specifically formulated for oral ingestion.

[0066] Aspect 47. The composition for use, the use, or the method according to any one of the preceding aspects, wherein the composition is used in a once-a-day multiple dose regimen.

[0067] Aspect 48. In any one of the aspects defined herein, said dosage unit or composition may be presented as a kit-of- parts containing a packaging unit, e.g. a blister pack, containing the daily oral dosage units comprising the estetrol component. The skilled person will additionally know that, within the scope of the present invention, each packaging unit, e.g. blister pack, may be numbered or otherwise marked.

[0068] Within the scope of the invention, each such packaging unit may be a sealed blister pack with a cardboard, paperboard, foil plastic backing and enclosed in a suitable cover.

[0069] Also envisaged in any one of the aspects of such packaging units as defined herein are bottles. The material of the bottle is not particularly limiting. In preferred embodiments, the bottle is a glass bottle characterized by a color capable of reducing or preventing degradation of the contents of the bottle by e.g. UV light while maintaining a degree of transparency that allows for visual inspection of the contents of said bottle. Suitable colors include without limitation amber, cobalt, or vintage green. In a particular embodiment of the kit-of-parts according to aspect 48, the packaging unit comprises 28 containers or a multitude of 28 containers, such as 2 to 12 times 28 containers.

[0070] The above and further aspects and preferred embodiments of the invention are described in the following sections and in the appended claims. The subject matter of the appended claims is hereby specifically incorporated in this specification.

[0071] BRIEF DESCRIPTION OF THE FIGURES

[0072] Figure 1. Study schedule for phase 2, randomized, double-blind, placebo-controlled proof-of-concept study to evaluate the efficacy and safety of estetrol (E4) in postmenopausal subjects with female sexual arousal disorder (Example 1). o.d.: once daily.

[0073] Figure 2. Vasomotor symptoms (VMS) (measured by number of hot flushes per week) frequency in 15 mg estetrol monohydrate, 20 mg estetrol monohydrate, and placebo treatment group. Statistical analysis via MMRM model of Change from Baseline to Week 4 and Week 12 for weekly Frequency of moderate to severe VMS; Intent-to- treat (ITT)- population; p-values between E4 treatments and placebo on the change from Baseline versus placebo (difference of LS means).

[0074] Figure 3. Proportion of subjects with at least 50% or 75% reduction from baseline in the 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.

[0075] Figure 4. VMS severity in 15 mg estetrol monohydrate, 20 mg estetrol monohydrate, and placebo treatment group. Statistical analysis via MMRM model of Change from Baseline to Week 4 and Week 12 for weekly Severity of moderate to severe VMS by FDA method; Intent-to-treat (ITT) population; p-values between E4 treatments and placebo on the change from baseline versus placebo (difference of LS means).

[0076] DETAILED DESCRIPTION

[0077] As used herein, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise.

[0078] The terms “comprising”, “comprises” and “comprised of’ as used herein are synonymous with “including”, “includes” or “containing”, “contains”, and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms also encompass “consisting of’ and “consisting essentially of’, which enjoy well-established meanings in patent terminology.

[0079] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints. This applies to numerical ranges irrespective of whether they are introduced by the expression “from... to...” or the expression “between... and...” or another expression.

[0080] The terms “about” or “approximately” as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, are meant to encompass variations of and from the specified value, such as variations of + / -10% or less, preferably + / -5% or less, more preferably + / -!% or less, and still more preferably + / -0.1% or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier “about” or “approximately refers is itself also specifically, and preferably, disclosed.

[0081] Whereas the terms “one or more” or “at least one”, such as one or more members or at least one member of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g. any >3, >4, >5, >6 or >7 etc. of said members, and up to all said members. In another example, “one or more” or “at least one” may refer to 1, 2, 3, 4, 5, 6, 7 or more.

[0082] The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known, or part of the common general knowledge in any country as of the priority date of any of the claims.

[0083] Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. All documents cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings or sections of such documents herein specifically referred to are incorporated by reference.

[0084] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the invention. When specific terms are defined in connection with a particular aspect of the invention or a particular embodiment of the invention, such connotation or meaning is meant to apply throughout this specification, i.e. also in the context of other aspects or embodiments of the invention, unless otherwise defined. For example, embodiments directed to products are also applicable to corresponding features of methods and uses.

[0085] In the following passages, different aspects or embodiments of the invention are defined in more detail. Each aspect or embodiment so defined may be combined with any other aspect(s) or embodiment(s) unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

[0086] Reference throughout this specification to “one embodiment”, “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the appended claims, alternative combinations of claimed embodiments are encompassed, as would be understood by those in the art.

[0087] Unless indicated otherwise, all methods, steps, techniques and manipulations that are not specifically described in detail can be performed and have been performed in a manner known per se, as will be clear to the skilled person. Reference is for example again made to standard handbooks as well as to the general background art referred to herein and to the further references cited therein.

[0088] In view of the unexpected findings made by the inventors and described in detail in the Examples section, a first aspect of the invention is related to the use of an estetrol component for treating and / or preventing female sexual arousal disorder (FSAD). Hence, the invention equally encompasses the use of a composition for the manufacturing of a medicament for treating FSAD, wherein said composition comprises from about 14 mg to about 25 mg of an estetrol component, and further encompasses the use of a composition comprising an estetrol component for treating FSAD, wherein said composition comprises from about 14 mg to about 25 mg of an estetrol component. Consequently, the invention encompasses a method of treating FSAD in a subject, wherein said method comprises the step of administering a composition comprising from about 14 mg to about 25 mg of an estetrol component.

[0089] The term “estetrol component”, as used throughout this document, encompasses substances selected from the group consisting of estetrol, esters of estetrol, esters of estetrol wherein the hydrogen atom of at least one of the hydroxyl groups has been substituted by an acyl radical of a hydrocarbon carboxylic, sulfonic acid or sulfamic acid of 1-25 carbon atoms, estetrol hydrates such as estetrol monohydrate; and combinations thereof. It is understood that when estetrol is mentioned throughout any section of this specification, any estetrol-containing component (i.e. compound) and / or estetrol derivative (such as an estetrol ester) is also envisaged. More preferably, in the context of the present disclosure, a particularly preferred estetrol component suitable for the dosage units, medical uses and methods of treatment described herein is estetrol (including estetrol hydrates). Most preferably, said estetrol component is estetrol monohydrate.

[0090] The term “estetrol” as used herein refers to 1,3,5 (10)-estratrien-3,15alpha,16alpha,17beta-tetrol or 15alpha- hydroxyestriol as well as hydrates of estetrol, e.g. estetrol monohydrate. “Estetrol”, or short “E4” is an estrogen steroid produced by the foetal human liver (PubChem CID: 27125). Estetrol may be described as a 3-hydroxy steroid corresponding to 17beta-estradiol wherein the 15a and 16a positions are substituted for two additional hydroxy groups. It is known that estetrol is an estrogen receptor agonist (Coelingh Bennink et al., Climacteric, 2008). The estetrol may be chemically synthetised, synthesised by the use of (mutant) recombinant enzymes, or synthesised by any combination thereof. It is therefore evident that the terms “estetrol” and “estetrol components” equally encompass further chemically modified estetrol. Estetrol may be indicated in the art by its molecular formula: C18H24O4, or by structural formula (I).

[0091] Formula (I) In preferred embodiments the estetrol component is estetrol or an ester thereof. In further embodiments, the estetrol component is estetrol monohydrate. A skilled person appreciates that estetrol monohydrate corresponds to estetrol containing one molecule of water, and that the core structural formula of estetrol does not differ from Formula (I). By means of illustration and not limitation, the structural formula of estetrol monohydrate is indicated by Formula (II):

[0092] Formula (II)

[0093] Preferred subjects in the present context are female subjects. The term “subject”, or “patient” as used herein refers to female human subjects, preferably peri- and / or post-menopausal female subjects. The female subject envisaged herein may be subjects in need of, or deemed in need of a treatment for alleviating estrogen deficiency symptoms (such as menopause-associated symptoms which may include a sexual arousal disorder such as FSAD), or predicted to be in need of such a treatment in a foreseeable future point in time due to for example entering the peri-menopausal stage of life.

[0094] The medical condition to which the invention relates is Female Sexual Arousal Disorder (FSAD). FSAD is characterised by an inability to attain sexual arousal or to maintain arousal until the completion of a sexual activity. As indicated in the background section, according to DSM IV-TR, FSAD is to be diagnosed upon fulfilment of the following three criteria:

[0095] A. Persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement.

[0096] B. The disturbance causes marked distress or interpersonal difficulty.

[0097] C. The sexual dysfunction is not better accounted for by another Axis I disorder (mental health and substance use disorders (SUDs)), except another Sexual Dysfunction and is not due exclusively to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.

[0098] Hence, particularly preferred subjects in the present context are subject that have been diagnosed to have FSAD, and more preferably subjects that have been diagnosed to have FSAD according to the above three criteria DSM IV-TR (A, B, and C). A skilled person appreciates that criterion C as indicated above does not exclude the diagnosis of sexual dysfunctions when modifiable contributory factors and / or causes are identified in the subject or present in the subject. Optionally, the modifiable contributory factors and / or causes are physiological factors and / or physiological causes. Optionally, the modifiable contributory factors and / or causes are selected from menopause, genitourinary syndrome of menopause (GSM), or the combination thereof. “Genitourinary syndrome of menopause” and the abbreviation thereof “GSM” is a condition well known to a skilled person and has been described in detail throughout the art (e.g. in Portman et al., Menopause, 2014, 10.1097 / GME.0000000000000329). In brief, GSM refers to a group of unwanted effects that may occur due to thinning of the epithelial linings of the vagina and urethra caused by estrogen deficiency. These effects include without limitation vulvovaginal atrophy (WA) and urinary complaints, symptoms of vaginal dryness, itching, dyspareunia, dysuria, urinary frequency and an increased risk of (optionally) recurrent urinary infections.

[0099] A person of ordinary skill in the art appreciates that sexual arousal differs markedly from related concepts such as libido. Indeed, sexual arousal is an indication of the physiological response to sexual stimuli, while libido is used to describe a baseline level of interest in sexual activities. The physiological aspects of female arousal are intricate, but may be summarized as follows. During arousal, the Bartholin glands located on either sides of the vaginal opening produce mucus having as purpose lubrication of the area to make sexual intercourse more comfortable. In addition, increased genital blood flow will result in genital swelling. Furthermore, an increase in heart and breathing rates as well as in blood pressure occur. In addition, vasocongestion results in a sexual flush that fades after oigasm occurs (Calabro et al., Brain Behav, 2019, DOI: 10.1002 / brb3.1389).

[0100] Several subtypes of FSAD have been described in the art and are each envisaged in the context of the present specification. Subtypes of FSAD may be categorized in view of different parameters such as but not limited to onset and / or context. Hence, optionally the FSAD is lifelong FSAD. Preferably, the FSAD may be acquired FSAD. Optionally, the FSAD may be generalized FSAD. Alternatively, the FSAD may be situational FSAD (e.g. partnerspecific). The duration the FSAD has existed in a subject and the extent to which it is partner- or situation-specific, as opposed to generalized in nature, may be the result of different causative factors. The causative factors are not limiting for the invention.

[0101] The term “FSAD” as used herein encompasses subtypes such as but not limited to Female Cognitive Arousal Disorder (FCAD) and Female Genital Arousal Disorder (FGAD).

[0102] Female genital arousal disorder (FGAD) is characterized by the distressing difficulty or inability to attain or maintain adequate genital response, including vulvovaginal lubrication, engorgement of the genitalia, and sensitivity of the genitalia associated with sexual activity, for >6 months. Causes of this disorder are related to (i) vascular injury or dysfunction and (ii) neurologic injury or dysfunction. Arousal may be associated with nongenital responses such as nipple hardening and erection, skin flushing, increased heart rate, blood pressure, and respiration rate. If the problem with genital arousal is due to insufficient stimulation, then FGAD should not be diagnosed. Vulvovaginal conditions such as atrophy, infection, or inflammatory disorders of the vulva or vagina, vestibulodynia, and clitorodynia should be excluded before the diagnosis of FGAD is made (Parish et al., J Sex Med, 2016, 10.1016 / j.jsxm.2016.09.020). FGAD may manifest with mild, moderate, or severe distress over the symptoms, which may vary over time (American Psychological Association, DSM-5, 2013; Watters and Bagby, Psychol Assess, 2018, DOI: 10.1037 / pas0000605). FGAD is usually acquired and generalized (present in all situations and all partners). FC AD is characterized by the distressing difficulty or inability to attain or maintain adequate mental excitement associated with sexual activity as manifested by problems with feeling engaged or mentally turned on or sexually aroused for >6 months. FCAD may be lifelong or acquired after a period of normal functioning and may be situational (present only in certain situations or with a specific partner) or generalized. FCAD may manifest with mild, moderate, or severe distress over the symptoms, which may change over time (American Psychological Association, DSM-5, 2013; Watters and Bagby, Psychol Assess, 2018, DOI: 10.1037 / pas0000605).

[0103] Women may experience FCAD and FGAD independently or in various combinations.

[0104] The lubrication-swelling response described above is medically distinct from the condition known as “dyspareunia”, the latter being indicative of painful sexual activity that may arise due to a number of causes including vulvodynia, postpartum dyspareunia, endometriosis, inadequate vaginal lubrication or arousal, and / or anogenital causes (e.g. anal fissures, hemorrhoids). Hence, dyspareunia may be a consequence of inadequate lubrication or arousal, but cannot be used as a synonym for or used interchangeably with FSAD.

[0105] Thus, in highly preferred embodiments, the subject is (or subjects are) diagnosed to have FSAD. The diagnosis may be made by one or more self-reporting questionnaires, by a medical practitioner, or a combination thereof.

[0106] It is to be appreciated that in the present context a subject may be diagnosed to have or considered to have FSAD, but equally FSAD and at least one or more distinct female sexual disorders. Preferably, the at least one or more distinct female sexual disorder is selected from the group consisting of: Hypoactive Sexual Desire Disorder (HSDD), Female Orgasmic Disorder (FOD), and / or dyspareunia.

[0107] HSDD is defined in DSM-IV-TR by the monosymptomatic criterion “persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity” that causes “marked distress or interpersonal difficulty (Brotto, Arch Sex Behav, 2010, DOI: 10.1007 / sl0508-009-9543-l).

[0108] FOD is defined in DSM-IVby the diagnostic criteria:

[0109] A. Persistent or recurrent delay in, or absence of, orgasm following a normal sexual excitement phase. Women exhibit wide variability in the type or intensity of stimulation that triggers orgasm. The diagnosis of Female Orgasmic Disorder should be based on the clinician’s judgment that the woman’s orgasmic capacity is less than would be reasonable for her age, sexual experience, and the adequacy of sexual stimulation she receives.

[0110] B. The disturbance causes marked distress or interpersonal difficulty.

[0111] C. The orgasmic dysfunction is not better accounted for by another Axis I disorder (except another sexual dysfunction) and is not due exclusively to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (Graham, Arch Sex Behav, 2010, DOI: 10.1007 / s 10508-009-9542-2).

[0112] Dyspareunia is defined in DSM-IV-TR by the diagnostic criteria:

[0113] A. Recurrent or persistent genital pain associated with sexual intercourse in either a male or a female.

[0114] B. The disturbance causes marked distress or interpersonal difficulty. C. The disturbance is not caused exclusively by Vaginismus or lack of lubrication, is not better accounted for by another Axis 1 disorder (except another Sexual Dysfunction) and is not due exclusively to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (Binik, Arch Sex Behav, 2010, 10.1007 / sl0508-009-9563-x).

[0115] The terms “treatment” or “treat” are to be interpreted as both the therapeutic treatment of a symptom, disease or condition that has already developed, leading to (clinical) manifestations, as well as prophylactic or preventive measures, wherein the goal of the treatment is to prevent, lessen, or reduce the chances of incidence of an undesired affliction, such as to prevent occurrence, development and progression of symptoms, (clinical) conditions related to menopause. Beneficial or desired clinical results may include, without limitation, alleviation of one or more symptoms, improvement of one or more biological markers associated with FSAD, diminishment of the extent (i.e. a reduction in severity) of the FSAD symptoms, stabilisation (i.e. not worsening) of FSAD symptoms, delay or slowing of the manifestation of FSAD disease symptoms, and the like.

[0116] “Prevention” or “prevent” as used in the context of the invention refers to an aversion of manifestation of a condition or disease image in a subject, i.e. the establishment of preventive measures or prophylactic measures. Preventive treatment refers to treatments wherein the object is to avoid a subject’s body or an element thereof to show (worsening of) symptoms of an undesired physiological or psychological change. As used herein, the term “prevent” includes both preventing symptoms from occurring and preventing symptoms of worsening.

[0117] As used herein, the terms "therapeutic treatment" or "therapy" and the like, refer to treatments wherein the aim is to change a subjects body or a part of a subjects body from an undesired physiological state, disease or disorder which is caused by aging, to a desired state, such as a less severe state (e.g., amelioration, or even back to its normal, healthy state (e.g., restoring the health, the physical integrity and the physical well-being of a subject), to keep it (i.e., not worsening) at said undesired physiological status (e.g., stabilization), or slow down progression to a more severe or worse state compared to said undesired physiological change or disorder). Measurable lessening includes any statistically significant decline in a measurable marker or symptom. Statistically significant as used herein refers to p values below 0.05, which is a commonly accepted cut-off score in statistical analysis as a skilled person appreciates.

[0118] In embodiments, the subject may be a hormone deregulated subject. In the context of the present invention, the deregulation is determined or established by comparison of the hormone level of the subject with a representative value of an adult, healthy female subject. The cause of the hormone deregulation is particularly limiting for the present disclosure, and may be of a natural cause (such as menopausal hormonal changes) but may equally be caused by a pathologic condition or deficiency. In certain embodiments, the hormone deregulation is an estrogen deregulation, such as an 17p-estradiol deregulation. In such embodiments, the 17p-estradiol differs at least about 15%, preferably at least about 25%, more preferably at least about 50% from a representative 17p-estradiol value for female adult subjects. In cases wherein the endogenous estrogen production of the female subject is reduced, the subject may be considered to be a subject suffering from estrogen-deficiency syndrome.

[0119] The term "17p-estradiol" refers to (17beta)-estra-l,3,5(10)-triene-3,17-diol and may interchangeably be indicated by the terms “estradiol”, “oestradiol”, or “E2”, and is an estrogen endogenously produced by the human body. More particularly, estradiol is the predominant estrogen hormone produced by the human ovaries during the initial half of the menstrual cycle (i.e. the follicular phase). Estradiol is also involved in the maintenance of bone density, reduction of vasomotor symptoms, and maintenance of the normal structure of the female genital organs in menopausal subjects.

[0120] Embodiments concerning subjects characterised by an estrogen depletion (i.e. hypoestrogenism, or estrogen deficiency syndrome) are envisaged by the invention. While the invention is primarily directed to treating and / or preventing FSAD symptoms in a context of menopause, a skilled person will appreciate that FSAD and FSAD symptoms can also present themselves in a female subject that has a medical condition which is not menopause but nonetheless results in similar symptoms, or even the same set of symptoms. The exact cause of FSAD in the subject is thus not particularly limited in the context of the present invention and may therefore be caused by the non-limiting causes of menopause, hypogonadism, castration, primary ovarian failure, aromatase inhibitor, treatment with a gonadotropin-releasing hormone agonist, gonadotropin-releasing hormone analogue breast cancer treatment, and / or treatment with a selective estrogen receptor modulator (e.g. tamoxifen, raloxifene, bazedoxifene, bisphosphonates).

[0121] In certain embodiments, the subject is a female menopausal, perimenopausal, or postmenopausal subject. In certain embodiments, the subject is a menopausal, perimenopausal, or postmenopausal subject having an 17p- estradiol level of less than about 100 pg / ml, preferably less than about 50 pg / ml, preferably less than about 30 pg / ml, more preferably less than about 20 pg / ml, more preferably less than about 20 pg / ml, most preferably less than about 10 pg / ml. In alternative embodiments, the subject is a menopausal, perimenopausal, or postmenopausal subject that is characterised by having follicle-stimulating hormone concentrations of at least about 20 milliinternational units per millilitre (mlU / ml), preferably at least about 25 mlU / ml, more preferably at least about 30 mlU / ml, more preferably at least about 35 mlU / ml, most preferably at least about 40 mlU / ml.

[0122] “Menopausal subjects”, used interchangeably in the art with “post-menopausal subjects” or “climacteric subjects” are female subjects that that have not had menstrual bleeding for a year which is accompanied by a decrease or discontinuation in hormone production by the ovaries (such as 17p-estradiol).

[0123] According to the US FDA, the criteria for post-menopausal status are:

[0124] • At least 12 months of spontaneous amenorrhea; or

[0125] • At least 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU :mL; or

[0126] • At least 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.

[0127] Alternatively worded, “menopause” may be described as a biological condition characterised by impairment or cessation of ovarian primary function. Menopause may be accompanied by a broad range of clinical symptoms which are variable in severity such as but not limited to vasomotor dysfunction, vaginal dryness, mood changes, sleep disturbances, insomnia, urinary incontinence, cognitive changes, somatic complaints, and sexual dysfunction. Methodologies to diagnose menopause have been described in the art and are therefore known to a person skilled in the art (Nelson, Menopause, Lancet, 2008).

[0128] “Perimenopause” refers to a period of life which begins approximately three to four years prior to menopause and ends one year after the final menstrual period, and is characterised by persistent irregular menstrual cycles, extreme fluctuations in hormonal levels, frequent anovulation and the appearance 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 “post menopause” or “postmenopausal” is indicative for female subjects that are characterised by a permanent cessation of menstrual periods. This permanent cessation is determined retrospectively after an observation of 12 months of amenorrhea without any other obvious pathological or physiological cause. The term “post menopause” also includes menopause as the consequence of premature ovarian failure, surgery (ovariectomy for example), chemotherapy or radiotherapy for cancer, and certain diseases (for example, infections or hypothyroidism).

[0129] Thus, in the context of the present invention the female subject is a menopausal, perimenopausal, or postmenopausal subject.

[0130] Preferably, the subject is a female subject of adult age. More preferably, the subject is a female subject of middle age or elder age. Yet more preferably, the subject is a female subject of at least about 40 years of age, preferably of at least about 50 years of age, preferably of at least about 55 years of age, more preferably of at least about 60 years of age, more preferably of at least about 65 years of age. Alternatively, the subject may be a female subject of between about 40 and about 90 years, preferably of between about 45 and about 85 years of age, preferably of between about 50 and about 80 years of age, more preferably of between about 55 and about 75 years of age, more preferably of between about 60 and about 70 years of age or between about 65 and about 75 years of age. In certain embodiments, the female subject is at most about 90 years of age, preferably at most about 85 years of age, more preferably at most about 80 years of age, more preferably at most about 75 years of age, more preferably at most about 70 years of age, more preferably at most about 65 years of age, more preferably at most about 60 years of age.

[0131] The subject may be a non-hysterectomized subject or a hysterectomized subject. Optionally, the subject is a hysterectomized subject. Hence, in certain embodiments, the subject is a non-hysterectomized menopausal subject. In alternative embodiments, the subject is a hysterectomized menopausal subject. “Hysterectomized” in the present context indicates that the subject no longer has a uterus due to surgical removal thereof (hysterectomy). The hysterectomy may be a partial hysterectomy or a total hysterectomy. Typically, a total hysterectomy involves the complete (or essentially complete) removal of the uterus and cervix, and a partial hysterectomy indicates the complete (or essentially complete) removal of the uterus leaving a portion (i.e. supra-cervical stump) of the cervix.

[0132] The subject may have been the subject of surgical removal of one ovary or both ovaries (oophorectomy). Removal of the female gonads, the ovaries, is interchangeably referred to throughout the art as female castration. Women who undergo total hysterectomy with bilateral salpingo-oophorectomy (BSO) (removal of both ovaries, i.e. castration) lose most of their hormone production, including estrogens and progesterones.

[0133] In certain embodiments, the subject is characterized by a decline in sexual function. Optionally, the decline in sexual function is a recent decline in sexual function, such as a decline in sexual function in the past 6 months, preferably in the last 4 months, preferably in the last 3 months, most preferably in the last 2 months.

[0134] “Diagnosed with”, “diagnosing”, and diagnosis are indicative for a process of recognising, deciding on, or concluding on a disease, condition, or (adverse side effect) in a subject on the basis of symptoms and signs and / or from results of various diagnostic procedures (such as, for example, from knowing the presence, absence and / or quantity of one or more biomarkers of or (pre)clinical symptoms characteristic for the diagnosed disease or condition).

[0135] “A pharmaceutically effective amount” refers to an amount necessary to obtain a physiological effect and may indicate a therapeutically effective amount and / or a prophylactically effective amount. The physiological effect may be achieved by a single dose or by multiple doses.

[0136] A “therapeutically effective amount” or “therapeutically effective dose” indicates an amount of estetrol component that when administered brings about a clinical positive response with respect to treatment of a subject afflicted by (optionally menopause-associated) FSAD.

[0137] Preferably, the composition described herein comprises a daily dose of estetrol component, e.g. a daily dose of from about 14 mg to about 25 mg of estetrol component, preferably from about 15 mg to about 25 mg of estetrol component, or is used in a manner that the daily dose of estetrol component received by the subject is from about 14 mg to about 25 mg of estetrol component, preferably from about 15 mg to about 25 mg of estetrol component. More particularly, the composition described herein comprises a daily dose of estetrol component selected from estetrol, an ester of estetrol, estetrol monohydrate, or any combination thereof, e.g. a daily dose of from about 14 mg to about 25 mg of estetrol, an ester of estetrol, or estetrol monohydrate, or is used in a manner that the daily dose of estetrol, an ester of estetrol, or estetrol monohydrate received by the subject is from about 14 mg to about 25 mg of estetrol, an ester of estetrol, or estetrol monohydrate. Yet more particularly, the composition described herein comprises a daily dose of estetrol component selected from estetrol, estetrol monohydrate, or any combination thereof, e.g. a daily dose of from about 14 mg to about 25 mg of estetrol, an ester of estetrol, or estetrol monohydrate, or is used in a manner that the daily dose of estetrol, an ester of estetrol, or estetrol monohydrate received by the subject is from about 14 mg to about 25 mg of estetrol, an ester of estetrol, or estetrol monohydrate.

[0138] More preferably, the composition described herein comprises a daily dose of estetrol, e.g. a daily dose of from about 14 mg to about 15 mg of estetrol, more preferably a daily dose of from about 14 mg to 14.5 mg of estetrol, more preferably a daily dose of about 14.2 mg estetrol.

[0139] More preferably, the composition described herein comprises a daily dose of estetrol, e.g. a daily dose of from about 18 mg to about 20 mg of estetrol, more preferably a daily dose of from about 18.5 mg to 19.5 mg of estetrol, more preferably a daily dose of about 18.9 mg estetrol.

[0140] The term “daily” indicates that the recited amounts are the cumulative amount that is administered to a subject per day. A skilled person understands that if the estetrol component is administered only once per day (i.e. daily), that the amount of estrogen administered in that single administration will be the daily dose. Alternatively, a skilled person appreciates that if the estetrol component is administered more than once per day (e.g. 2 times or 3 times) the daily amount will correspond to the sum of estetrol component administered during each administration event within a total time window of about 24 hours. In embodiments where different estetrol components are comprised in the composition (e.g. estetrol monohydrate and an estetrol ester), it is within the capacities of a skilled person to verify the amount of estetrol each estetrol component corresponds to. Preferred embodiments within the context of the invention comprise the administration of a single estetrol component, such as but not limited to estetrol monohydrate. Yet alternatively, the composition may be administered to the subject in a once-a-day multiple dose regimen.

[0141] A skilled person is aware that terms such as “quantity”, “amount” and “level” are synonyms and have a well- defined meaning in the art. The terms as used herein may particularly refer to an absolute quantification of a molecule such as a steroid, in (a sample taken from) a subject, or to a relative quantification of a molecule or analyte in a sample, i.e., relative to another value such as relative to a reference value as taught herein, or to a range of values indicating a base-line of a certain parameter. These values or ranges of values may be obtained from one single subject or from a group of subjects (i.e. at least two subjects).

[0142] In any of the embodiments described herein, an improvement in FSAD is obtained after a period of administrating the composition to a subject, such as after a period of 12 weeks of administration. In preferred embodiments, the improvement of FSAD is characterized by an improvement of one or more of the following parameters after 12 weeks:

[0143] - sexual distress assessed by Female Sexual Distress Scalc-Dcsirc / Arousal / Orgasm (FSDS-DAO) total score or percentage of Satisfying Sexual Events (SSE) captured in arousal diary;

[0144] - sexual function assessed by Sexual Function Questionnaire (SFQ-28) total score;

[0145] - sexual function assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) - customized;

[0146] - Patient Global Impression of Change (PGIC) at week 12;

[0147] - severity of sexual arousal disorder as assessed by Patient Global Impression of Severity (PGIS).

[0148] The terms “arousal diary” and “sexual event diary (SED)” are used interchangeably herein.

[0149] The terms FSDS-DAO, SFQ-28, PROMIS, PGIC, and PGIS are known to a skilled person. The Female Sexual Distress Scale — Revised (FSDS-R) questionnaire is a 13-item distress scale that historically has been consistently used as the measure of distress in most clinical trials for treatments of female sexual disorders. More recently, the questionnaire has been further revised to include items specific to arousal and orgasm as clinical end points. This further revision is the FSDS-DAO (Desire, Arousal, Orgasm) questionnaire and includes a question specifically directed to gauge the distress level associated with female orgasmic disorder (Derogatis et al., J Patient Rep Outcomes, 2021, DOI: 10.1186 / s41687-021-00359-l). Sexual Event Diary (SED) to Capture Satisfying Sexual Events (SSE) Similarly, the Sexual Function Questionnaire (SFQ) and later the streamlined iteration Sexual Function Questionnaire 28 (SQF-28) was developed to evaluate a woman’s sexual function. Notably, SFQ enables evaluation of subtypes of arousal such as arousal-lubrication and arousal-sensation, which are of value for diagnosing FSAD. The SFQ-28 provides specific assessment of sexual functioning (Symonds et al., J Sex Med., 2023, DOI: 10.1093 / jsxmed / qdac04). The Patient-Reported Outcomes Measurement Information System (PROMIS) is a set of person-centered measures that evaluates and monitors physical, mental, and social health of subjects (Bevans et al., Nurs Outlook, 2015, DOI: 10.1016 / j.outlook.2014.05.009). It can be used with the general population and with individuals living with chronic conditions. The Patient Global Impression of Change (PGIC) is a single, self-administered question asking subjects to rate how their condition has changed since a certain point in time. Similarly, the Patient Global Impression of Severity (PGIS) is a single self-administered question asking subjects to rate the severity of a condition at a certain point in time.

[0150] In particular embodiments, the treatment with the estetrol component results in an improvement in sexual arousal as evaluated by FSDS-DAO item 14 (“concerned by arousal difficulties”) when compared to baseline. Preferably, the improvement is evaluated after 2 weeks, preferably after 4 weeks, preferably after 6 weeks, preferably after 8 weeks, preferably after 10 weeks, most preferably after 12 weeks of administration of the composition. Optionally, the improvement in sexual arousal as evaluated by FSDS-DAO item 14 is improved by at least about 10%, preferably at least about 15%, preferably by at least about 20%, preferably by at least about 25%, preferably by at least about 30%, preferably by at least about 40%, preferably by at least about 50%, preferably by at least about 60%, preferably by at least about 70%, preferably by at least about 80%, preferably by at least about 90% in the subject or the group of subjects when compared to baseline. Optionally, the score of sexual arousal as assessed by FSDS-DAO item 14 after 12 weeks compared to baseline is improved by at least 1, preferably by at least 2, more preferably by at least 3, most preferably by 4.

[0151] In particular embodiments, the treatment with the estetrol component results in an improvement in sexual arousal as evaluated by an increase in percentage of Satisfying Sexual Events (SSE) of at least about 10%, preferably at least about 15%, preferably at least about 20%, preferably at least about 25%, preferably at least about 30%, preferably at least about 40%, preferably at least about 50%, preferably at least about 60%, preferably at least about 70%, preferably at least about 80%, more preferably at least about 90%, most preferably at least about 100%. when compared to baseline.

[0152] In particular embodiments, the treatment with the estetrol component results in an improved arousal-sensation domain preferably as evaluated by SFQ-28 questions 6 to 9 (Frequency of warmth during sexual activity; Intensity of warmth during sexual activity; Frequency of pulsating during sexual activity; Intensity of pulsating during sexual activity) when compared to baseline. Preferably, the improvement is evaluated after 2 weeks, preferably after 4 weeks, preferably after 6 weeks, preferably after 8 weeks, preferably after 10 weeks, most preferably after 12 weeks of administration of the composition when compared to baseline. Optionally, the improvement in arousal-sensation domain as preferably evaluated by SFQ-28 questions 6 to 9 is improved by at least about 10%, preferably at least about 15%, preferably by at least about 20%, preferably by at least about 25%, preferably by at least about 30%, preferably by at least about 40%, preferably by at least about 50%, preferably by at least about 60%, preferably by at least about 70%, preferably by at least about 80%, preferably by at least about 90% in the subject or the group of subjects when compared to baseline. Optionally, the improvement in arousal-sensation domain assessed by SFQ-28 questions 6 to 9 is improved by a positive change in the response to one or more of said questions 6 to 9. Preferably, the arousal-sensation domain assessed by SFQ-28 is improved by a positive change in the response to question 6, 7, 8, 9, or any combination thereof.

[0153] In particular embodiments, the treatment with the estetrol component results in an improved arousal and lubrication as evaluated by PROMIS sexual function and satisfaction measures (SexFS) when compared to baseline. Preferably, the improvement is evaluated after 2 weeks, preferably after 4 weeks, preferably after 6 weeks, preferably after 8 weeks, preferably after 10 weeks, most preferably after 12 weeks of administration of the composition when compared to baseline. Optionally, the improvement in PROMIS SexFS is improved by at least about 10%, preferably at least about 15%, preferably by at least about 20%, preferably by at least about 25%, preferably by at least about 30%, preferably by at least about 40%, preferably by at least about 50%, preferably by at least about 60%, preferably by at least about 70%, preferably by at least about 80%, preferably by at least about 90% in the subject or the group of subjects when compared to baseline. Optionally, the improved arousal and lubrication as assessed by PROMIS SexFS is deducted by an improved response of the subject to item ID SFACT201 (How often have you and a partner spent time holding or hugging each other romantically?), SFACT202 (How often have you and a partner kissed each other romantically?), SFACT203 (How often have you touched a partner's chest, breasts, or nipples?), SFACT204 (How often has a partner touched your chest, breasts, or nipples?), SFACT205 (How often have you touched a partner's genitals (private parts)?), SFACT206 (How often has a partner touched your genitals (private parts)?), SFACT207 (How often have you given a partner oral sex?), SFACT208 (How often has a partner given you oral sex?), SFACT209 (How often have you put fingers or a dildo or other sex toy into a partner’s vagina?), SFACT210 (How often has a partner put fingers or a dildo or other sex toy into your vagina?), SFACT212 (How often have you had vaginal sex (a partner putting his penis into your vagina)?), SFACT213 (How often have you masturbated (touched yourself) while with a partner?), SFACT214 (How often have you masturbated (touched yourself) while alone?), SFACT215 (How often have you had anal sex?), or any combination thereof when considered preferably over a time period of 30 days. ft is to be appreciated that in instances throughout the specification wherein reference is made to “when compared to baseline”, said “baseline” indicates a point in time prior to the commencement of the treatment, which is the subject of the invention. At said baseline, FSAD was according to preferred embodiments diagnosed by an expert, preferably in accordance with DSM-IV-TR, with a total score on the FSDS-DAO >18 and a score on the FSDS- DAO-Item 14 >3, at screening. Hence, in certain embodiments the baseline is a point in time prior to the start of the treatment wherein the subject is not undergoing treatment with compositions of the present invention. Alternatively, in certain embodiments the baseline is a point in time prior to the start of the treatment wherein the subject is not treated with any means or products that comprise hormones such as estrogens or progestins. In yet alternative embodiments, the baseline is a point in time prior to the start of the treatment wherein the subject is not treated with any means or products that comprise estrogens. In yet alternative embodiments, the baseline is a point in time prior to the start of the treatment wherein the subject is not treated with any means or products that comprise an estetrol component.

[0154] In particular embodiments, the treatment with the estetrol component results in an improvement in sexual arousal as assessed by a PGIC scale. Preferably, the treatment with the estetrol component results in an improvement in sexual arousal as assessed by an improvement in sexual arousal on a 7-point Likert PGIC scale at week 12. More preferably, the improvement in sexual arousal as assessed by an improvement in sexual arousal as indicated on a 7-point Likert PGIC scale of at least 1 point, preferably at least 2 points, preferably at least 3 points, preferably at least 4 points, preferably at least 5 points, preferably at least 6 points, more preferably by 7 points at week 12.

[0155] In particular embodiments, the treatment with the estetrol component results in a decrease in severity of sexual arousal dysfunction as assessed by a PGIS scale. Preferably, the treatment with the estetrol component results in a decrease in severity of sexual arousal dysfunction as assessed on a 7-point Likert PGIS scale. More preferably, the decrease in severity of sexual arousal dysfunction as indicated on a 7-point Likert PGIS scale of at least 1 point, preferably at least 2 points, preferably at least 3 points, preferably at least 4 points, preferably at least 5 points, preferably at least 6 points, more preferably by 7 points.

[0156] As indicated above, the improvement induced by the composition for use, the use, or the method described herein is particularly prevalent in subjects diagnosed to have FSAD. Hence, particularly preferred subjects in the context of the present invention are subjects characterized by a total score at screening (i.e. prior to administration of the composition subject of the invention) on the FSDS-DAO questionnaire of at least 18, preferably higher than 18. Further particularly preferred subjects in the context of the present invention are subjects characterized by a total score at screening (i.e. prior to administration of the composition subject of the invention) on FSDS-DAO item 14 of at least 3, preferably higher than 3. Highly preferred subjects in the context of the present invention are subjects characterized by a total score at screening on the FSDS-DAO questionnaire of at least 18 and characterized by a total score at screening on FSDS-DAO item 14 of at least 3.

[0157] The composition of the present invention is particularly suited for formulation as an oral dosage unit, as evidenced by the Examples enclosed herewith. Preferably, the oral dosage unit for use according to the invention is swallowed, i.e. ingested and passes through the ingestive system of the subject. Alternatively worded, the dosage unit described herein is administered orally, i.e. the dosage unit is for use through oral ingestion. More preferably, the oral dosage unit for use according to the invention is swallowed as a whole without any prolonged presence in the oral cavity than required for swallowing. In an alternative embodiment, However, equally envisaged are dosage units formulated towards alternative administration methods such as but not limited to sublingual, buccal, or sublabial dosage units. In contrast to oral administration, these aim to bypass the first-pass effect, i.e. a phenomenon in which a dmg gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation. The first pass effect is often associated with the liver, as this is a major site of drug metabolism. However, the first pass effect can also occur in the lungs, vasculature, gastrointestinal tract, and other metabolically active tissues in the body. A sublingual, buccal or sublabial dosage unit thus differs from an oral dosage unit according to the invention.

[0158] “Dosage unit”, interchangeably used with “dosage form” herein and in the art indicates a physical preparate that is suitable for administration to a subject, without the necessity to adapt the drug product prior to administration, i.e. the final beneficial product. A dosage unit therefore indicates a ready -to-administer composition. The term is not limiting for any other particulars of the treatment, such as frequency of administration and / or any characteristic of the dosage unit (taste, appearance, size, etc.). “Oral dosage unit” encompasses any dosage unit that is intended to and / or suitable for administration to a subject by means of the oral cavity. (Immediate or near-immediate) ingestion of the dosage unit is envisaged but not a limitation for the oral dosage unit of the invention, as detailed further below. The composition or dosage unit may be administered once daily, or a specified number of times during a 24 hour period. In certain embodiments the oral dosage unit is specifically formulated for administration by ingestion. Hence, “oral dosage unit” as used herein refers to a dosage unit which is administered orally.

[0159] In the context of the present invention, each dosage unit preferably comprises from about 14 mg to about 25 mg, preferably from about 15 mg to about 25 mg of an estetrol component as pharmaceutically acceptable ingredient, or comprises from about 14 mg to about 25 mg, preferably from about 15 mg to about 25 mg of estetrol, preferably estetrol monohydrate. The presence of an estetrol component as pharmaceutically acceptable ingredient does not exclude the presence of one or more further pharmaceutical ingredients and / or pharmaceutically acceptable ingredients in the dosage unit. The term “pharmaceutically acceptable” as used herein is consistent with the art and means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof. Non-limiting suitable excipients are described further throughout the disclosure.

[0160] As detailed above, the composition which is subject of the present invention comprises from about 14 mg to about 25 mg, preferably from about 15 mg to about 25 mg of an estetrol component. Optionally, the composition is administered at a daily amount of estetrol component equivalent to from about 14 mg to about 25 mg of estetrol monohydrate. Preferably, the composition comprises from about 14 mg to about 20 mg of estetrol and is administered daily. More preferably, the composition comprises from about 14 mg to about 20 mg of estetrol monohydrate and is administered daily.

[0161] In further embodiments, the composition comprises from about 14 mg to about 25 mg, preferably from about 15 mg to about 20 mg of estetrol component, preferably wherein the estetrol component is estetrol, estetrol monohydrate, or an ester of estetrol. Preferably the composition comprises from about 14 mg to about 25 mg of estetrol monohydrate, more preferably from about 14 mg to about 20 mg estetrol monohydrate. In alternative embodiments, the composition comprises from about 14 mg to about 25 mg of estetrol or an ester thereof, preferably from about 14 mg to about 20 mg of estetrol or an ester thereof.

[0162] Optionally, the composition comprises about 17 mg of estetrol component, or an amount of estetrol component equivalent to a daily dose of about 17 mg of estetrol component. In further embodiments, the composition comprises about 17 mg of estetrol monohydrate, or an amount of estetrol component equivalent to a daily dose of about 17 mg of estetrol monohydrate. In alternative further embodiments, the composition comprises about 17 mg of estetrol or ester thereof, or an amount of estetrol component equivalent to a daily dose of about 17 mg of estetrol or an estetrol ester.

[0163] In alternative embodiments, the composition comprises from about 12 mg to about 28 mg, from about 13 mg to about 27 mg, from about 14 mg to about 26 mg, from about 15 mg to about 25 mg, from about 16 mg to about 24 mg, from about 17 mg to about 23 mg, from about 18 mg to about 22 mg, or from about 19 mg to about 21 mg, or from about 13 mg to about 17 mg, or from about 14 mg to about 16 mg, or from about 18 mg to about 22 mg, or from about 19 mg to about 21 mg of an estetrol component, or an amount of estetrol component equivalent to a daily dose of from about 12 mg to about 28 mg of estetrol, from about 13 mg to about 27 mg, from about 14 mg to about 26 mg, from about 15 mg to about 25 mg, from about 16 mg to about 24 mg, from about 17 mg to about 23 mg, from about 18 mg to about 22 mg, or from about 19 mg to about 21 mg, or from about 13 mg to about 17 mg, or from about 14 mg to about 16 mg, or from about 18 mg to about 22 mg, or from about 19 mg to about 21 mg of an estetrol component. In preferred alternative embodiments, the composition comprises from about 12 mg to about 28 mg, from about 13 mg to about 27 mg, from about 14 mg to about 26 mg, from about 15 mg to about 25 mg, from about 16 mg to about 24 mg, from about 17 mg to about 23 mg, from about 18 mg to about 22 mg, or from about 19 mg to about 21 mg, or from about 13 mg to about 17 mg, or from about 14 mg to about 16 mg, or from about 18 mg to about 22 mg, or from about 19 mg to about 21 mg of estetrol monohydrate, or an amount of estetrol component equivalent to a daily dose of from about 12 mg to about 28 mg, from about 13 mg to about 27 mg, from about 14 mg to about 26 mg, from about 15 mg to about 25 mg, from about 16 mg to about 24 mg, from about 17 mg to about 23 mg, from about 18 mg to about 22 mg, or from about 19 mg to about 21 mg, or from about 13 mg to about 17 mg, or from about 14 mg to about 16 mg, or from about 18 mg to about 22 mg, or from about 19 mg to about 21 mg of estetrol monohydrate. In yet alternative embodiments, the composition comprises from about 12 mg to about 28 mg, from about 13 mg to about 27 mg, from about 14 mg to about 26 mg, from about 15 mg to about 25 mg, from about 16 mg to about 24 mg, from about 17 mg to about 23 mg, from about 18 mg to about 22 mg, or from about 19 mg to about 21 mg, or from about 13 mg to about 17 mg, or from about 14 mg to about 16 mg, or from about 18 mg to about 22 mg, or from about 19 mg to about 21 mg of estetrol or an ester thereof, or an amount of estetrol component equivalent to a daily dose of from about 12 mg to about 28 mg, from about 13 mg to about 27 mg, from about 14 mg to about 26 mg, from about 15 mg to about 25 mg, from about 16 mg to about 24 mg, from about 17 mg to about 23 mg, from about 18 mg to about 22 mg, or from about 19 mg to about 21 mg, or from about 13 mg to about 17 mg, or from about 14 mg to about 16 mg, or from about 18 mg to about 22 mg, or from about 19 mg to about 21 mg of estetrol or an ester thereof.

[0164] Optionally, the composition comprises about 15 mg of estetrol component (e.g. from 13 to 17 mg or from 14 to 16 mg), or an amount equivalent to about 14.2 mg of estetrol. Optionally, the composition may comprise about 14.2 mg of estetrol. In further optional embodiments the composition comprises about 15 mg of estetrol monohydrate.

[0165] Alternatively, the composition comprises about 20 mg of estetrol component (e.g. from 18 to 22 mg or from 19 to 21 mg), or an amount equivalent to about 20 mg of estetrol. Optionally, the composition may comprise about 20 mg of estetrol. Preferably, the composition comprises 18.9 mg estetrol. In further optional embodiments the composition comprises about 20 mg of estetrol monohydrate.

[0166] The estetrol component may be comprised as a multitude of particles in the composition. The particle size of the estetrol component is not particularly limiting. By means of illustration and not limitation, suitable particle sizes may be expressed by means of particle-size distribution values such as but not limited to D(10), D(50), and D(90). A skilled person is well aware how to interpret these parameters. “Particle-size distribution”, commonly abbreviated as “PSD” is a numerical value expressing a relative amount of particles according to size, wherein the relative amount of particles is preferable expressed by mass. For example, the D 10 or Dv(10) value signifies the point in the size distribution, up to and including which, 10% of the total volume of the sample (i.e. a collection of particles) is contained. For example, a D10 of 10 pm means that 10% of the sample has a size of maximum 10 pm. 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. The span is calculated according to the following formula: (D90 - D10) / D50. A skilled person appreciates that representative particle-size distribution values can only be derived from a representative sample.

[0167] Optionally, the estetrol particles have a D(10) from about 0.5 pm to about 10 pm, preferably from about 1 pm to about 5 pm, more preferably of from about 1.5 pm to about 2.5 pm. Optionally, the estetrol particles have a D(50) of less than about 20 pm, preferably less than about 12 pm, more preferably from about 5 pm to about 15 pm, preferably from about 6 pm to about 12 pm, more preferably from about 7 pm to about 11 pm, most preferably from about 8 pm to about 12 pm. Optionally, the estetrol particles have a D(90) from about 15 pm to about 50 pm, preferably from about 20 pm to about 30 pm, more preferably from about 22 pm to about 28 pm. A multitude of measurement techniques are available for determining particle-size distribution values and include sieve analysis, air elutriation analysis, photo analysis, optical counting, electro resistance counting, sedimentation, laser diffraction, laser obscuration, time of transition, acoustic spectroscopy, ultrasound attenuation microscopy, by means of a cascade impactor, or any combination thereof. Unless explicitly mentioned otherwise, the particlesize distribution values of the present disclosure are obtained by laser diffraction analysis. Laser diffraction analysis, interchangeably annotated in the art by laser diffraction spectroscopy, is a particle measurement technology based on interpretation of laser diffraction patterns passed through an object. Laser diffraction is capable to measure the geometrical dimensions of a particle. Laser diffraction protocols have been described in detail in the art on numerous occasions (e.g. as reviewed in detail in a context of particle analysis in Eshel et al., Soil Science Society of America Journal, 2004).

[0168] It is evident that any of the compositions and dosage units may suitably contain one or more pharmaceutically acceptable excipients. The term “pharmaceutically acceptable” as used herein is consistent with the art and means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof.

[0169] The compositions and dosage units described herein may comprise in addition to the estetrol component one or more additionally active pharmaceutical ingredients that are considered to beneficial in treating or preventing FSAD. For example, the compositions and dosage units described herein may comprise sildenafil in addition to the estetrol component.

[0170] The oral dosage unit described herein may be a solid or semi solid dosage unit such as a tablet, a capsule, a cachet, a pellet, a pill, powder, or granules, or any combination thereof. For example, the oral dosage unit subject of the invention may be a tablet comprising estetrol component-containing granules or a capsule comprising estetrol component-containing granules. The term "solid or semi-solid dosage unit" also encompasses capsules that contain a liquid, e.g. an oil, in which the present estetrol component and / or the optional progestogenic component is dissolved or dispersed.

[0171] Tablets and equivalent solid and semi-solid dosage units can suitably contain materials such as binders (e.g. hydroxypropylmethyl cellulose, polyvinyl pyrrolidone (povidone, PVP), other cellulosic materials and starch), diluents (e.g. lactose (monohydrate) and other sugars, starch (e.g. maize starch), dicalcium phosphate and cellulosic materials), disintegrating agents (e.g. starch polymers and cellulosic materials (e.g. sodium starch glycolate) and lubricating agents (e.g., (magnesium) stearates and talc). These tablets and equivalent solid dosage units may be prepared by any suitable means, which have been described in detail in the art (e.g. Kaur, Int Res J Pharm, 2012). Non-limiting examples of processing the estetrol component when manufacturing the dosage unit include wet granulation, e.g. using an aqueous solution or an organic solution, direct compression, 3D printing, or by coating carrier particles with the estetrol component using an organic or inorganic solvent.

[0172] As described above, the composition, and hence the (oral) dosage unit may comprise one or more suitable excipients. The term “excipient” as used interchangeably herein and in the art with "carrier' ’ may be indicative for any solvent, diluent, buffer (including but not limited to neutral buffered saline, phosphate buffered saline, or optionally Tris-HCl, acetate or phosphate buffers), solubiliser (including but not limited to Tween 80 or Polysorbate 80), colloid, dispersion medium, vehicle, filler, chelating agent (including but not limited to EDTA or glutathione), amino acid, protein, disintegrant, binder, lubricant, wetting agent, stabiliser, emulsifier, sweetener, colorant, flavoring, aromatiser, thickener, any agent suitable to achieve a depot effect, coating, antifungal agent, any preservative (including but not limited to Thimerosal™, benzalkonium chloride, or benzyl alcohol), antioxidant (including but not limited to ascorbic acid, sodium metabisulfite), tonicity controlling agent, absorption delaying agent, adjuvant, bulking agent (including but not limited to lactose, mannitol) and any other ingredient that may influence any parameter or characteristic of the oral dosage unit subject of the invention. A skilled person understands that one or more excipients may be used in the oral dosage unit on condition that the one or more excipient is compatible with the one or more pharmaceutical ingredient (i.e. in the context of the present invention at least the estetrol component) and that a pharmaceutically acceptable formulation is obtained.

[0173] In certain embodiments, the excipient may be an active pharmaceutical ingredient excipient, binder excipient, carrier excipient, co-processed excipient, coating system excipient, controlled release excipient, diluent excipient, disintegrant excipient, dry powder inhalation excipient, effervescent system excipient, emulsifier excipient, lipid excipient, lubricant excipient, modified release excipient, penetration enhancer excipient, permeation enhancer excipient, pH modifier excipient, plasticiser excipient, preservative excipient, preservative excipient, solubiliser excipient, solvent excipient, sustained release excipient, sweetener excipient, taste making excipient, thickener excipient, viscosity modifier excipient, filler excipient, compaction excipient, dry granulation excipient, hot melt extrusion excipient, wet granulation excipient, rapid release agent excipient, increased bioavailability excipient, dispersion excipient, solubility enhancement excipient, stabilizer excipient, capsule filling excipient, or any combination hereof. A skilled person is aware that use of such media and agents for pharmaceutical active substances is common practice and incorporation of these excipients is hence well known in the art. It is evident that all of the used ingredients should be non-toxic in the concentration contained in the final pharmaceutical composition and should not negatively interfere with the activity of the one or more pharmaceutically active ingredients, in this context at least the estetrol component.

[0174] Optionally, the composition is comprised in a tablet and comprises next to estetrol excipients fulfilling the functions of a first or a further filler, superdisintegrant, binder, disintegrant, and lubricant. An excipient can perform several of these functions. So can a binder also be a disintegrant. A tablet can also contain two or more excipients that perform the same function, such as two different binders. In preferred embodiments, the composition is comprised in a tablet comprising estetrol, lactose, sodium starch glycolate, maize / com starch, povidone, and magnesium stearate. Preferably, the composition is comprised in a tablet comprising estetrol monohydrate, lactose monohydrate, sodium starch glycolate type A, maize / com starch, povidone such as povidone K30 or Povidone 30LP, and magnesium stearate. Optionally, the tablet is coated with a coating agent. In further optional embodiments, the coating agent comprises hypromellose, hydroxypropylcellulose, titanium dioxide, red iron oxide, hydrogenated cottonseed oil, and talc. By means of illustration and not limitation, suitable coating agents are AquaPolish orange 034.23 MS, AquaPolish P blue 064.65 MS, AquaPolish yellow 024.15 MS or AquaPolish pink 044.08 MS. The skilled person is aware that such coatings may be used in combination with a suitable amount of purified water. A skilled person further appreciates that any excipients present in any dosage unit such as an oral dosage unit should adhere to pharmaceutical grade industry quality standards such as Ph. Eur. and USP-NF.

[0175] The dosage unit may be suitable or even specifically manufactured for sublingual, buccal, and / or sublabial administration (i.e. implying a prolonged presence in the oral cavity of the subject). In such embodiments, the solid dosage unit is able to rapidly release the estetrol component when contacted with an aqueous solvent such as saliva. Hence, in these embodiments the solid dosage unit is an orodispersible dosage unit which releases at least about 50%, preferably at least about 60%, more preferably at least about 70%, yet more preferably at least about 80%, 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, most preferably within about 90 seconds. The dosage unit may be an orodispersible dosage unit. In such embodiments, the dosage unit rapidly disintegrates in the oral cavity when it comes into contact with saliva and to disperse the estetrol component into the saliva so it may be absorbed through the mucosal lining of the oral cavity. A skilled person is aware of methods to determine the release rate of an estetrol component from a dosage unit. Non-limiting standardized tests generally accepted in the field include the disintegration test according to Ph. Eur. 2.9.1 (“Disintegration of tablets and capsules”) and USP <701> (“Disintegration”), for example using water as the disintegration medium.

[0176] The term “sublingual” as used herein refers to the pharmacological route of administration by which the estetrol component diffuses into the blood through tissues under the tongue.

[0177] The term “buccal” as used herein refers to the pharmacological route of administration by which the estetrol component diffuses into the blood through tissues of the buccal vestibule, the area inside the mouth between the lining of cheek (the buccal mucosa) and the teeth / gums.

[0178] The term “sublabial” as used herein refers to the pharmacological route of administration by which the estetrol component is placed between the lip and the gingiva.

[0179] In certain embodiments, the estetrol component is comprised in an immediate release dosage unit or composition.

[0180] In certain embodiments, the estetrol component is formulated into a solid dosage unit, including but not limited to hard capsules, soft capsules, tablets, coated tablets such as lacquered tablets or sugar-coated tablets, granules, aqueous or oily solutions, syrups, emulsions, suspensions, ointments, pastes, lotions, gels, inhalants or suppositories.

[0181] As indicated above, the term “oral administration” intends to imply oral ingestion, i.e. swallowing. In embodiments wherein the effective amount of an estetrol component is administered by means of oral administration, the oral dosage unit according to the invention is preferably a solid or semi-solid dosage unit such as tablets, capsules, cachets, pellets, pills, powders and granules. The term "solid or semi-solid dosage unit " also encompasses capsules that contain a liquid, e.g. an oil, in which the present estetrol component and / or the optional progestogenic component is dissolved or dispersed. Tablets and equivalent solid and semi-solid dosage units can suitably contain materials such as binders (e.g. hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, other cellulosic materials and starch), diluents (e.g. lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g. starch polymers and cellulosic materials) and lubricating agents (e.g., stearates and talc). These tablets and equivalent solid dosage units may be prepared by any suitable means, which have been described in detail in the art (e.g. Kaur, Int Res J Pharm, 2012). Non-limiting examples of processing the estetrol component when manufacturing the dosage unit include wet granulation, e.g. using an aqueous solution or an organic solution, direct compression, 3D printing, or by coating carrier particles with the estetrol component using an organic or inorganic solvent. By means of illustration and not limitation, an oral dosage unit comprising the composition subject of the present disclosure may be manufactured by a process involving wet granulation. A skilled person appreciates that a wet granulation process may suitable comprise the successive steps of: dispensing and sieving of the active ingredient(s) and excipients, blending the sieved materials in a processor, granulation, screening (i.e. further sieving) of the granules, and one or more blending steps of the sieved granules with one or more further excipients. Afterwards, if desired in view of the final dosage unit the granules may be compressed into for example a tablet, optionally involving a coating step of the tablets.

[0182] In certain embodiments, the estetrol component is the sole (i.e. single, only) pharmaceutically active ingredient part of the composition. The term “pharmaceutically active ingredient”, interchangeably used throughout the present disclosure with “pharmaceutically active agent” is to be interpreted according to the definition of the term by the World Health organisation: “a substance used in a finished pharmaceutical product (FPP), intended to display pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings”. More particularly, in certain embodiments no progestogenic component is co-administered with the estetrol component (neither in the same composition or oral dosage unit nor in a further composition or dosage unit that is co-administered). In embodiments wherein the hepatically impaired subject underwent hysterectomy, the estetrol component is preferably administered as sole pharmaceutically active ingredient.

[0183] In alternative embodiments, the composition comprises at least one further pharmaceutically active ingredient in addition to the estetrol component.

[0184] Optionally, the dosage form comprises as a further pharmaceutically active ingredient a progestogenic component, or the method of treatment comprises a step of co-administering a progestogenic component to the subject. While embodiments wherein the progestogenic component is comprised in the same composition as the estetrol component are preferred, embodiments wherein the progestogenic component is administered by means of a separate composition or dosage unit are equally envisaged.

[0185] The terms “progestogen”, “gestagen”, or“gestogen” and derived hereof “progestogenic components” as used both herein and in the art refer to any molecule that produces effects similar to those of the natural female sex hormone progesterone in the body of a subject. Progestogens are considered to be agonists of the progesterone receptors and their functions have been thoroughly examined in the art (inter alia discussed in Kuhl, Climacteric, 2005). Progestins are a subgroup of progestogens that comprise synthetic progestogens. While the above terms may be used interchangeably in the art, there is a general understanding that when progestin is mentioned, synthetic progestogens are meant.

[0186] Examples of progestogenic components envisaged by the invention include without limitation: levonorgestrel, norgestimate, norethisterone, dydrogesterone, drospirenone, 3 -beta-hydroxy desogestrel, 3-ketodesogestrel, 17- deacetylnorgestimate, 19-norprogesterone, acetoxypregnenolone, allylestrenol, amgestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, fluorogestone acetate, gastrinone, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, lynestrenol, mecirogestone, medroxyprogesterone, megestrol, melengestrol, nomegestrol, norethindrone, norethynodrel, norgestrel (including d-norgestrel, and dl-norgestrel), norgestrienone, normethisterone, progesterone, quingestanol, (17a)-17-hydroxy-ll-methylene-19-norpregna-4, 15-dien-20-yn-3- one, tibolone, trimegestone, algestone-acetophenide, nestorone, promegestone, 17-hydroxyprogesterone esters, 19-nor-17hydroxyprogesterone, 17alpha-ethynyltestosterone, 17alpha-ethynil-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(ll)-diene-21, 17beta-carbolactone or tanaproget and precursors of these components that are capable of liberating these progestagens in vivo.

[0187] The progestogenic components may be selected from the group comprising: progesterone, drospirenone, norethisterone, norethisteron-acetate (NETA), dydrogesterone, levonorgestrel (LNG), etonogestrel, norgestrel, nomegestrol, nomegestrol-acetate (NOMAC), trimegestone, nestorone, dydrogesterone, gestodene, desogestrel, norgestimate, cyproterone acetate, dienogest, and chlormadinone. Particularly preferred progestagens in the present context include without limitation drospirenone, progesterone and dydrogesterone.

[0188] In certain embodiments, the progestogen is a naturally occurring progestogen. In alternative embodiments, the progestogen is a progestin.

[0189] “Drospirenone” (abbreviated as DRSP, PubChem CID: 68873) is an example of a progestogenic component and enjoys a widespread use in Combined Oral Contraceptives (commonly abbreviated as COCs) due to its antimineralocorticoid and antiandrogenic activity combined with a general low off-target activity. In general, drospirenone-containing COCs are referred to as fourth generation COCs. Non-limiting examples of commercially available COCs comprising drospirenone are known as “Yaz®” and “Yasmin®”. An illustrative example of a drospirenone only progestogen pill is “Slynd®”, which is also commercially available. Additionally, hormone replacement therapy compositions comprising an estrogen such as estradiol and drospirenone are available such as “Angeliq®”. Drospirenone may alternatively be indicated in the art by its molecular formula C24H30O3, or by the structural formula (III):

[0190] Formula (III)

[0191] It is understood that when the term “drospirenone” is used herein, any drospirenone derivatives are also envisaged.

[0192] The methods described herein may include the administration of drospirenone to the subject receiving the estetrol component. In certain embodiments, the composition may comprise from about 0.25 mg to about 10 mg drospirenone, or a progestogenic component in an amount equivalent to a daily dose from about 0.25 mg to about 10 mg drospirenone. Preferably, the composition may comprise from about 1 mg to about 4 mg drospirenone or a progestogenic component in an amount equivalent to a daily dose from about 1 mg to about 4 mg drospirenone. More preferably, the composition may comprise from about 1 mg to about 3 mg of drospirenone, or a progestogenic component in an amount equivalent to a daily dose from about 1 mg to about 3 mg drospirenone. Yet more preferably, the composition may comprise from about 2.5 mg to about 3.5 mg of drospirenone, or a progestogenic component in an amount equivalent to a daily dose of from about 2.5 to about 3.5 mg of drospirenone.

[0193] Optionally, the composition comprises an estetrol component, preferably estetrol or estetrol monohydrate, in an amount from about 15 mg to about 25 mg and drospirenone in an amount of from about 0.25 mg to about 10 mg. In further optional embodiments, the composition comprises from about 15 mg to about 20 mg of an estetrol component, preferably estetrol or estetrol monohydrate, and from about 1 mg to about 4 mg drospirenone. In yet further optional embodiments, the composition comprises about 15 mg or about 20 mg of an estetrol component, preferably estetrol or estetrol monohydrate, and about 3 mg of drospirenone.

[0194] “Progesterone” (commonly abbreviated as “P4”; PubChem CID 5994) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of women and constitutes the major progestogen in the body. Progesterone is a well-documented substance and has been used in the art for indications including but not limited to contraception, female hormone replacement therapy, and feminizing hormone therapy. Progesterone may be indicated in the art by reference to its structural formula C21H30O2, or by the structural formula (IV):

[0195] Formula (IV)

[0196] It is understood that when the term “progesterone” is used herein, any progesterone derivatives are also envisaged.

[0197] In certain embodiments, the composition may comprise from about 10 mg to about 500 mg, preferably from about 25 mg to about 300 mg progesterone, or a progestogenic component in an amount equivalent to a daily dose from about 10 mg to about 500 mg, preferably from about 25 mg to about 300 mg progesterone. Preferably, the composition may comprise from about 100 mg to about 200 mg progesterone or a progestogenic component in an amount equivalent to a daily dose from about 100 mg to about 200 mg progesterone.

[0198] Optionally, the composition comprises an estetrol component, preferably estetrol or estetrol monohydrate, in an amount from about 15 mg to about 25 mg and progesterone in an amount of from about 25 mg to about 300 mg. In further optional embodiments, the composition comprises from about 15 mg to about 20 mg of an estetrol component, preferably estetrol or estetrol monohydrate, and from about 100 mg to about 200 mg progesterone. In yet further optional embodiments, the composition comprises about 15 mg or about 20 mg of an estetrol component, preferably estetrol or estetrol monohydrate, and from about 100 mg to about 200 mg of progesterone. In another embodiment, progesterone is used at a daily dose of about 100 mg to about 200 mg when it is used sequentially, for example when it is administered during about 14 days every month. In yet another embodiment, progesterone is used at a daily dose of about 100 mg to about 200 mg when it is used sequentially, for example when it is administered during about 14 days after the estetrol component has been administered for a minimum of 12 weeks and no longer than 13 weeks. Preferably, progesterone is used once daily for 14 consecutive days after completion of treatment with the estetrol component.

[0199] The progestin “dydrogesterone” (PubChem CID 9051), interchangeably indicated in the art such as “isopregnenone” and “didrogesteron”, has been used for numerous medical indications including dysfunctional bleeding, infertility, dysmenorrhea, endometriosis, and menopause hormone therapy. Dydrogesterone may be indicated in the art by reference to its structural formula C21H28O2 or by the structural formula (V):

[0200] Formula (V)

[0201] It is understood that when the term “dydrogesterone” is used herein, any dydrogesterone derivatives are also envisaged.

[0202] In certain embodiments, the composition may comprise from about 1 mg to about 20 mg dydrogesterone, or a progestogenic component in an amount equivalent to a daily dose from about 5 mg to about 10 mg dydrogesterone. Preferably, the composition may comprise from about 1 mg to about 20 mg dydrogesterone or a progestogenic component in an amount equivalent to a daily dose from about 5 mg to about 10 mg dydrogesterone.

[0203] Optionally, the composition comprises an estetrol component, preferably estetrol or estetrol monohydrate, in an amount from about 15 mg to about 25 mg and dydrogesterone in an amount of from about 1 mg to about 20 mg. In further optional embodiments, the composition comprises from about 15 mg to about 20 mg of an estetrol component, preferably estetrol or estetrol monohydrate, and from about 5 mg to about 10 mg dydrogesterone. In yet further optional embodiments, the composition comprises about 15 mg or about 20 mg of an estetrol component, preferably estetrol or estetrol monohydrate, and from about 5 mg to about 10 mg of dydrogesterone.

[0204] In the context of the present invention, other compounds (i.e. components, agents) may be used in conjunction with the estetrol component for administering to women who have an uterus. Selective Estrogen Receptor Modulators (SERMs) defines a category of such compounds, which are contemplated as useful complements to the estetrol component in the methods of the invention. A preferred SERM for use in the context of the present invention is bazedoxifene. In the methods and compositions further described herein, it has to be understood that when reference is made to a “progestogenic component”, such reference includes SERMs and in particular bazedoxifene. Preferably, the bazedoxifene is administered at a daily dose of from about 10 mg to 50 mg. More preferably, bazedoxifene is administered at a daily dose of from about 15 to about 25 mg. Most preferably, bazedoxifene is administered at a daily dose of about 20 mg.

[0205] The composition may be formulated into a dosage unit that is to be administered to a subject using any time interval deemed appropriate by a skilled person. A preferred administration scheme in the context of the present invention is a daily administration scheme (i.e. one administration every about 24 hours). In such embodiments, the composition described herein is therefore representative of a daily composition, a daily dosage unit. In alternative embodiments, the composition is formulated for a multiple dose per day administration scheme, which then accumulates to achieve the dose inline with the present invention, e.g. about 15 to about 25 mg of the estetrol component.

[0206] Optionally, the dosage unit is administered to a subject by means of a continuous administration schedule. The terms "continuous" and ’’continuously” as used herein, means that the dosage units are administered at relatively regular intervals, with no (therapeutically) significant interruptions. Naturally, minor interruptions may occur that do not affect the overall effectiveness of the present method, and indeed such aberrations are encompassed by the present invention. In a preferred embodiment, and more arithmetically, the administration regimen is deemed to be continuous if the longest interval between two subsequent administrations is not more than about 3.5 times as long as the average interval. Even more preferably said longest interval is not more than about 2.5 times, most preferably not more than about 1.5 times as long as the average interval. By means of illustration and not limitation, the treatment strategies and methods of treatment described herein preferably employ continuous administration of the estetrol component during a period of at least 10 days, preferably of at least 20 days.

[0207] Alternatively, the dosage unit is administered to a subject by means of a sequential administration schedule. It is to be appreciated that the term “sequential” means an administration during, for example, 10 to 14 days each month or during 14 days every 3 months. Sequential administration schedules are particularly envisaged wherein a progestogenic component is part of the composition or treatment described herein.

[0208] A further aspect of the invention is directed to packaging units comprising the dosage units described herein. The packaging units may comprise at least 14, preferably at least 21, even more preferably at least 28, containers for holding separately packaged and individually removable dosage units, wherein each container comprises at least one dosage unit comprising of from about 14 to about 25 mg of an estetrol component. Preferably, the separately packaged and individually removable dosage units are oral dosage units. More preferably, each of the separately packaged and individually removable dosage units comprise about 14 or about 20 mg of estetrol component, preferably about 15 mg or about 20 mg of estetrol or estetrol monohydrate.

[0209] Optionally, the packaging units additionally comprise at least 10, preferably 12, more preferably 14, additional containers for holding separately packaged and individually removable dosage units, wherein each additional container comprises at least one dosage unit comprising a progestogenic component. Optionally, each of the additional containers for holding the dosage units comprising the progestogenic component are individually visually arranged next to a container holding a dosage unit comprising the estetrol component when these two dosage units have to be administered on the same day. Optionally, the packaging unit additionally comprises the same number of additional containers for holding separately packaged and individually removable oral dosage forms, wherein each additional container comprises at least one daily, preferably solid, oral dosage form comprising a progestogen, preferably wherein said progestogen is selected from drospirenone, progesterone and dydrogesterone.

[0210] A skilled person will understand that the embodiments described above which are directed to packaging units may equivalently be presented as a kit-of-parts containing a first packaging unit, e.g. a blister pack, containing the daily oral dosage units comprising the estetrol component, and a second, distinct, packaging unit, e.g. a second, distinct, blister pack, containing the daily oral dosage units comprising the progestogen.

[0211] The skilled person will additionally know that, within the scope of the present invention, each packaging unit, e.g. blister pack, may be numbered or otherwise marked.

[0212] The packaging units may be provided in any suitable packaging means known in the art, non-limiting examples being troches, sachets, pouches, bottles, films, sprays, microcapsules, implants, rods or blister packs.

[0213] By means of illustration and not limitation, each packaging unit may be a sealed blister pack with a cardboard, paperboard, foil plastic backing and enclosed in a suitable cover. Also envisaged in any one of the aspects defined herein are packaging units such as bottles. The material of the bottle is not particularly limiting. In preferred embodiments, the bottle is a glass bottle characterised by a colour capable of reducing or preventing degradation of the contents of the bottle by e.g. UV light while maintaining a degree of transparency that allows for visual inspection of the contents of said bottle. Suitable colours include without limitation amber, cobalt, or vintage green.

[0214] In a particular embodiment of the invention the packaging unit comprises 28 containers or a multiple of 28 containers, such as 2 to 12 multiple of 28 containers.

[0215] While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as follows in the spirit and broad scope of the appended claims. The herein disclosed aspects and embodiments of the invention are further supported by the following non-limiting examples. The following specific experimental examples are provided in support of the claimed invention but are not to be seen as limiting the scope of the invention.

[0216] EXAMPLES

[0217] EXAMPLE 1 : A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PROOF-OF- CONCEPT STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ESTETROL IN POSTMENOPAUSAL SUBJECTS WITH FEMALE SEXUAL AROUSAL DISORDER

[0218] Investigational Medicinal Products (IMPs):

[0219] Test Product: Estetrol monohydrate 20 mg (E4 20 mg), equivalent to estetrol 18.9 mg

[0220] Reference Product: Placebo

[0221] Indication(s): Female Sexual Arousal Disorder in Postmenopausal Subjects

[0222] Estimated Number of Subjects:

[0223] Approximately 76 enrolled / randomized subjects (38 subjects per treatment arm) (Based on an estimated drop-out rate).

[0224] 52 evaluable subjects in total (26 evaluable subjects per treatment arm).

[0225] Rationale:

[0226] Female Sexual Arousal Disorder (FSAD), a subtype of female sexual dysfunction, is an inability to attain, or to maintain an adequate lubrication-swelling response of sexual excitement; it may manifest as a decrease in vaginal lubrication and a decrease in genital sensation related to blood flow and can cause marked distress and / or interpersonal difficulty (Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV]). There is no currently approved treatment for FSAD. Estrogen has a role in maintaining genital tissue structural integrity and pelvic nerve-stimulated genital blood flow. This study will be conducted with a natural estrogenic steroid called estetrol, that is normally produced by human foetal liver. Phase 2 and 3 studies of estetrol (E4) for vasomotor symptom relief suggest improvement in dyspareunia and vaginal dryness in participants with these complaints at baseline. This Phase 2 proof-of-concept (POC) study will assess the efficacy and safety of E4 20 mg for the treatment of FSAD associated with menopause.

[0227] Study objectives:

[0228] Primary Objective: To assess the efficacy of E4 20 mg in the treatment of FSAD associated with menopause.

[0229] Secondary Objectives: To assess changes in sexual function and satisfaction, patient-reported improvement in sexual arousal symptoms.

[0230] Safety Objectives: To evaluate adverse events and other safety outcomes of study drug.

[0231] Study Design and Methodology:

[0232] This study is a pilot, randomized, double-blind, placebo-controlled, two-arm parallel group, POC Phase 2 study that will be conducted in hysterectomized postmenopausal women diagnosed with FSAD.

[0233] Eligible subjects will be randomized in a 1 : 1 ratio and will receive E4 20 mg or placebo, orally, once daily, for 12 weeks.

[0234] The study schedule is summarized in Figure 1.

[0235] Study Population:

[0236] Hysterectomized postmenopausal women, > 40 up to < 65 years at randomization / treatment allocation, diagnosed with FSAD by an expert and in accordance with the Diagnostic and Statistical Manual of Mental Disorders 4th edition-text revision (DSM-IV-TR), with a total score on the Female Sexual Distress Scale- Desire / Arousal / Orgasm (FSDS-DAO) > 18 and a score on the FSDS-DAO-Item 14 > 3, at screening are to be enrolled. Study Duration:

[0237] The treatment duration with the IMP (E4 20 mg or placebo) is 12 weeks. Individual subject participation may be up to 28 weeks. This includes a washout period of up to 8 weeks, a screening period of up to 4 weeks, a treatment period of 12 weeks, followed by a 4-week follow-up period.

[0238] Criteria for Evaluation:

[0239] Efficacy:

[0240] • Co-primary endpoints: o Change from baseline to Week 12 in feeling concerned by difficulties with sexual arousal, assessed by FSDS-DAO Item 14. o Change from baseline to Week 12 in the Sexual Function Questionnaire (SFQ-28) Arousal- Sensation Domain (Questions 6 to 9).

[0241] • Key secondary endpoint: o Change from baseline to Week 12 in arousal and lubrication assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) sexual function and satisfaction (SexFS) measures.

[0242] • Secondary endpoints: o Change from baseline to Week 12 in sexual function (i.e. distress) assessed by:

[0243] FSDS-DAO - total score,

[0244] Percentage of Satisfying Sexual Events (SSE) - captured in arousal diary. o Change from baseline to Week 12 in sexual function assessed by SFQ-28 - total score. o Change from baseline to Week 12 in sexual function assessed by PROMIS - SexFS - customized. o Patient Global Impression of Change (PGIC) at week 12. o Change from baseline to Week 12 in severity of sexual arousal disorder as assessed by Patient Global Impression of Severity (PGIS).

[0245] Safety: o Frequency of treatment emergent adverse events (TEAEs) (including treatment-emergent serious adverse events [TESAEs]). o Vital sign measurements and routine clinical laboratory tests results (hematology and chemistry) at each measured time point.

[0246] Statistical Methods: Sample Size Determination:

[0247] Sample size has been determined for a 5% two-sided Type I error and a power of 80% to detect a 1 -point difference between groups in SFQ-28 arousal sensation score (items 6 to 9), assuming a standard deviation (SD) of 1.25 points, considering the use of a two-sample t-test. As no relevant information is available on the variability of FSDS-DAO item 14, this scale has not been considered in the sample size estimation. This trial will, however, provide important information for considering this parameter in the design of future studies. Based on this calculation the above assumptions on the SFQ-28 arousal sensation score, approximately 26 evaluable subjects / arm (52 subjects in total) are required. Based on an estimated drop-out rate of approximately 30%, approximately 38 subjects / arm, i.e., 76 subjects in total, will be randomized in this study.

[0248] Primary variables:

[0249] FSDS-DAO-Item 14, SFQ-28 Arousal-Sensation Domain (questions 6 to 9).

[0250] Secondary variables:

[0251] PROMIS-SexFS, FSDS-DAO-total score, percentage of SSE captured in an arousal diary, SFQ-28-total score, PROMIS- SexFS customized, PGIC and PGIS.

[0252] Safety parameters:

[0253] Adverse events (AEs) including serious adverse events (SAEs), TEAEs including TESAES, clinical laboratory parameters, vital signs.

[0254] Analysis of primary and secondary variables:

[0255] Descriptive statistics will be presented by IMP for all primary and secondary efficacy variables for each measurement timepoint.

[0256] Categorical factors will be summarized using frequencies and / or percentages. Continuous and ordinal (when applicable) variables will be described using means and SD, minimum, maximum, median and quartiles.

[0257] Analyses of primary and secondary variables will be performed on the full analysis set (FAS, i.e., all subjects randomized in the study with baseline and Week 12 assessments).

[0258] A sensitivity analysis will be performed on the intention-to-treat (ITT, i.e., all randomized subjects) set.

[0259] Differences between treatment arms may be presented to compare continuous and discrete outcomes. Differences and comparisons may be accompanied by 95% confidence intervals (Cis) as well as p-values.

[0260] The change from baseline to Week 12 in feeling concerned by difficulties with sexual arousal, assessed by FSDS- DAO Item 14 and the change from baseline to Week 12 in the SFQ28 Arousal-Sensation Domain (Questions 6 to 9) will both be summarized descriptively and analysed using analysis of covariance (ANCOVA) models.

[0261] The models will include treatment group as the fixed effect. The corresponding baseline scores will be included in the model as a covariate. The estimate for the treatment difference, 95% Cis, and p-values will be presented. The change in arousal and lubrication (PROMIS- - SexFS), FSDS-DAO- - total score, percentage of SSE, sexual function (SFQ-28- - total score and PROMIS- - SexFS customized), and PGIS from Baseline to Week 12 will be summarized descriptively and analyzed by ANCOVA, tike the co-primary endpoints.

[0262] The number and percentage of subjects reported as improved in severity for PGIS or improved (minimally, much, or very much) in PGIC will be presented with treatments being compared by Chi-square tests. PGIS and PGIC ratings will also be analyzed as response frequencies using the Cochran-Mantel-Haenszel (CMH) test for the row mean score difference.

[0263] Analyses will be performed using SAS® v9.4 or a later version in a secure and validated environment with a two- sided significance level of 0.05. In this exploratory POC study, no adjustment for multiplicity of testing will be performed.

[0264] Analysis of safety parameters:

[0265] The assessment of safety will be based on the frequency of AEs and SAEs (with and without regard to causality) and the review of individual values for clinical laboratory data and vital signs focusing on the detection of abnormal values and potentially clinically significant abnormalities determined upon Investigator’s considerations. Clinical laboratory parameters and vital signs will be summarized by using descriptive statistics (as appropriate). Number of subjects with at least one abnormal value will be tabulated (counts and percentages) for each parameter in summary shift tables by IMP.

[0266] Rationale for the Clinical Study

[0267] The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, text revision (DSM-IV-TR) criteria for the diagnosis of FSAD include several criteria for appropriate diagnosis:

[0268] A. Persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement.

[0269] B. The disturbance causes marked distress or interpersonal difficulty.

[0270] C. The sexual dysfunction is not better accounted for by another Axis I disorder (except another Sexual Dysfunction) and is not due exclusively to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.

[0271] Psychiatric diagnosis is recommended primarily for criterion “C”.

[0272] The American Foundation of Urological Diseases defines FSAD as “a persistent or recurring inability to attain or maintain sufficient sexual excitement that causes personal distress”. FSAD may occur independently of or concurrently with other distinct female sexual disorders, such as HSDD, female orgasmic disorder and / or dyspareunia. Although psychosocial factors clearly contribute to the disorder, medical and physiological factors, including reduced vaginahclitoral blood flow, altered hormonal environment, prior pelvic surgery (for example hysterectomy), vaginal injury from childbirth or use of certain medications, may be the primary basis for the disorder. Prior studies of sexual arousal problems in women have focused primarily on self-reported lack of vaginal lubrication. There is no currently approved treatment for FSAD. In this study, participants must be diagnosed by an expert interview in accordance with the Diagnostic and Statistical Manual of Mental Disorders 4th edition-text revision (DSM-IV-TR) for FSAD. In addition, participants must have a total score at screening on the Female Sexual Distress Scale-Desire / ArousaFOrgasm (FSDS-DAO) > 18 and a score on the FSDS-DAO-Item 14 > 3. This Phase 2 proof-of-concept (POC) study will assess the efficacy and safety of E4 20 mg for the treatment of FSAD associated with menopause.

[0273] Study Objectives and Endpoints

[0274] Investigational Plan

[0275] Overall Study Design and Plan

[0276] This study is a pilot, randomized, double-blind, placebo-controlled, two-arm parallel group, POC Phase 2 study that will be conducted in hysterectomized postmenopausal women diagnosed with FSAD. Eligible subjects will be randomized in a 1 : 1 ratio and will receive E4 20 mg or placebo, orally, once daily, for 12 weeks.

[0277] Subjects will be admitted into the study after informed consent / assent has been obtained, a medical history and gynaecological history have been performed and inclusion / exclusion criteria have been met. Subjects must have a clinical diagnosis of FSAD to qualify for inclusion in this study. FSAD is to be diagnosed by an expert structured interview and in accordance withDSM-IV-TR, with a total score on the FSDS-DAO >18 and a score on the FSDS- DAO-Item 14 >3, at screening.

[0278] For the washout period, in case the subject uses medication that is not allowed during the duration of the study, she will be asked to stop that medication. The subject will return for the screening after a variable washout period that depends on the type of prior medication. Subjects not using medication that need to be stopped and washed out can continue with the screening procedures. At washout visit and screening visit, only available inclusion / exclusion criteria at that time point will be checked.

[0279] During the screening period the final eligibility will be confirmed; if screening requirements cannot be met within 4 weeks, the screening period may be extended with prior Medical Monitor’s approval, but screening period may not exceed 8 weeks. The initial efficacy measurements will be provided at the screening to provide a baseline measurement.

[0280] The treatment period will be initiated on Day 1 when eligibility will be confirmed for randomization to occur prior to dispensing the Investigational Medicinal Product (IMP). Subjects will be informed about the use of the electronic Patient-Reported Outcomes (ePRO) system, the daily administration of the IMP, the need to remain compliant and how to contact the sites for any questions or reporting of changes in health conditions. The treatment period will continue for 12 weeks with an additional visit at week 4. The efficacy assessments will be collected at week 12.

[0281] There will be a post-treatment 30-day Follow-up Period for reporting any onset of changes in health, follow up of any TEAEs.

[0282] Rationale for the Study Design

[0283] The design of this study is in line with the requirements of the FDA draft guidance “Low sexual interest, desire, and / or arousal in women: developing drugs for treatments, guidance for industry” (U.S. Department of Health and Human Services, FDA, Center for Drug Evaluation and Research [CDER]), October 2016.

[0284] Selection of Study Population

[0285] Inclusion Criteria

[0286] Subjects who meet all of the following criteria are eligible for the study:

[0287] 1. Signed and dated written informed consent form and any required privacy authorization prior to the initiation of any study procedure, after the nature of the study has been explained according to local regulatory requirements.

[0288] 2. Females, > 40 to < 65 years of age at randomization / treatment allocation visit with vasomotor menopausal symptoms.

[0289] 3. FSAD was diagnosed by an expert and in accordance with DSM-IV-TR, with a total score on the FSDS- DAO >18 and a score on the FSDS-DAO-Item 14 >3, at screening.

[0290] 4. Postmenopausal status defined for hysterectomized subjects as any of the following:

[0291] Serum FSH >40 mIU / mL and E2 <20 pg / mL (values obtained after washout of estrogen / progestin containing drug, see exclusion criteria 17, 19 and 20). or at least 6 months postsurgical bilateral oophorectomy.

[0292] 5. Documented hysterectomy (with or without oophorectomy) must have occurred at least 6 months prior to the start of screening. Hysterectomy can be total or subtotal (i.e., cervix was not removed).

[0293] 6. Body mass index (BMI) > 18.0 kg / m2up to < 38.0 kg / m2.

[0294] 7. A mammogram that shows no sign of significant disease performed during screening or within 9 months prior to the start of screening. Subjects must have a breast imaging-reporting and data system (BI-RADS) score of 1 or 2 to emol in the study. An incomplete mammogram result, i.e., BI-RADS 0, is not acceptable and requires further assessment. The site must obtain a copy of the official report for the subject's study file.

[0295] 8. Have a vagina.

[0296] 9. Based on clinical interview, subject experienced 'normal' past sexual function . 10. Sexual activity at least two times each month during the last 6 months and agrees to have sexual activity at least two times each month for the duration of the study. Sexual activity can include any activity that may result in sexual stimulation or sexual pleasure e.g., intercourse, caressing, foreplay, masturbation, and oral sex.

[0297] 11. Good physical and mental health, in the judgement of the Investigator as based on medical history, physical and gynecological examination, and clinical assessments performed prior to Visit 1.

[0298] 12. Able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions.

[0299] 13. Able and willing to complete study daily diaries and questionnaires.

[0300] Exclusion Criteria

[0301] Subjects who have any of the following during the screening visit are not eligible for enrolment in this study.

[0302] 1. History of malignancy, with the exception of basal cell or squamous cell carcinoma of the skin if diagnosed more than 1 year prior to the screening visit. The exception is only for basal cell carcinoma or squamous cell carcinoma of the skin if either of them were diagnosed more than 1 year prior to the screening of the subject

[0303] 2. Any clinically significant findings found by the Investigator at the breast examination and / or on mammography suspicious of breast malignancy that would require additional clinical testing to rule out breast cancer (however, simple cysts confirmed by ultrasound are allowed).

[0304] 3. Abnormal cervical cytology on Papanicolaou (PAP) smear within the prior year that will require any follow-up evaluation or treatment during the study. Subject must have a normal PAP smear within the prior year to emol in the study. The site must obtain a copy of the official report for the subject's study file. If no written normal result is available within 1 year before the start of screening, the subject must have a PAP test performed during screening.

[0305] 4. Systolic blood pressure (BP) higher than 140 mmHg, diastolic BP higher than 90 mmHg during screening. BP measurements at screening may be repeated if values are outside the inclusion criteria after sitting for an additional 5 to 10 minutes. The last reading will be used for eligibility. Subjects with mild to moderate hypertension who are controlled on a stable antihypertension regimen may be enrolled at the discretion of the investigator if they meet all inclusion / exclusion criteria. Subjects using methyldopa or clonidine containing antihypertensive medication will not be included.

[0306] 5. History of venous or arterial thromboembolic disease (e.g., superficial or deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), or first-degree family history of VTE.

[0307] 6. History of known acquired of congenital coagulopathy or abnormal coagulation factors, including known thrombophilia.

[0308] 7. Laboratory values of glycated haemoglobin above 7.5%. Laboratory values of haemoglobin Ale assessed during the last 6 months, and during washout and screening should be considered.

[0309] 8. Are current smokers. 9. Presence or history of gallbladder disease unless cholecystectomy has been performed.

[0310] 10. Diagnosis or treatment of systemic lupus erythematosus.

[0311] 11. Any malabsorption disorders including gastric by-pass surgery.

[0312] 12. History of acute liver disease in the preceding 12 months before the start of screening or presence or history of chronic or severe liver disease (alanine transaminase or aspartate transaminase >2x upper limit of normal (ULN), bilirubin >1.5 ULN), or liver tumours.

[0313] 13. Chronic or current acute renal impairment (estimated glomerular filtration rate < 60 mL / min).

[0314] 14. Inadequately treated hyperthyroidism with abnormal thyroid stimulating hormone (TSH) and free thyroxine (T4) at screening. Subjects with low or high TSH are allowed if free T4 at screening is within normal range. Reflex T4 test to be performed at screening only if TSH at screening is outside normal range.

[0315] 15. Diagnosis or treatment of Porphyria.

[0316] 16. Diagnosis or treatment of major psychiatric disorder (e.g., schizophrenia, bipolar disorder, etc.) in the judgement of the Investigator.

[0317] 17. Use of estrogen / progestin containing drug(s) up to: a. 1 week before screening start for vaginal non-systemic hormonal products (rings, creams, gels). b. 4 weeks before screening start for vaginal or transdermal estrogen or estrogen / progestin products. c. 8 weeks before screening start for oral estrogen and / or progestin products and / or selective estrogen receptor modulator therapy. d. 3 months before screening start for progestin implants or estrogen alone injectable drug therapy. e. 6 months before screening start for estrogen pellet therapy or progestin injectable dmg therapy.

[0318] 18. Use of androgen / dehydroepiandrosterone (DHEA) containing drugs: a. 8 weeks before screening start for oral, topical, vaginal, or transdermal androgen. b. 6 months before screening start for implantable or injectable androgen therapy.

[0319] 19. Use of phytoestrogens or black cohosh for treatment of vasomotor symptoms up to 2 weeks before the start of screening.

[0320] 20. Use of estrogen agonist / antagonist, e.g., ospemifene, within 8 weeks of screening.

[0321] 21. Not willing to stop any hormonal products as described in exclusion criteria 17, 18, 19 and 20, during their participation in the study.

[0322] 22. History or presence of allergy / intolerance to the IMP or dmgs of this class or any component of it, or history of drug or other allergy that, in the opinion of the Investigator contraindicates subject’s participation. 23. History of alcohol or substance abuse (including marijuana, even if legally allowed) or dependence in the previous 12 months before the start of screening as determined by the Investigator, based on reported observations.

[0323] 24. Sponsor or Contract Research Organization (CRO) employees or employees under the direct supervision of the Investigator and / or involved directly in the study.

[0324] 25. Subjects with known or suspected history of a clinically significant systemic disease, unstable medical disorders, life-threatening disease or current malignancies that would pose a risk to the subject in the opinion of the Investigator.

[0325] 26. Participation in another investigational drug clinical study within 1 month (30 days) or having received an investigational dmg within the last month (30 days) before the start of screening.

[0326] 27. Is judged by the Investigator to be unsuitable for any reason.

[0327] 28. Planned major surgery during the clinical study.

[0328] 29. Any clinically significant abnormality identified on the screening 12-lead electrocardiogram (ECG).

[0329] 30. History of unresolved sexual trauma or abuse that is contributing to any sexual dysfunction problem (desire, arousal, orgasm, etc.) as determined by the clinical interview.

[0330] 31. Have experienced a recent major life stress (e.g., loss of income, death of a family member) or relationship discord that could interfere with sexual activity (except distress related to FSAD).

[0331] 32. Have a primary complaint of anorgasmia, vaginismus, low desire, or any other primary sexual complaint aside from problems with genital arousal, as determined by the clinical interview.

[0332] 33. Have undergone major pelvic or abdominal surgery that may have caused nerve damage, including vulvectomy, colostomy, cystostomy, and bladder neck suspension.

[0333] 34. Have undergone vulvo-vaginal laser therapy within 3 months of screening.

[0334] 35. Current vaginal infection requiring medication (can be enrolled after treatment completed) .

[0335] 36. History of human immunodeficiency virus (HIV) and / or hepatitis B and / or hepatitis C.

[0336] 37. Recent sexually transmitted infection requiring ongoing treatment.

[0337] 38. Clinically significant abnormal gynaecological findings.

[0338] Treatments:

[0339] The treatment(s) to be used in this study are outlined below in Table 1. Table 1. Study treatments

[0340] FCT: film-coated tablet; FCT: film-coated tablet

[0341] Active Treatment

[0342] Active substance: Estetrol monohydrate

[0343] Strength: E4 20 mg

[0344] Dosage form: Film coated tablet (FCT)

[0345] Excipients: Lactose monohydrate, sodium starch glycolate type A, com starch, purified water, povidone, magnesium stearate, AquaPolish® yellow 024.15 MS (containing hypromellose, hydroxypropylcellulose, cottonseed oil, talcum, titanium dioxide, iron oxide yellow and iron oxide red) Primary packaging: Blister pack (polyvinyl chloride [P VC] / Aluminum) containing 28 tablets per blister

[0346] Placebo (Visually Matching the Active Treatment)

[0347] Active substance: No active substance

[0348] Dosage form: FCT

[0349] Excipients: StarLac® (co-processed excipient containing lactose monohydrate and maize starch), magnesium stearate, AquaPolish® yellow 024.15 MS (containing hypromellose, hydroxypropylcellulose, cottonseed oil, talcum, titanium dioxide, iron oxide yellow and iron oxide red) Primary packaging: Blister pack (PVC / Aluminum) containing 28 tablets per blister (primary packaging)

[0350] Selection and Timing of Dose for Each Subject

[0351] Subjects will be instructed to take the IMP once daily at approximately the same time of the day for 12 weeks. An electronic diary (ediary) will be provided for the subjects to track their compliance with the daily intake.

[0352] Permitted Concomitant Medications / Vaccinations

[0353] Thyroid treatment

[0354] Thyroid treatments are allowed (exclusion criterion 14).

[0355] Antihypertensives

[0356] Subjects with mild to moderate hypertension who are controlled on a stable antihypertension regimen may be enrolled if they meet the BP criteria at screening (systolic BP<140 mmHg, diastolic BP<90 mmHg). Subjects using methyldopa or clonidine containing antihypertensive medication may not be included in the study.

[0357] Vaccination

[0358] Subjects can be vaccinated with a regulatory approved Coronavirus Disease 2019 (CO VID-19) vaccine according to national guidelines but should not participate in a CO VID-19 clinical study. Recommendation on the timing of the COVID-19 vaccination in relation to study assessments, due to possible acute reaction on vaccination:

[0359] • The vaccination should be performed preferably after regular visits with the planned blood collections. • Otherwise minimum one week before regular visits with blood sample collections.

[0360] Rationale for timing restriction: the acute reaction on vaccination may cause transitory changes in biochemistry (liver enzymes, lactate dehydrogenase (LDH) etc.), it is not a common reaction but may happen. The possible transitory increase in temperature may cause changes in absorption of study drug, pharmacokinetic (PK) fluctuations, etc. In case of any acute condition, the scheduled visit should be postponed (if no safety issues) until the status of the subject improves.

[0361] The vaccination during the study should be reported as concomitant medication. Any AE that occurs after vaccination should be properly reported.

[0362] Prohibited Concomitant Medications Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the ongoing study. As indicated in the criteria for the medicines and therapies to be discontinued in the washout period the medication that are prohibited during the treatment period and the respective duration of the washout period are listed in Table 2:

[0363] Table 2. Washout of prior medication

[0364]

[0365] DHEA = dehydroepiandrosterone.

[0366] ’If tapering off a medication is required per Investigator’s medical judgement, the washout period should only start after last dose of such medication.

[0367] 2When a subject starts a washout period, it is important to ensure that the subject will have sufficient time to randomize within the enrolment period.

[0368] To confirm compliance with the rules of unauthorized concomitant therapy, blood samples for the analysis of E2 concentrations will be taken during Visits 2 and 3 at Weeks 4 and 12, respectively.

[0369] FSAD Diagnostic Structured Interview

[0370] At screening, all subjects who are potentially eligible, based on the partially completed initial in-person screening criteria, will be scheduled to have a structured interview for the determination of primary FSAD (DSM IV criteria). The interview will be scheduled with sexual medicine experts that have been trained for the assessment of FSAD using a video conference interview process under the guidance of telemedicine regulations controlled under Health Insurance Portability and Accountability Act (HIPAA) regulations.

[0371] Efficacy Measurements Assessed

[0372] The following efficacy measurement scales will be presented to the subjects to complete: Female Sexual Distress Scale-Desire / Arousal / Orgasm (FSDS-DAO)

[0373] FSDS-DAO is a validated 15-item self-assessment of sexual feelings and problems. All responses are on a scale ranging from 0 ("never feel bothered ") to 4 (" always feel bothered"). Total Scores range from 0 (never feel bothered) to 60 (always feel bothered). Lower scores on this scale represent an increase in sexual desire and indicate a better outcome (improvement). A higher score on this scale indicates a worse outcome. FSDS-DAO will be assessed at screening and Week 12 (± 3 days). Change from baseline to Week 12 in feeling concerned by difficulties with sexual arousal, assessed by FSDS-DAO Item 14 will be assessed. The FSDS-DAO has been described on numerous occasions in the art and is publicly available (e.g. Derogatis et al., J Patient Rep Outcomes, 2021, DOI: 10.1186 / S41687-021-00359-1).

[0374] Sexual Function Questionnaire (SFQ-28)

[0375] The Sexual Function Questionnaire (SFQ) is a self-report outcome measure of female sexual function. It has recently been refined to create a 28-item version (SFQ-28) including the addition of a new arousal-cognitive domain. The SFQ-28 is a multidimensional and patient-centered tool and is used to check for all areas of the sexual response. The SFQ-28 was used to determine sexual dysfunction and is made up of 28 questions with 7 domains of dysfunction. The SFQ-28 can also be used as a screening tool for women with sexual dysfunction, being able to detect both the presence of sexual dysfunction and the specific components of sexual function affected. The SFQ-28 will be assessed at screening and Week 12 (+ 3 days). The further refinement and validation of SFQ to SFQ-28 has been described in the art (Symonds et al., J Sex Med, 2012; DOI: 10.1111 / j.1743- 6109.2011.02627.x.

[0376] Patient-Reported Outcomes Measurement Information System (PROMIS) Sexual Function and Satisfaction Measures (SexFS)

[0377] The PROMIS SexFS offers researchers a reliable and valid set of tools to measure self-reported sexual function and satisfaction among diverse men and women. The PROMIS SexFS v2 is a comprehensive, customizable measurement system with evidence for validity in diverse populations. A score of 50 (SD 10) on each domain corresponds to the average for US adults sexually active in the past 30 days. The domains shared among the measures include desire / interest in sexual activity, lubrication and vaginal discomfort / pain, orgasm, and satisfaction. Items in the PROMIS SexFS, is rated on a 5-point scale regarding sexual function experienced over the past 30 days. The PROMIS SexFS is a set of measures that includes separate domains for interest in sexual activity (4 items), global satisfaction with sex life (7 items), orgasm (1 item), lubrication (8 items) and vaginal discomfort (10 items). PROMIS SexFS will be assessed at screening and Week 12 (+ 3 days). PROMIS SexFS development was published in e.g. Flynn et al, J Sex Med, 2014, DOI: 10.1111 / j.1743-6109.2012.02995.x.

[0378] Sexual Function Questionnaire Sexual Event Diary (SED) to Capture Satisfying Sexual Events (SSE)

[0379] The SED is a patient-reported outcome instrument that has been developed for assessing sexual satisfaction and sexual functioning during a discrete sexual event. The SED is an 11 -item questionnaire that is filled out by the subject within 24 hours of a sexual event. Items assess the type and timing of sexual event and if medication was used, 2 binary items assess if the sexual event was satisfactory and if the subject reached orgasm, and six 5-point Likert scale items assess desire, mental arousal / cxcitcmcnt. physical arousal / excitement, presence and strength of distracting thoughts, the ability to let go, and experienced pleasure. Percentage of SSE will be calculated. SED is described in detail in e.g. van Nes et al., J Seks Med, 2017, DOI: 10.1016 / j.jsxm.2017.09.008.

[0380] Patient Global Impression of Change (PGIC)

[0381] PGIC is used to evaluate the condition of sexual arousal disorder being studied and assess if there has been an improvement or decline in the condition, as judged by the patient. At week 12, each enrolled subjects will be asked to rate their overall experience using a 7-point Likert scale as reproduced below.

[0382] “Since the start of the study, my overall status is:

[0383] Tick one box ONLY:

[0384] [ ] Very much improved (Score 1)

[0385] [ ] Much improved (Score 2)

[0386] [ ] Minimally improved (Score 3)

[0387] [ ] No change (Score 4)

[0388] [ ] Minimally worse (Score 5)

[0389] [ ] Much worse (Score 6)

[0390] [ ] Very much worse (Score 7)”

[0391] Reference: Hurst and Bolton, J Manipulative Physiol Ther, 2004, DOI: 10.1016 / j.jmpt.2003.11.003.

[0392] Patient Global Impression of Severity (PGIS)

[0393] The PGIS is used by the subject to assess her sense of severity of the clinical condition under investigation and thus, within the present context, to evaluate sexual arousal disorder. At week 12, each enrolled subjects will be asked to rate their severity of sexual arousal dysfunction on a 7-point Likert scale as reproduced below:

[0394] “Please rate the severity of your sexual arousal disorder right now:

[0395] Tick one box ONLY:

[0396] [ ] Not present (Score 1)

[0397] [ ] Very mild (Score 2)

[0398] [ ] Mild (Score 3)

[0399] [ ] Moderate (Score 4)

[0400] [ ] Moderately severe (Score 5)

[0401] [ ] Severe (Score 6)

[0402] [ ] Extremely severe (Score 7)' Safety Measurements Assessed

[0403] The PI or appropriately delegated and trained designee as indicated in site-specific Delegation of Authority log may perform the safety assessments as indicated in the Schedule of Assessments in a blinded fashion.

[0404] Statistical Methods

[0405] Descriptive statistics will be presented by IMP for all primary and secondary efficacy variables for each measurement timepoint.

[0406] Categorical factors will be summarized using frequencies and / or percentages. Continuous and ordinal (when applicable) variables will be described using means and Standard Deviation (SD), minimum, maximum, median and quartiles.

[0407] Differences between treatment arms may be presented to compare continuous and discrete outcomes. Differences and comparisons may be accompanied by 95% confidence intervals (Cis) as well as p-values. More details will be provided in the statistical analysis plan (SAP).

[0408] Analyses will be performed using server-based SAS® v 9.4 or a later version in a secure and validated environment with a two-sided significance level of 0.05.

[0409] During the study, subjects may be exposed to possible known or unknown intercurrent events that could perhaps impact the estimand, such as treatment discontinuation due to a specific adverse effect or perhaps lack of effect. The treatment policy strategy will be adopted for handling all known or unknown intercurrent events in this study. To this end, the ITT principle will serve as the analytical basis for interpreting the estimand. In other words, treatments will be compared regardless of the occurrence of any such intercurrent event. While no further data are collected after subjects discontinue from the study, all data collected up until time of discontinuation will be utilized in the analyses.

[0410] Efficacy and Safety Endpoints

[0411] Primary Efficacy Endpoint

[0412] • Co-primary endpoints: o Change from baseline to Week 12 in feeling concerned by difficulties with sexual arousal, assessed by FSDS-DAO Item 14. o Change from baseline to Week 12 in the SFQ-28 Arousal-Sensation Domain (Questions 6 to 9).

[0413] Secondary Efficacy Endpoint(s)

[0414] • Key secondary endpoint: o Change from baseline to Week 12 in arousal and lubrication assessed by PROMIS SexFS measures.

[0415] Secondary endpoints: o Change from baseline to Week 12 in sexual function (i.e. distress) assessed by:

[0416] FSDS-DAO - total score,

[0417] Percentage of SSE - captured in arousal diary. o Change from baseline to Week 12 in sexual function assessed by SFQ-28 - total score. o Change from baseline to Week 12 in sexual function assessed by PROMIS SexFS - customized. o PGIC at Week 12. o Change from baseline to Week 12 in severity of sexual arousal disorder as assessed by PGIS.

[0418] Safety Endpoints

[0419] The safety endpoints include the following :

[0420] • Adverse events (AEs)

[0421] • Serious adverse events (SAEs)

[0422] • TEAEs

[0423] TESAES

[0424] • Clinical laboratory parameters

[0425] • Vital signs

[0426] Analysis populations

[0427] Three analysis populations will be used in the analysis of the clinical data:

[0428] The analysis populations will include the following:

[0429] • Safety Set: Includes all subjects who receive at least one dose of IMP. This will be used for all safety analyses.

[0430] • FAS: Includes all randomized subjects with baseline and Week 12 efficacy assessments. This will be the primary analysis population for the efficacy analyses.

[0431] • ITT Set: Includes all randomized subjects. This will be used as a sensitivity analysis for the efficacy analyses.

[0432] Efficacy Analyses

[0433] Demographic and Baseline Variables

[0434] Demographic and baseline variables include age, ethnic origin, height, weight, BMI. Other baseline information includes medical and surgical history, and prior and concomitant medications. Prior and concomitant medications will be coded using the WHO Drug Dictionary and summarized by drug class and drug name for each treatment group and for all subjects combined. Medical and surgical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, current version) and summarized by system organ class and preferred term and by high level term and preferred term for each treatment group and for all subjects combined.

[0435] Primary Efficacy Endpoint

[0436] The change from baseline to Week 12 in feeling concerned by difficulties with sexual arousal, assessed by FSDS- DAO Item 14 and the change from baseline to Week 12 in the SFQ28 Arousal-Sensation Domain (Questions 6 to 9) will both be summarized descriptively and analysed using analysis of covariance (ANCOVA) models.

[0437] The models will include treatment group as the fixed effect. The corresponding baseline scores will be included in the model as a covariate. The estimate for the treatment difference, 95% Cis, and p-values will be presented.

[0438] The primary analysis will be based on the FAS. The ITT Set will be used as a sensitivity analysis.

[0439] Secondary Efficacy Endpoints

[0440] The change in arousal and lubrication (PROMIS - SexFS), FSDS-DAO - total score, percentage of SSE, sexual function (SFQ28 - total score and PROMIS - SexFS customized) and PGIS from baseline to Week 12 will be summarized descriptively and analyzed by ANCOVA, like the co-primary endpoints.

[0441] The number and percentage of subjects reported as improved in severity for PGIS or improved (minimally, much, or very much) in PGIC will be presented with treatments being compared by Chi-square tests. PGIS and PGIC ratings will also be analyzed as response frequencies using the Cochran-Mantel-Haenszel (CMH) test for the row mean score difference.

[0442] Safety Analyses

[0443] Safety data include TEAEs, vital signs and clinical laboratory assessments. Safety analyses will be performed on the Safety Set. All safety data will be listed by treatment and subject in data listings. No inferential analyses are planned.

[0444] The extent of exposure will be summarized using descriptive statistics.

[0445] Concomitant medications will be coded using the WHO Drug Dictionary and summarized by drug class and drug name for each treatment group.

[0446] Adverse events will be coded using the MedDRA. TEAEs will be defined as any event with a start date occurring on or after treatment Day 1.

[0447] The incidence of TEAEs will be summarized by body system and MedDRA preferred term, overall and by treatment group. If a subject reports the same AE more than once, then that subject will only be counted once for the summary of that AE, using the most severe intensity or highest relationship to study medication.

[0448] TEAEs will be summarized as follows: All TEAEs.

[0449] • All TEAEs by intensity.

[0450] • All TEAEs by relationship to study drug.

[0451] • All treatment-emergent SAEs,

[0452] • All TEAEs led to premature discontinuation of study.

[0453] Clinical laboratory parameters will be summarized by using descriptive statistics (as appropriate). The number and percentage of subjects with clinically significant laboratory values will be calculated. Laboratory shift tables (e.g., cross-tabulations of below the lower limit of the normal range [LLN], within normal limits [WNL], and above the upper limit of the normal range [ULN] from baseline at each scheduled visit) will be used to display changes in levels from normal to high, etc.

[0454] For vital signs, descriptive statistics (e.g., n, mean, SD, median, minimum, and maximum values, the number and percentage of subjects in specified categories) will be used to summarize the absolute values and change from baseline at each time point.

[0455] Determination of Sample Size

[0456] Sample size determination is this exploratory study is focused on the arousal sensation section of the SFQ-28 questions 6 to 9 and the FSDS-DAO item 14 (concern about arousal difficulties). Both of these scales have been validated for use in their entity based on previously developed instruments.

[0457] Epidemiological studies have found that approximately 12-64% experienced arousal difficulty and having a questionnaire such as the SFQ-28 that can assess this difficulty is paramount of this study that is key to the diagnosis of FSAD. The SFQ-28 also demonstrated excellent internal consistency, test-retest reliability, and known groups validity in both FSAD and HSDD populations.

[0458] The SFQ-28 has three subsections sections that assess arousal in sensation, lubrication and cognitive. For this study the subsection of sensation is included in items 6 to 9 (arousal sensations). During the validation study the mean validity score for 114 subjects with SFQ-28 for this subsection was 8.25 (standard error [SE] of 0.31) with an intraclass coefficient of correlation (ICC) of 0.87. It is thus expected that the sub-scoring of items 6 through 9 will be applicable to measure change in sensation of arousal over time. The total variance can then be estimated to (0.31 XA / 114)2= 10.955, with in inter-subject variance of (0.87x 10.955) = 9.531 and a residual within-subject variance of (10.955-9.531) = 1.424. Assuming a moderate correlation of 0.5 between the baseline and the postdose score ratings, the standard deviation expected for the change from baseline can then be estimated as / (2X1.421X(1 - 0.5)) = 1.193.

[0459] The 15-item FSDS-DAO retains the 13 items from the Likert-type FSDS-R scale, includes 2 new items that ask women to rate their level of distress related to arousal and orgasm, items related to the expected effect of the IMP in this study. The total score is calculated as the sum of the responses and ranges from 0 to 60, with higher scores indicating a greater level of distress. Item 14 is reported to not have a floor or ceiling response in the validation publication. Unfortunately, the variance of this item has not been made available in this publication or others that have used this questionnaire. Therefore, the variation over time and between subjects can be measured in this study and determine if there is a significant change in concern to arousal response over time.

[0460] The secondary endpoints will provide the change over time of the total score of the entire FSDS-DAO. FSDS- DAO has demonstrated evidence supporting validity, reliability, and responsiveness and is thus considered to be fit for purpose for this study.

[0461] Sample size has been determined for a 5% two-sided Type I error and a power of 80% to detect a 1 -point difference between groups in SFQ-28 arousal sensation score (items 6 to 9), assuming a SD of 1.25 points, considering the use of a two-sample t-test.

[0462] As no relevant information is available on the variability of FSDS-DAO item 14, this scale has not been considered in the sample size estimation. This trial will, however, provide important information for considering this parameter in the design of future studies.

[0463] Based on this calculation the above assumptions on the SFQ-28 arousal sensation score, approximately 26 evaluable subjects / arm (52 subjects in total) are required. Based on an estimated drop-out rate of approximately 30%, approximately 38 subjects / arm, i.e., 76 subjects in total, will be randomized in this study.

[0464] Statistical / Analytical Issues

[0465] Adjustments for Covariates

[0466] The statistical analysis of the primary and secondary endpoints will be adjusted for their value at baseline (where applicable).

[0467] No adjustments for any other covariates is planned to be performed during the data analysis.

[0468] EXAMPLE 2 : A DOSE-FINDING STUDY TO SELECT THE DAILY ORAL DOSE OF ESTETROL (E4) FOR THE TREATMENT OF MENOPAUSE-ASSOCIATED SYMPTOMS IN POST-MENOPAUSAL WOMEN

[0469] Study enrolment and duration:

[0470] Enrolment was approximately 18 months. Individual subject participation was up to 27 weeks: up to 6 weeks prescreening and washout, up to 4 weeks screening and mn-in period, up to 91 days (13 weeks) of E4 / placebo treatment followed by 2 weeks (14 days) of progestin therapy and a Follow up visit 1 week after completion of progestin therapy in non-hysterectomised subjects only.

[0471] Primary Efficacy Objective:

[0472] To define the minimum effective dose (MED) of the oral dose of E4 by evaluating changes in frequency and in severity of moderate to severe vasomotor symptoms (VMS).

[0473] Methodology:

[0474] This was a prospective, multicentre, randomised, placebo-controlled, double-blinded, dose-finding study. Subject Population:

[0475] Eligible subjects were hysterectomised and non-hysterectomised post-menopausal women aged 40 to 65 years, inclusive, presenting at least 7 moderate to severe hot flushes / day or at least 50 moderate to severe hot flushes / week.

[0476] Diagnosis and Inclusion Criteria:

[0477] The subjects have met all of the following inclusion criteria at the randomization visit. These criteria were assessed during the screening period:

[0478] 1. Women aged 40 to 65 years, inclusive, presenting at least 7 moderate to severe hot flushes / day or at least 50 moderate to severe hot flushes / week in the week preceding randomization.

[0479] 2. Body Mass Index (BMI) between 18.0 and 35.0 kg / m2, inclusive.

[0480] 3. Post-menopausal status defined as levels of follicle stimulating hormone (FSH) >40 IU / L and:

[0481] - amenorrhoea for at least 12 consecutive months or,

[0482] - amenorrhoea for at least 6 months with estradiol (E2) < 20 pg / mL or,

[0483] - at least 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy with a copy of the pathology report or a statement on letterhead from the subject's physician documenting both ovaries were removed is required.

[0484] 4. For non-hysterectomised women: intact uterus withbi-layer endometrial thickness <5 mm on TVUS.

[0485] 5. Negative pregnancy test.

[0486] 6. Good physical and mental health, in the judgement of the Principal Investigator (PI), on the basis of medical, surgical and gynaecological history, physical examination, gynaecological examination, clinical laboratory, and vital signs.

[0487] 7. Subject has provided signed and dated written informed consent before admission to the study.

[0488] 8. Subject is able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions.

[0489] Exclusion Criteria:

[0490] 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:

[0491] 1. For non-hysterectomised women: uterine disease or medical condition including : a. Bi-layer endometrial thickness >5mm as determined by TVUS; b. Presence of fibroid(s) that obscure(s) evaluation of endometrium by TVUS; c. History or presence of uterine cancer; d. Presence of endometrial hyperplasia; e. Presence of an endometrial polyp with hyperplastic or malignant epithelium.

[0492] 2. Undiagnosed vaginal bleeding in the last 12 months.

[0493] 3. Any history of malignancy with the exception of basal cell (excluded if within the prior 2 years) or squamous cell (excluded if within the prior one year) carcinoma of the skin. Any clinically significant findings at the breast examination and / or on mammography suspicious of breast malignancy that would require 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 had a written documentation of a mammogram performed within the last 9 months.

[0494] 4. Abnormal cervical Pap smear in non-hysterectomised subjects (written documentation of prior test within 18 months or test at screening exam) with evidence of cervical dysplasia greater than low grade squamous intraepithelial lesion (LSIL). Women with a diagnosis of atypical squamous cells of undetermined significance (ASCUS) were enrolled.

[0495] 5. Systolic blood pressure (BP) outside the range 90 to 140 mmHg, diastolic BP outside the range 60 to 90 mmHg, and / or heart rate outside the range 40 to 100 bpm. Subjects with mild to moderate hypertension who were controlled on a stable antihypertension regimen were enrolled if they met the inclusion / exclusion criteria.

[0496] 6. Any clinically significant abnormality identified on the screening 12-lead ECG.

[0497] 7. History of venous or arterial thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), history of known coagulopathy or abnormal coagulation factors.

[0498] 8. Diabetes mellitus with poor glycaemic control in the last 6 months assessed by laboratory values of glucose outside the normal ranges and glycated haemoglobin above 7%.

[0499] 9. Dyslipoproteinaemia predisposes the subject to atherosclerotic cardiovascular disease (ASCVD). If a subject had a 10 years ASCVD score > 5% as calculated using the ASCVD risk estimator (ACC / AHA Cardiovascular risk assessment guideline, 2013), she was not be included in the trial. In all cases, LDL cholesterol level > 190 mg / dL or triglycerides plasma level > 400 mg / dL were exclusionary. If a subject was receiving a lipid-lowering therapy, her treatment had to be on a stable dose for at least 1 month before screening and the same eligibility criteria had to be used.

[0500] 10. Smoking >10 cigarettes / day or use of >1 ml / day of nicotine containing liquid for electronic cigarette.

[0501] 11. Presence or history of gallbladder disease, unless cholecystectomy had been performed.

[0502] 12. Systemic lupus erythematosus.

[0503] 13. Multiple sclerosis.

[0504] 14. Acute or chronic liver disease.

[0505] 15. Acute or chronic renal impairment, including severe renal impairment. 16. Uncontrolled thyroid disorders.

[0506] 17. Subject had a history of major depression or post-traumatic stress disorder (PTSD) within 2 years, OR a history of other major psychiatric disorder at any time (e.g., schizophrenia, bipolar disorder, etc.).

[0507] 18. Use of estrogen or progestin containing drug(s). A washout period is required before the Run-in Period in case of use of: a. Vaginal hormonal products (rings, creams, gels): washout of at least 4 weeks; b. Transdermal estrogen or estrogen / progestin: washout of at least 4 weeks; c. Oral estrogen and / or progestin: washout of at least 4 weeks;

[0508] Current users of progestin implants or estrogen alone injectable dmg therapy were not allowed to participate unless the treatment was stopped more than 3 months ago. Current users of estrogen pellet therapy or progestin injectable dmg therapy were not allowed to participate unless the treatment was stopped more than 6 months ago.

[0509] 19. Use of non-hormonal treatments to reduce hot flushes. A washout period of 1 week was required before the Run-in Period in the case of use of non-hormonal prescription and over-the-counter (OTC) treatments for hot flushes (such as anti-depressants paroxetine, escitalopram, venlafaxine, desvenlafaxine, and clonidine; or phytoestrogens, black cohosh, etc.). If one of these treatments was concomitantly taken with an estrogen or progestin-containing drug, washout periods could be combined and did not have to be sequential.

[0510] 20. Use of medication that may affect the outcome of the VMS endpoints within 28 days before the Run-in Period. This included (but was not limited to): SSRIs [selective serotonin reuptake inhibitors], SNRIs [serotonin and norepinephrine reuptake inhibitors], dopaminergic or antidopaminergic drugs, or gabapentin.

[0511] 21. History or presence of allergy to the investigational product or drugs of this class, or history of drug or other allergy that, in the opinion of the Investigator contraindicated subject participation.

[0512] 22. History or presence of allergy or intolerance to any component of the investigational product.

[0513] 23. History of alcohol or substance abuse or dependence in the 12 months as determined by the Investigator, i.e. subject consumed excessive alcohol, abused drugs, or had a condition that could compromise the subject’s ability to comply with study requirements in the Investigator’s opinion.

[0514] 24. Sponsor or Contract Research Organization (CRO) employees, or personnel in the department of the Investigator and relatives affiliated with this study.

[0515] 25. Subjects with porphyria and subjects with known or suspected history of a clinically significant systemic disease, unstable medical disorders, life-threatening disease or current malignancies that would pose a risk to the subject in the opinion of the Investigator.

[0516] 26. Participation in another investigational drug clinical study within 1 month (30 days) or had received an investigational drug within the last 3 months (90 days). 27. Was judged by the Investigator to be unsuitable for any reason.

[0517] Number of subjects:

[0518] Intention-To-Treat Principle

[0519] This principle asserts that the effect of a treatment policy can be best assessed by evaluating on the basis of the intention to treat a subject (i.e. the planned treatment regimen) rather than the actual treatment given. It has the consequence that subjects allocated to a treatment group should be followed up, assessed and analysed as members of that group irrespective of their compliance to the planned course of treatment.

[0520] Further, the intention-to-treat principle implies that the primary analysis should include all randomised subjects.

[0521] Preservation of the initial randomisation in analysis is important in preventing bias and in providing a secure foundation for statistical tests. In many clinical trials the use of the full analysis set provides a conservative strategy. Under many circumstances it may also provide estimates of treatment effects which are more likely to mirror those observed in subsequent practice.

[0522] In the present study, the Intention-To-Treat group included a total of 257 patients.

[0523] Subjects were randomly allocated to one of the 5 treatment arms in a 1:1: 1: 1:1 ratio. The randomisation was stratified by centre.

[0524] Study visits:

[0525] Test Product and Reference Therapy, Dose, and Mode of Administration

[0526] All treatments (Estetrol monohydrate, hereinafter E4, [2.5 mg, 5 mg, 10 mg, 15 mg] capsule) were administered once daily (QD) per os for at least 12 consecutive weeks until the last biological assessments (Day 91 maximum) had been performed.

[0527] Placebo, 1 capsule administered QD per os for at least 12 consecutive weeks until the last biological assessments (Day 90 maximum) have been performed.

[0528] If during the course of the trial, a double layer endometrial thickness > 15 mm was detected on TVUS and / or abnormal uterine bleeding (in the judgement of the gynaecologist in light of the estrogen therapy) was reported by a non-hysterectomised woman, she underwent an endometrial biopsy and was treated with progestin (10 mg dydrogesterone) QD until end of Week 11 in a sequential way (i.e., a 14 day progestin treatment period followed by a 14 day progestin treatment pause) in addition to the E4 / placebo treatment. If the endometrial biopsy showed endometrial hyperplasia, the subject participation was immediately stopped and the treatment of hyperplasia was performed as per local guidelines. If an abnormal uterine bleeding occured again after a first normal endometrial biopsy, a thorough gynaecological examination and a TVUS were performed. If necessary in the judgment of the gynaecologist, a second endometrial biopsy was performed.

[0529] After the E4 / Placebo treatment period, all non-hysterectomised subjects (including those having received the progestin previously) received progestin therapy for 14 days with 10 mg dydrogesterone QD. Results

[0530] Genito-urinary symptoms (GSM)

[0531] Change from baseline to week 12 in the following GSM symptoms (WA subject self- assessment) were recorded: a) Vaginal dryness (sensation of dryness or burning in the vagina; none=0 mild=l, moderate=2 or severe=3): * p<0.05 vs placebo at week 12.

[0532] E4 = estetrol monohydrate b) Vaginal and / or vulvar irritation / itching (sensation of abnormal irritation or sensitive condition in the vagina; none=0, mild=l, moderate=2 or severe=3):

[0533] E4 = estetrol monohydrate c) Vaginal pain associated with sexual activity (sensation of pain with sexual intercourse none=0, mild=l, moderate=2 or severe=3): * p<0.05 vs placebo at week 12; ** p<0.001 vs placebo at week 12.

[0534] E4 = estetrol monohydrate

[0535] The evolution of the VVA symptoms points to an overall improvement, with the strongest effect for the 15 mg daily dose. For vaginal pain associated with sexual activity, significant differences with placebo are observed with the doses of 5, 10 and 15 mg daily with p-values of 0.0246, 0.0004 and 0.0006, respectively. Vaginal dryness, however, which is generally considered as the most bothersome symptom, is only significantly improved by the 15 mg daily dose, with a p-value of 0.0291.

[0536] Measurements related to treatment side effects

[0537] 1. Number of patients with biopsies

[0538] E4 = estetrol monohydrate

[0539] 2. Adverse Events (AEs)

[0540] E4 = estetrol monohydrate

[0541] It can be seen from the Table above that the patients in the 15 mg group present less TEAEs than patients in the 10 mg group. In the 10 mg group of patients who had AEs, the average was 3.2 AEs per patient. By comparison, in the 15 mg group, patients who had AEs had on average 2.6 AEs. Globally, those data show that the 15 mg daily dose provides a significant relief of VMS without generating additional AEs for the patients. In addition, there were less requirements for biopsies in the 15 mg per day group than in the 10 mg per day group.

[0542] This is confirmed by the following statistical analysis. Using a Poisson regression model with a random effect for the patient and treatment group as a covariate to model the count of TEAEs in the different treatment groups, it can be shown that there is no statistical difference between the treatment groups (p value of 0.099). Second, a chi- square test was used to assess if the prevalence of patients reporting TEAEs in each treatment group was similar. No statistical difference was found between the treatment groups (p value of 0.575).

[0543] 3. Patients leaving the study

[0544] E4 = estetrol monohydrate EXAMPLE 3: A CLINICAL STUDY TO ASSESS THE EFFECT OF TREATMENT WITH ESTETROL

[0545] MONOHYDRATE ON THE SEXUAL DOMAIN SCORE AS PART OF QUALITY OF LIFE

[0546] A clinical study was designed to evaluate the effect of treatment with E4 (Estetrol monohydrate) 15 mg or 20 mg or placebo for up to 13 consecutive weeks on the severity and frequency of vasomotor symptoms (VMS) in both hysterectomized and non-hysterectomized postmenopausal participants. For endometrial protection, all nonhysterectomized participants were treated with 200 mg progesterone (P4) once daily for 14 consecutive days, after completion of the E4 / placebo treatment.

[0547] Outcome Measures:

[0548] As one of the outcome measures, change from baseline to Week 12 in health-related quality of life assessment (HRQoL) using the menopause-specific Quality of Life (MENQOL) questionnaire [Time Frame: Baseline and Week 12] was assessed.

[0549] The MENQOL is self-administered questionnaire used to assess changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes / No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were be converted to the analysis score ranging from 1-8 where No=l, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual.

[0550] Inclusion Criteria:

[0551] • Signed and dated written informed consent form and any required privacy authorization prior to the initiation of any trial procedure, after the nature of the trial has been explained according to local regulatory requirements;

[0552] • Females, > 40 up to < 65 years of age at randomization;

[0553] • For hysterectomized subjects: documented hysterectomy must have occurred at least 6 weeks prior to the start of screening. Hysterectomy can be total or subtotal (i.e., cervix was not removed);

[0554] • For non-hysterectomized subjects: utems with bi-layer endometrial thickness < 4 mm on TVUS;

[0555] • For non-hysterectomized subjects: an evaluable endometrial biopsy taken during screening that reveals no abnormal results, i.e., presence of hyperplasia (simple or complex, with or without atypia), presence of carcinoma, and presence of disordered proliferative endometrium findings. The screening biopsy should have sufficient endometrial tissue for diagnosis;

[0556] • Seeking treatment for relief of VMS associated with menopause;

[0557] 1. At least 7 moderate to severe bothersome VMS per day or at least 50 moderate to severe bothersome VMS per week in the last 7 consecutive days during the Screening period;

[0558] • Body mass index > 18.0 kg / m2to < 38.0 kg / m2;

[0559] • A mammogram that shows no sign of significant disease performed during screening or within 9 months prior to the start of screening; Post-menopausal status defined as any of the following:

[0560] • For non-hysterectomized subjects:

[0561] 1. at least 12 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) >40 milli-Intemational unit (mIU) / mL (value obtained after washout of estrogen / progestin containing drugs, see exclusion criteria 18 and 20);

[0562] 2. or at least 6 months of spontaneous amenorrhea with semm FSH >40 mIU / mL and E2 <20 pg / mL (<73.4 pmol / L, value obtained after washout of estrogen / progestin containing drugs, see exclusion criteria 18 and 20);

[0563] 3. or at least 6 weeks postsurgical bilateral oophorectomy;

[0564] • For hysterectomized subjects:

[0565] 1. serum FSH >40 mIU / mL and E2 <20 pg / mL (<73.4 pmol / L, values obtained after washout of estrogen / progestin containing drug see exclusion criteria 18 and 20);

[0566] 2. or at least 6 weeks post-surgical bilateral oophorectomy.

[0567] • Good physical and mental health, in the judgement of the Investigator as based on medical history, physical and gynecological examination and clinical assessments performed prior Visit 1;

[0568] • Able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions;

[0569] • Able and willing to complete trial daily paper diaries (if applicable) and questionnaires.

[0570] Exclusion Criteria:

[0571] • History of malignancy with the exception of basal cell or squamous cell carcinoma of the skin if diagnosed more than 1 year prior to the Screening visit;

[0572] • Any clinically significant findings found by the Investigator at the breast examination and / or on mammography suspicious of breast malignancy that would require additional clinical testing to rule out breast cancer (however, simple cysts confirmed by ultrasound are allowed);

[0573] • Papanicolaou (PAP) test with atypical squamous cells undetermined significance (ASC-US) or higher (low-grade intraepithelial lesion [LSIL], atypical squamous cells- cannot exclude high-grade intraepithelial lesion [HSIL] [ASC-H], HSIL, dysplastic or malignant cells) in sub-totally hysterectomized and non-hysterectomized subjects. Note: ASC-US is allowed if a reflex human papilloma virus (HPV) testing is performed and is negative for high-risk oncogene HPV subtypes 16 and 18;

[0574] • For non-hysterectomized subjects:

[0575] 1. History or presence of uterine cancer, endometrial hyperplasia, or disordered proliferative endometrium; 2. Presence of endometrial polyps;

[0576] 3. Undiagnosed vaginal bleeding or undiagnosed abnormal uterine bleeding;

[0577] 4. Endometrial ablation;

[0578] 5. Any uterine / endometrial abnormality that in the judgment of the investigator contraindicates the use of estrogen and / or progestin therapy. This includes presence or history of adenomyosis or significant myoma;

[0579] • Systolic blood pressure (BP) higher than 130 mmHg, diastolic BP higher than 80 mmHg during screening;

[0580] • History of venous or arterial thromboembolic disease (e.g., superficial or deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), or first-degree family history of venous thromboembolism (VTE);

[0581] • History of known acquired or congenital coagulopathy or abnormal coagulation factors, including known thrombophilia's;

[0582] • Laboratory values of fasting glucose above 125 mg / dL (>6.94 mmol / L) and / or glycated hemoglobin above 7%;

[0583] • Dyslipoproteinemia (LDL >190 mg / dL [>4.91 mmol / L] and / or triglycerides >300 mg / dL [>3.39 mmol / L]);

[0584] • Subjects smoking >15 cigarettes per day;

[0585] • Presence or history of gallbladder disease, unless cholecystectomy has been performed;

[0586] • Systemic lupus erythematosus;

[0587] • Any malabsorption disorders including gastric by-pass surgery;

[0588] • History of acute liver disease in the preceding 12 months before the start of screening or presence or history of chronic or severe liver disease [alanine transaminase (ALT) or aspartate transaminase (AST) >2x upper limit of normal (ULN), bilirubin >1.5 ULN]; or liver tumors;

[0589] • Chronic or current acute renal impairment (estimated glomerular filtration rate <60 ml / min);

[0590] • Porphyria;

[0591] • Diagnosis or treatment of major psychiatric disorder (e.g., schizophrenia, bipolar disorder, etc.), in the judgement of the Investigator;

[0592] Use of estrogen / progestin containing drug(s) up to:

[0593] 1. 1 week before screening start for vaginal non systemic hormonal products (rings, creams, gels); 2. 4 weeks before screening start for vaginal or transdermal estrogen or estrogen / progestin products;

[0594] 3. 8 weeks before screening start for oral estrogen and / or progestin products and / or selective estrogen receptor modulator therapy;

[0595] 4. 8 weeks before screening start for intrauterine progestin therapy;

[0596] 5. 3 months before screening start for progestin implants or estrogen alone injectable drug therapy;

[0597] 6. 6 months before screening start for estrogen pellet therapy or progestin injectable drug therapy;

[0598] • Use of androgen / dehydroepiandrosterone (DHEA) containing drugs:

[0599] 1. 8 weeks before screening start for oral, topical, vaginal or transdermal androgen;

[0600] 2. 6 months before screening start for implantable or injectable androgen therapy;

[0601] • Use of phytoestrogens or black cohosh for the treatment of VMS up to 2 weeks before the start of screening;

[0602] • For the women participating in the Efficacy Study part: use of prescription or over-the-counter products used for the treatment of VMS, e.g., anti-depressants: paroxetine, escitalopram, methyldopa, opioid and clonidine up to 4 weeks before the start of screening, and venlafaxine and desvenlafaxine up to 3 months before the start of screening , and not willing to stop these during their participation in the trial;

[0603] • Not willing to stop any hormonal products as described in exclusion criteria 18, 19 and 20, during their participation in the trial;

[0604] • Inadequately treated hyperthyroidism with abnormal TSH and free T4 at screening. Subjects with low or high TSH are allowed if free T4 at screening is within normal range;

[0605] • History or presence of allergy / intolerance to the investigational product or dmgs of this class or any component of it, or history of drug or other allergy that, in the opinion of the Investigator contraindicates subject participation;

[0606] • History of alcohol or substance abuse (including marijuana, even if legally allowed) or dependence in the previous 12 months before the start of screening as determined by the Investigator, based on reported observations;

[0607] • Sponsor or contract research organization (CRO) employees or employees under the direct supervision of the Investigator and / or involved directly in the trial;

[0608] • Subjects with known or suspected history of a clinically significant systemic disease, unstable medical disorders, life-threatening disease or current malignancies that would pose a risk to the subject in the opinion of the Investigator;

[0609] • Participation in another investigational drug clinical trial within 1 month (30 days) or having received an investigational drug within the last month (30 days) before the start of screening; • Is judged by the Investigator to be unsuitable for any reason;

[0610] • For non-hysterectomized subjects to be included in the USA and Canada: history or presence of allergy to peanuts.

[0611] Results:

[0612] The Sexual functioning Domain Score as part of the MENQOL scores of the subjects treated with both doses of estetrol monohydrate were significantly improved when compared to placebo treatment. This improvement stems from the distinct parameters “Avoiding Intimacy”, “Change in Sexual Desire” and “Vaginal Dryness” that contribute to the Sexual functioning Domain Score.

[0613] * Sexual functioning Domain Score = Sum of all parameters of sexual domain

[0614] E4 = estetrol monohydrate

[0615] EXAMPLE 4: COMPARISON OF ENDOMETRIAL THICKNESS IN SUBJECTS RECEIVING 15 MG OR 20 MG ESTETROL MONOHYDRATE

[0616] Further data were generated in a phase III clinical trial that indicate a lack of difference in endometrial increase for 15 mg and 20 mg of estetrol. No significant difference in endometrial thickness could be observed upon comparison of the 15 mg estetrol with the 20 mg estetrol treatment group, as substantiated by an adjusted p-value of 0.8560 by ANCOVA analysis summarized in the below Table. Full details of the referenced clinical study “C301” can be found online (https: / / clinicaltrials.gov / ct2 / show / NCT04209543).

[0617] Table: ANCOVA on Endometrial Thickness (mm) at Week 13 - Difference (C301 Efficacy part - SAF - Non hysterectomized) Tukey adjustment

[0618] E4 = estetrol monohydrate In addition, a clinical study was designed to evaluate the effect of 15 or 20 mg estetrol (E4) monohydrate, or placebo on the severity and frequency of vasomotor symptoms (VMS) and the safety of E4 20 mg. The study was a prospective, multicentre, randomised, placebo-controlled, double-blinded, dose-finding study. Eligible subjects were hysterectomised and non-hysterectomised post-menopausal women aged 40 to 65 years, inclusive, presenting at least 7 moderate to severe hot flushes / day or at least 50 moderate to severe hot flushes / week. All treatments (15 mg or 20 mg estetrol monohydrate capsule or placebo) were administered once daily per os for at least 12 consecutive weeks until the last biological assessments had been performed.

[0619] From the data, it could be deducted that estetrol significantly decreased the frequency of moderate to severe VMS (Figure 2). In addition, estetrol treatment resulted in a higher number of women that experienced a reduced VMS frequency than placebo (Figure 3). Finally, estetrol monohydrate significantly decreased the severity of moderate to severe VMS (Figure 4). Both in terms of VMS frequency and VMS intensity, 20 mg estetrol monohydrate further improved the effects obtained with 15 mg estetrol monohydrate.

Claims

CLAIMS1. A composition comprising about 14 mg to about 25 mg of an estetrol component, for use in treating female sexual arousal disorder (FSAD).

2. The composition for use according to claim 1, wherein the estetrol component is estetrol monohydrate.

3. The composition for use, wherein the composition comprises about 20 mg of estetrol monohydrate.

4. The composition for use according to any one of claims 1 to 3, wherein the subject is a female menopausal, perimenopausal, or post-menopausal subject.

5. The composition for use according to any one of claims 1 to 4, characterized by an improvement of one or more of the following parameters after 12 weeks:- sexual distress assessed by Female Sexual Distress Scalc-Dcsirc / Arousal / Orgasm (FSDS-DAO) total score or percentage of Satisfying Sexual Events (SSE) as preferably captured in an arousal diary;- sexual function assessed by Sexual Function Questionnaire (SFQ-28) total score;- sexual function assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) SexFS or PROMIS SexFS- customized;- Patient Global Impression of Change (PGIC) at week 12;- severity of sexual arousal disorder as assessed by Patient Global Impression of Severity (PGIS).

6. The composition for use according to any one of claims 1 to 5, characterized by an improved sexual arousal as assessed by FSDS-DAO item 14, preferably characterized by an improved sexual arousal as assessed by FSDS- DAO item 14 after 12 weeks compared to baseline.

7. The composition for use according to any one of claims 1 to 6, characterized by an improved arousal-sensation domain as assessed by SFQ-28 questions 6 to 9, preferably characterized by an improved arousal-sensation domain as assessed by SFQ-28 questions 6 to 9 after 12 weeks compared to baseline.

8. The composition for use according to any one of claims 1 to 7, characterized by an improved arousal and lubrication as assessed by PROMIS SexFS, preferably characterized by an improved arousal and lubrication as assessed by PROMIS SexFS after 12 weeks compared to baseline.

9. The composition for use according to any one of claims 1 to 8, characterized by an improvement in sexual arousal as assessed by a PGIC scale at week 12, preferably characterized by an improvement in sexual arousal as assessed by an improvement in sexual arousal on a 7-point Likert scale at week 12.

10. The composition for use according to any one of claims 1 to 9, characterized by a decrease in severity of sexual arousal dysfunction as assessed by a PGIS scale, preferably characterized by a decrease in severity of sexual arousal dysfunction as assessed on a 7-point Likert scale when compared to baseline.

11. The composition for use according to any one of claims 1 to 10, wherein the subject has been diagnosed to have FSAD, preferably wherein the subject has been diagnosed to have FSAD according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition-text revision (DSM IV-TR) criteria forthe diagnosis of FSAD:- persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement;- the disturbance causes marked distress or interpersonal difficulty;- the sexual dysfunction is not better accounted for by another Axis I disorder and is not due exclusively to the direct physiological effects of a or a general medical condition.

12. The composition for use according to claim 11, wherein the subject is further characterized by a total score at screening on the FSDS-DAO > 18 and a score on the FSDS-DAO-Item 14 > 3.

13. The composition for use according to any one of claims 1 to 12, wherein the FSAD is Female Cognitive Arousal Disorder (FCAD) or Female Genital Arousal Disorder (FGAD).

14. The composition for use according to any one of claims 1 to 13, wherein the subject is affected by at least one distinct female sexual disorder in addition to FSAD, preferably wherein the subject is affected by at least one distinct female sexual disorder in addition to FSAD wherein said disorder is selected from the group consisting of: hypoactive sexual desire disorder (HSDD), female orgasmic disorder, and / or dyspareunia.

15. The composition for use according to any one of claims 1 to 14, wherein the composition further comprises a progestogenic component, preferably wherein the progestogenic component is drospirenone, more preferably wherein the progestogenic component is from 1 mg to 4 mg of drospirenone.

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