Treatment of hirsutism, polycystic ovarian syndrome and other associated conditions

Abstract

This invention refers to a new treatment of hirsutism, wherein a combination of dienogest and ethinyl estradiol is administered to a subject in need thereof.

Description

[0001] TREATMENT OF HIRSUTISM, POLYCYSTIC OVARIAN SYNDROME AND OTHER ASSOCIATED CONDITIONS

[0002] Technical field of the invention

[0003] The present invention refers to the treatment of hirsutism and hyperandrogenism, and in particular to the management of polycystic ovarian syndrome-associated hirsutism with an oral controlled-release formulation containing dienogest (DNG) 2 mg and ethinyl estradiol (EE) 0.02 mg in a 24 / 4 regimen.

[0004] Background

[0005] Polycystic Ovarian Syndrome (PCOS) is a heterogeneous endocrine and metabolic disorder defined by androgen excess and ovarian dysfunction, provided that other diagnoses have been excluded. As possibly the most common endocrine and metabolic disorder in women of reproductive age, the prevalence of PCOS ranges from ~6% to -20% when using evolving diagnostic criteria. PCOS arises from a complex interaction of genetic and environmental factors, with diverse clinical implications affecting reproduction (infertility, hyperandrogenism, hirsutism), metabolism (insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, adverse cardiovascular risk profiles), and psychological health (increased anxiety, depression, and worsened quality of life). Hirsutism is the main manifestation of hyperandrogenism associated with PCOS affecting between 65-75% of women with PCOS. To date, most medication used to manage PCOS are used in an off-label fashion. Current management strategies for PCOS include reduction of excess androgen, for which combined oral contraceptives (COCs) remain the first-line pharmacological treatment. The progestin component of COCs suppresses luteinising hormone (LH) secretion, resulting in a decline in ovarian androgen production, protects the endometrium, regulates menstrual cycles, and reduces hyperandrogenism in women with PCOS. The oestrogen component of COCs increases circulating levels of sex-hormone binding globulin (SHBG), which can decrease serum free testosterone concentrations. In terms of effectiveness, low-dose COCs containing neutral or antiandrogenic progestins should be the first choice in the treatment of PCOS. Existing evidence suggests that the benefits of oral contraception outweigh the risks for most women with PCOS; however, there are still concerns about the metabolic and cardiovascular safety of COCs for the long-term management of women with PCOS.

[0006] Hence, there is a need to provide a safe and regulated alternative for treating hirsutism, hyperandrogenism and / or PCOS and / or the symptoms thereof that is widely acceptable to the subjects in need thereof.Summary of the invention

[0007] The present invention overcomes the limitations of the prior art by providing a new treatment using dienogest and ethinyl estradiol and compositions comprising dienogest and ethinyl estradiol.

[0008] Hence, in a first aspect, a controlled release composition is provided that comprises a combination of DNG and EE for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof.

[0009] In a preferred aspect, the composition may be for the use in treating hirsutism associated to polycystic ovarian syndrome (PCOS).

[0010] In another preferred aspect, the composition is intended for a once daily administration.

[0011] In another preferred aspect, the composition may comprise 2 mg of DNG and 0.02 mg of EE. In another preferred aspect, the composition is intended for use in treating mild, moderate and / or severe hirsutism.

[0012] In another preferred aspect, the subject may be a human subject with a body mass index < 30 and / or a body mass index > 30; or the subject in need thereof may be a woman with hyperandrogenism.

[0013] In another preferred aspect, the composition may be administered once daily for 24 days, followed by administration of a placebo for 4 days.

[0014] In another preferred aspect, the composition may be administered over a period of at least 4 months, preferably over a period of at least 9 months.

[0015] In another aspect of the invention, a controlled release composition comprising a combination of DNG and EE is provided for the use in treating hirsutism, polycystic ovarian syndrome, hirsutism associated with PCOS, hyperandrogenism, hyperandrogenism associated with PCOS, menstrual cycle irregularities, and / or menstrual cycle irregularities associated with PCOS in a subject in need thereof.

[0016] Drawings

[0017] Figure 1. Least square (LS) Mean change from baseline in total adapted modified Ferriman-Gallwey (mFG) score (MMRM; full analysis set). The adapted mFG score was determined by the investigator for the participant’s terminal hair growth at the chest, upper abdomen, lower abdomen, thighs, back, arm, and buttocks (minimum score 0; maximum score 28).Figure 2. Quality of life: PCOSQ domain scores at baseline and end of Cycle 9 (or study discontinuation (full analysis set). The PCOSQ covers 26 items measuring five domains: emotions (8 items), body hair (5 items), weight (5 items), infertility problems (4 items) and menstrual problems (4 items) using a 7-point Likert-type scale in which 7 represents optimal function and 1 the poorest function). The lower the score, the greater the negative impact on the health-related quality of life. The total score is a sum of all domain scores. PCOSQ refers to polycystic ovary syndrome questionnaire.

[0018] Figure 3. Proportion of participants with scheduled bleeding / spotting by reference period (full analysis set). Six months prior to screening bleeding data was collected at the screening visit (the recalled data was as defined by the participant as ‘scheduled’). Bleeding data during the trial was collected via self-completed e-diary and reminded participants to complete their entries. Scheduled bleeding during the trial was defined as vaginal bleeding starting 2-4 days after the last active tablet was taken. P<0.005 for all reference periods

[0019] Detailed description of the invention

[0020] Definitions

[0021] As used herein, the term "dienogest (DNG)" or "17a-cyanomethyl-17-B-hydroxyestra-4,9-dien-3-one " is defined for purposes of the invention as comprising (i) unsalified dienogest (also known as dienogest base), its pharmaceutically acceptable salts and mixtures thereof; as well as (ii) esters, solvates, complexes, polymorphs, hydrates or prodrugs of (i) as used herein. Preferably, the dienogest in the composition is unsalified dienogest, a pharmaceutically acceptable salt thereof, or a mixture thereof. Dienogest has PubChem CID number: 68861. As used herein, the term "ethynyl estradiol (EE)" or "17a-ethinylestradiol" is defined for purposes of the invention as comprising (i) unsalified ethynyl estradiol (also known as ethynyl estradiol base), its pharmaceutically acceptable salts and mixtures thereof; as well as (ii) esters, solvates, complexes, polymorphs, hydrates or prodrugs of (i) as used herein. Preferably, the ethinyl estradiol in the composition is unsalified ethynyl estradiol, a pharmaceutically acceptable salt thereof, or a mixture thereof. Ethynyl estradiol has PubChem CID number: 5991.

[0022] Esters of DNG and / or EE may be prepared through functionalization of hydroxyl and / or carboxyl groups that may be present within the molecular structure of the compound (Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-lnterscience, 1992). Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids and the like, and those formed with free carboxyl groups such as those derived from sodium,potassium, ammonium, calcium, ferric hydroxides, isopropyl amine, triethylamine, 2-ethylamino ethanol, histidine, procaine or similar.

[0023] As used herein, the mass of DNG and / or EE in any dosage form of the invention or of a test, reference, control or comparator dosage form comprising DNG and / or EE refers to the amount (mass) of unsalified DNG and / or EE, or a pharmaceutically salt of DNG and / or EE, or a mixture thereof.

[0024] As used herein with respect to the dosage form of the invention, the term "oral", "oral dosage form", "oral pharmaceutical dosage form", "oral administration", "oral compositions" "oral pharmaceutical compositions", “oral contraceptive compositions”, "oral tablets", "oral capsules", "orally ingested", "orally", "oral route" and the like all refer to any method of administration through the mouth. The oral dosage form of the invention is usually ingested intact, although it may be ingested tampered (e.g., crushed) and usually with the aid of water or a beverage to hasten passage through the mouth.

[0025] As used herein, the term "controlled release" dosage forms mean pharmaceutical preparations which release an active ingredient from a dosage form or a portion thereof in other than an immediate release fashion. Controlled release pharmaceutical compositions are made by incorporating a controlled release material (e.g., controlled release excipients) in the dosage form. Controlled release dosage forms are sometimes designed to accomplish pharmaceutical, pharmacokinetic, pharmacodynamic, therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form.

[0026] As used herein, the term "controlled release" is interchangeably with “modified release”, "prolonged release", "slow release", "sustained release", "long acting" and the like. Controlled release dosage forms release the active ingredient from a dosage form or a portion thereof over an extended period of time (over a period of time of 4, 6 hours or 8 hours or greater, preferably over for period greater than about 8 hours, and most preferably over for period greater than about 10 hours, 12, 14, 16, 18, 20, 22 or 24 hours. Controlled release dosage forms may be either delayed onset formulations, i.e., "delayed onset, extended release" (e.g., a delay in release of 1 , 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours after ingestion, preferably at least 2 hours after ingestion) or "extended release" (i.e., without a significant initial delay in release). In some embodiments, these controlled release compositions are formulated to be suitable for daily administration.

[0027] As used herein, "controlled release material", "controlled release means", "rate controlling means", "rate controlling excipient", "rate controlling ingredient", "rate controlling material", "release rate controlling means", "release rate controlling excipient", "release rate controlling ingredient", "release rate controlling material", and "material to provide controlled release"means an in vitro or in vivo release rate controlling excipient or material incorporated in the dosage form whose function or primary function is to modify release (e.g., onset of release, rate of release, duration of release) of an active drug (e.g., DNG and / or EE) from a dosage form or a portion (i.e., cause the dosage form to release in other than an immediate release fashion). In more preferred embodiments of the invention, the controlled release material functions to provide one or more of the following, compared to immediate release DNG and / or EE: (1) change in the onset of release; (2) change in the rate of release; (3) change in the duration of release; (4) change in the time of peak plasma concentration; (5) change in the peak plasma concentration; (6) change in the extent of absorption; (7) change in the onset of therapeutic effect; (8) change in the duration of therapeutic effect; and (9) change in the gastrointestinal anatomic location of release.

[0028] As used herein, “treatment”, “treating” or “treat” refer to: (i) preventing or retarding a disease, disorder or condition from occurring in a subject which may be predisposed to the disease, disorder and / or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder or condition, i.e., arresting or slowing down its development or progression; (iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and / or condition, and / or (iv) preventing, inhibiting or relieving the symptoms of a disease, disorder and / or condition. In certain embodiments, such term refers to the amelioration or eradication of a disease or symptoms associated with a disease.

[0029] As used herein a "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary to achieve the desired therapeutic result, such as one or more of the following therapeutic results, such as a significant delay of the onset or progression of the disease; or a significant reduction of the severity of one or more symptoms. A therapeutically effective amount is also typically one in which any toxic or detrimental effect of the active ingredient or pharmaceutical composition is outweighed by the therapeutically beneficial effects.

[0030] “Hyperandrogenism” is a medical condition that is characterised by high levels of androgens, such as testosterone, which can be measured as free and / or total testosterone, dihydrotestosterone (DHT), androstenedione (A4), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulphate (DHEAS), which are commonly thought of being mal sex hormones, although they are also present in women but at lower levels. Other markers may be 17a-Hydroxyprogesterone (17OHP) and / or the sex-hormone binding globulin (SHBG). However, when their levels in women are too high, then symptoms such as acne, seborrhea, hair loss on the scalp, increased body or facial hair and irregular or even absent menstruation may be observed. Hyperandrogenism may be caused by external factors or may appearspontaneously. For example, it may be “hyperandrogenism associated with PCOS”, in which PCOS is the cause for a hypersecretion of androgenic hormones.

[0031] “Polycystic ovarian syndrome” (PCOS) is an endocrine disorder in women of reproductive age. Most important characteristics of PCOS are hyperandrogenism, anovulation, insulin resistance, and neuroendocrine disruption. Additionally, irregular menstrual periods, heavy periods, excess hair, acne, or infertility have been observed.

[0032] “Hirsutism” and “hirsutism associated with PCOS” is understood as excessive body hair on parts of the body where hair is normally absent or minimal. Hence, hirsutism in women may present as a male pattern of hair growth. The amount and location of the hair may be measured by a Ferriman-Gallwey (FG) score. The FG score uses up to 11 body areas to assess hair growth, whereas the modified FG (mFG) takes into account only 9 body parts. The body parts used in mFG score are chest, back, upper abdomen, lower abdomen, arm, buttocks, upper lip, chin, and thighs. The hair growth is rated from “0” (no growth of hair) to “4” (extensive hair growth). Herein, an adapted mFG score was used that assessed the following 7 body parts: chest, back, upper abdomen, lower abdomen, arm, buttocks, and thighs. A score of 7 or higher (> 7) is regarded as hirsutism according to the adapted mFG. It is also possible to differentiate between mild (adapted mFG = 7-13), moderate (adapted mFG = 14-19) and severe (adapted mFG > 19) hirsutism.

[0033] “Menstrual cycle irregularities” and “menstrual cycle irregularities associated with PCOS” refers to any menstrual cycle irregularity in which the women cannot predict their bleeding. This may include cases, in which women do not experience any bleeding at all, but also cases of oligomenorrhea amenorrhea or menorrhagia.

[0034] “Acne associated with hyperandrogenism” or “acne associated with PCOS” refers to the presence of acne in women due to increased testosterone, dihydrotestosterone and / or dehydroepiandrosterone levels, such as may occur because of hyperandrogenism and / or because of PCOS.

[0035] “Seborrhea” refers to overactive sebaceous glands causing skin issues and / or conditions, such as oily skin.

[0036] Clinical trials and results

[0037] The details for the clinical trial are described further below.

[0038] Combined oral dienogest (DNG) 2 mg / ethinyl estradiol (EE) 0.02 mg has been shown to reduce the androgen levels, increase SHBG levels, and significantly decrease total testosterone and free testosterone levels. Preferably, the combined DNG 2mg / EE 0.02 mg isin form of a controlled release form to obtain highest effect. Therefore, the DNG / EE combination has a high antiandrogenic potential and can be used in treating conditions that show abnormal values of these androgens, such as hyperandrogenism and hirsutism. In particular, the DNG / EE combination may be used to treat the conditions of hirsutism, polycystic ovarian syndrome, hirsutism associated with PCOS, hyperandrogenism, hyperandrogenism associated with PCOS, menstrual cycle irregularities, and / or menstrual cycle irregularities associated with PCOS, acne or seborrhea, and / or the symptoms of these conditions.

[0039] Additionally, the conditions hirsutism, polycystic ovarian syndrome, hirsutism associated with PCOS, hyperandrogenism, hyperandrogenism associated with PCOS, menstrual cycle irregularities, and / or menstrual cycle irregularities associated with PCOS, acne or seborrhea and / or their symptoms do not represent only directly observable physiological conditions affecting women, they also have a great influence on the quality of life, self-esteem and the body image of the affected women. For example, affected women express over proportionally that they have a negative body image, they experience increased anxiety, depression and decreased health-related quality of life and show overall a low self-esteem. Hence, treating the conditions of hirsutism, polycystic ovarian syndrome, hirsutism associated with PCOS, hyperandrogenism, hyperandrogenism associated with PCOS, menstrual cycle irregularities, and / or menstrual cycle irregularities associated with PCOS, acne or seborrhea, and / or the symptoms of these conditions, will help at the same time to increase and recover the self-esteem and the quality of life of the affected women.

[0040] In one preferred aspect, the controlled release formulation of oral DNG 2 mg / EE 0.02 mg is for use in treating acne associated with PCOS. Acne associated with PCOS is caused by the hormone imbalance due to PCOS, especially the excess of androgens. This PCOS-related acne often flares on the lower face, including the jawline, chin, and upper neck, which correspond to visible parts of the body. PCOS-related acne also causes lesions that are deeper, larger, and slower to resolve. Additionally, around the time of menstrual periods PCOS-related acne is getting worse. All this together further aggravates the patient’s perception of PCOS, especially in adult patients, and has negative impacts on the patient’s daily life and self-esteem.

[0041] The present invention provides now a treatment not only for PCOS and hirsutism, but also to PCOS-related conditions such as acne, which otherwise is not treatable and only off-label uses, and complex combinations of different treatments have been suggested so far.

[0042] In particular, a controlled-release formulation of oral DNG 2 mg / EE 0.02 mg in a 24 / 4-day regimen for up to nine 28-day consecutive cycles has shown excellent efficacy for the clinical management of hirsutism, polycystic ovarian syndrome, hirsutism associated with PCOS,hyperandrogenism, hyperandrogenism associated with PCOS, menstrual cycle irregularities, and / or menstrual cycle irregularities associated with PCOS, acne or seborrhea, and / or the symptoms of these conditions in women.

[0043] In particular, the controlled-release formulation of oral DNG 2 mg / EE 0.02 mg surprisingly allows to control the androgenic hormones and markers and brings them down to a normal, physiological level. Those normal, physiological levels, expressed as normal upper / lower reference ranges, are for adult women: Free testosterone: 33.01 / 2.98 mmol / L; testosterone: 1.66 / 0.28 nmol / L; androstenedione: 4.58 / 1.71 nmol / L; 17-OH progesterone: 12.51 / 1.06 nmol / L; dehydroepiandrosterone sulphate: 11 / 4 pmol / L (20-24 years), 9.2 / 2.7 pmol / L (25-35 years), 9.1 / 1.7 pmol / L (35-41 years); sex hormone binding globulin: 128 / 32.4 nmol / L; free androgen index: 0.18 / 7.07%; Insulin resistances 2.0 (insulin resistance unlikely), 2.0 - 2.5 (possible insulin resistance), 2.5 - 5.0 (insulin resistance probable), > 5.0 (mean values of type 2-diabetes).

[0044] In particular, the controlled-release formulation of oral DNG 2 mg / EE 0.02 mg provided a fast decrease of free testosterone already after only a few cycles. After 3 cycles, free testosterone decreased by about 72% with regard to the baseline before treatment and was in the range of normal healthy women. After 6 cycles, this level was maintained and with regard to the baseline, a 74% decrease was observed. However, with placebo, no change at all was observed, meaning that the control group still had abnormally high testosterone levels. The decrease in testosterone is relevant for all the treatment of all the conditions or symptoms thereof mentioned in this invention. All this has also an effect on PCOS-related conditions, such as PCOS-related acne and presents for the first time an effective treatment hereof. At the same time, the controlled-release formulation of oral DNG 2 mg / EE 0.02 mg provided an increase of SHBG levels, from about 30-40 nmol / L before the treatment to more than 140 nmol / L after 9 cycles. In the case of placebo, SHBG level maintained low and did not change. The controlled-release formulation of oral DNG 2 mg / EE 0.02 mg provided also good results for treating hirsutism and / or hirsutism associated with PCOS. After the treatment, about 46% of the women showed no hirsutism and their adapted mFG score was below 7. It was also observed that the more severe the hirsutism was, the higher was the effect of the combination DNG / EE of the invention.

[0045] The change of adapted mFG score after 9 cycles or after early discontinuation was a decrease of about 35% in the treatment group and only about 17% in the control group. Or said in a different manner, the adapted mFG score after 9 cycles or after early discontinuation decreased by 3.77 (a change of -3.77) in the treatment group, but only by 1.54 (a change of -1.54) in the control group.The change was observable over all subgroups of hirsutism severity. Hirsutism severity may be divided into mild hirsutism, moderate hirsutism or severe hirsutism depending on the mFG score: no hirsutism, score <7; mild hirsutism, score 7-13; moderate hirsutism, score 14-19; severe hirsutism 20-28. Hence, after 9 cycles or after early discontinuation, a significant change was observed for all severity groups lowering the score of hirsutism severity when treated with the formulation of the invention, but only a few any changes were observed when treated with placebo. In the DNG 2 mg / EE 0.02 mg treatment group, nearly 50% of the patients obtained a mFG score of less than 7.

[0046] The controlled-release formulation of oral DNG 2 mg / EE 0.02 mg affected also the menstrual cycle irregularities and was able to restore a regular bleeding. It was also observed that there were less women with “no bleeding” after treatment with DNG / EE of the invention. This was not the case with the control group that used the placebo. In the control group, through cycles 3 to 6, about 35-40% of the women showed no bleeding, whereas the treatment with the DNG / EE combination of the invention resulted only in about 15-20% in women with no bleeding. At the same time, treatment with the DNG / EE combination of the invention allowed women to have in general a regular scheduled bleeding. While about 6 months before the treatment with DNG / EE, less than 20% had such a regular scheduled bleeding, through cycles 3-6, more than 75% observed then a regular scheduled bleeding. This was not observed in the control group using the placebo. There, no improvement was detected.

[0047] “Scheduled bleeding” during the trial was defined as vaginal bleeding starting 2-4 days after the last active tablet was taken.

[0048] In detail, 6 months prior to the trial, about 15% of the women of the treatment group (the DNG / EE combination of the invention) had scheduled bleeding, while in the control group using placebo this were about 17% of the women. Within cycles 2-4, the scheduled bleeding in the treatment group increased to about 90%, and in the placebo group to about 42%. Through cycles 5-7, still about 82% of the women in the treatment group had scheduled bleeding, whereas in the control group this was only about 33%. When taking cycles 2-9 together, about 90% of the women in the treatment group experienced scheduled bleeding, but only about 54% of the placebo group. This is illustrated in Fig. 3.

[0049] The treatment with the DNG / EE combination of the invention showed also an improvement in the quality of life of the treated women, which was not observed with placebo. A PCOS questionnaire (PCOSQ) was used to determine the quality of life. This PCOSQ has been described, e.g. in Cronin L, Guyatt G, Griffith L, et al. Development of a health-related quality-of-life questionnaire (PCOSQ) for women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab 1998; 83(6): 1976-87. The PCOSQ covered 26 items measuring fivedomains: emotions (8 items), body hair (5 items), weight (5 items), infertility problems (4 items) and menstrual problems (4 items) using a 7-point Likert-type scale in which 7 represents optimal function and 1 the poorest function). The lower the score, the greater the negative impact on the health-related quality of life. The total score is a sum of all domain scores. The total score before the trial was in the treatment group 19.23, and in the control group 17.20. After the treatment was over after 9 cycles or after early discontinuation, the PCOSQ score improved in the treatment group to 24.61 by a factor of about 1.28, while the PCOSQ score of the control group only improved by a factor of about 1.16 to 20.08. Hence, the was a clear improvement in the treatment group versus the control group. This is illustrated below in table 1 and in Fig. 2.

[0050] Table 1: PCOSQ score

[0051]

[0052] T reatment group = controlled-release formulation of oral DNG 2 mg / EE 0.02 mg; control group = placebo; baseline = before the trial; end = after 9 cycles or after early discontinuation Additionally, the controlled-release formulation of oral DNG 2 mg / EE 0.02 mg showed no meaningful changes in the coagulation and fibrinolytic parameters indicating that a controlled release formulation does not impact in these factors. However, this is not the case in other similar COC products. These have an increased thrombose risk, such as venous thromboembolism (VTE). But the controlled-release formulation of oral DNG 2 mg / EE 0.02 mg with a reduced Cmax and a controlled Tmax did not affect haemostatic parameter and, thus there is a significantly reduced exposure of EE without compromising the bleeding profile. Hence, the controlled-release formulation of oral DNG 2 mg / EE 0.02 mg can be considered neutral regarding potential changes in blood coagulation as no effect on the liver-dependent coagulation factor has been observed.Controlled-release formulation

[0053] International application WO 2022 / 034209 A1 describes oral controlled-release formulations comprising DNG 2 mg / EE 0.02 mg suitable for the invention and is hereby incorporated by reference in its entirety.

[0054] In preferred embodiments, the dosage form of the invention is an oral dosage form, preferably a tablet, comprising: (i) 2 mg of DNG and 0.02 mg of EE, wherein at least 80%, preferably at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, and more preferably all the content of DNG and / or EE is intended for controlled release. In some embodiments, the dosage form said dosage form is suitable for dosing every 24 hours, i.e. the dosage form is a daily dosage form.

[0055] In particularly preferred embodiments, said composition is adapted to provide a pharmacokinetic profile for DNG and / or EE characterized by a Tmax from 3 h to 4h, further to oral administration under fasting conditions once daily for 7 days. Preferably, the pharmacokinetic profile of said composition further to oral administration under fasting conditions once daily for 7 days is further characterized by a Cmax of either DNG or EE of less than 60 ng / mL to 65 ng / mL.

[0056] In some embodiments, optionally in combination with any of the above, the composition is further characterized by its dissolution profile. In particular embodiments, the composition as is characterized by having a dissolution profile characterized in that between 30% and 60% of the amount initially present of either DNG or EE in said composition is dissolved within 2 hours. In preferred embodiments, at least 70%, preferably at least 80% of the amount initially present in said composition is dissolved within 5 hours.

[0057] The in vitro dissolution rate (or dissolution profile) of EE and / or DNG in the composition is preferably assessed by the LISP1 (baskets) method. Briefly, a tablet consisting of the composition comprising EE and DNG to be tested is placed in 900 mL of water at 37°C (± 0.5°C). The dissolution test is performed using a USP dissolution test apparatus 1 (baskets) at a stirring rate of 75 rpm. Alternatively, a tablet consisting of the composition comprising EE and DNG to be tested is placed in 500 mL of water at 37°C (± 0.5°C). The dissolution test is performed using a USP dissolution test apparatus 1 (baskets) at a stirring rate of 75 rpm. Hence, the dissolution test using 900 mL of water is referred to herein as “Dissolution Method I”; whereas the dissolution test using 500 mL of water is referred to herein as “Dissolution Method II”.

[0058] A composition with such an in vitro dissolution profile and / or the in vivo pharmacokinetic profile described above may be achieved in different ways.The release of the slow-release or controlled-release proportion of EE, preferably of EE and DNG, can be controlled by a large number of controlled release means. For example, controlled release may be obtained by using controlled release means suitable for coating retardation, matrix retardation, pellet retardation, osmotic retardation, or other forms of retardation. In coating retardation, the core of a pharmaceutical composition containing an active ingredient is provided with a coating which consist of one or more hydrophilic and / or hydrophobic polymers and slows down release of the active ingredient. In matrix retardation, the active ingredient is contained in a matrix which is formed from one or more excipients and controls release of the active ingredient.

[0059] In some embodiments, the oral dosage form comprising controlled release means, preferably in form of release rate controlling excipients, is selected from the group consisting of an oral dosage form comprising a slow release or controlled release coating, an oral dosage form comprising a pH-independent slow release or controlled release coating, an oral dosage form comprising an extended-release matrix, an oral dosage form comprising an osmotically-controlled system, or an oral dosage form comprising pellet or bead mixtures overcoated with a controlled release material. Preferably, the oral dosage form is an oral contraceptive composition.

[0060] Examples of release rate controlling excipients or controlled release means are inert plastics matrices, hydrocolloids, ion exchangers, slow-release coatings, gastro-resistant coatings, pellet mixtures, mixtures of minitablets and / or granules, microcapsules, osmotically controlled systems, erosion-controlled systems, diffusion-controlled systems and combinations thereof, fat- and wax-containing matrices.

[0061] In some embodiments, the oral dosage form comprises a plurality of pharmaceutically acceptable beads or pellets coated with the drug and overcoated with controlled release material. These beads or pellets may be compressed into tablets or filled into hard gelatine capsules. In other embodiments, the dosage form includes a capsule within a capsule, each capsule containing a different drug or the same drug(s). In some particular embodiments, the outer capsule may be an enteric coated capsule or a capsule containing an immediate release formulation to provide rapid plasma concentrations or a rapid onset of effect or a loading dose and the inner capsule contains an extended release formulation. In one embodiment of the invention, the dosage form involves one or more tablets within a capsule, wherein the EE and / or DNG can be either in the tablet and / or in one of the capsules. In one embodiment of the invention, the composition is ingested orally as a tablet or capsule, preferably as a tablet. In some other embodiments, the slow or controlled release behaviour is achieved by an osmotically driven release system, wherein the oral dosage form may comprise (i) a drug layer;and (ii) a displacement layer comprising an osmopolymer; and (b) a semipermeable wall surrounding the bilayer core having a passageway disposed therein for the release of the drug(s). In some preferred embodiments, the oral dosage form comprises a compressed tablet, compressed capsule or uncompressed capsule. In some preferred embodiments, the oral dosage form comprises a tablet.

[0062] It is an object of certain embodiments of the present invention to provide oral EE and DNG, wherein the EE is dispersed within a matrix, preferably wherein EE and DNG are dispersed within a matrix. In certain preferred embodiments the oral dosage form of the present invention comprises a matrix which includes a controlled release material and EE, preferably EE and DNG. In certain preferred embodiments, the matrix is compressed into a tablet and may be optionally overcoated with a coating that in addition to the controlled release material of the matrix may control the release of the EE, preferably EE and DNG, from the formulation, such that blood levels of the active ingredient(s), are maintained within the therapeutic range over an extended period of time. In some embodiments, the coating is for immediate disintegration and release of the active ingredient. In certain alternative embodiments, the matrix is encapsulated. In some preferred embodiments, the extended release oral dosage form of the present invention comprises a plurality of pharmaceutically acceptable extended release matrices comprising EE, DNG or EE and DNG, the dosage form maintaining the blood plasma levels of the active ingredient(s) within the therapeutic range over an extended period of time when administered to patients.

[0063] In some embodiments, the dosage form of the invention comprises oral DNG and EE formulated to release the EE, preferably the EE and DNG, from the dosage form or to initiate the release of the EE, preferably the EE and DNG, from the dosage form after a certain specific amount of time post-oral ingestion, or at an approximately specific anatomic location in the gastrointestinal tract, or when the dosage form is in contact with specific gastrointestinal conditions (e.g., pH range, osmolarity, electrolyte content, food content, pressure, time since first ingestion, osmotic pressure in the dosage form, osmotic pressure in the gastrointestinal tract, hydration, etc), said dosage form suitable for providing an orally effective therapeutic for a short, intermediate or extended duration of effect, said dosage form providing a rapid or delayed onset of clinical effect. Preferably, said dosage form initiates the release of the EE, preferably the EE and DNG, immediately after ingestion.

[0064] In some embodiments of the invention, EE, preferably EE and DNG, is in the form of multiparticulates. In some embodiments of the invention, EE, preferably EE and DNG, is dispersed in a matrix. In some embodiments of the invention, EE, preferably EE and DNG, is in the form of multiparticulates that can be dispersed in a matrix or contained in a capsule. In some embodiments of the invention, EE, preferably EE and DNG, is in a matrix that is in theform of pellets. In some embodiments of the invention, EE, preferably EE and DNG, is in coated beads. In some other embodiments of the invention, EE, preferably EE and DNG, is in the form of multiparticulates that are dispersed in a matrix and compressed into a tablet.

[0065] In some particularly preferred embodiments, the dosage form of the invention comprises an oral formulation (e.g., tablet or capsule) which is coated to prevent substantial direct contact of EE, preferably EE and DNG, with the oral cavity (e.g. tongue, oral mucosa), oropharyngeal mucosal surface, oesophagus or stomach. In some preferred embodiments, the dosage form of the invention comprises an oral formulation which is coated with a film or polymer.

[0066] In some embodiments, optionally in combination with any of the above, said extended release form is a tablet and may be coated or not. Preferably, said tablet is a film-coated tablet comprising a tablet core and a film coating, wherein the tablet core comprises the content of EE for slow or controlled release, preferably wherein the tablet core comprises the content of DNG and EE for slow or controlled release. Preferably, the coating film allows for immediate disintegration for fast, active release. For instance, this film can be the one-step film coating system (Opadry™ II) which combines polymer, plasticizer and pigment which allows for immediate disintegration for fast, active release (Colorcon® | Opadry® II Complete Aqueous Film Coating System).

[0067] In some embodiments, the extended release EE, preferably EE and DNG, dosage form of the invention is a solid dispersion. By reducing drug particle size and therefore improving drug wettability, the bioavailability may be substantially improved. In addition, surfactants may be included to stabilize the dosage form in order to increase solubility and reduce recrystallization (see Vasconcelos etal, Drug Discovery Today, 2007; 12:1068-75, which is herein incorporated in its entirety by reference).

[0068] In some embodiments, EE (preferably EE and DNG) may be dispersed within an extended-release matrix as described herein above. The term “extended-release matrix” refers to one or more hydrophilic polymers and / or one or more hydrophobic polymers and / or one or more other type hydrophobic materials. In some embodiments, said extended release matrix comprises one or more hydrophilic polymers and one or more hydrophobic polymers, such as in hydrophobic / hydrophilic matrix systems (PVAc / PVP). Suitable materials for inclusion in an extended-release matrix (also referred herein as polymeric matrix forming agents) are:

[0069] (a) Hydrophilic polymers include but are not limited to gums, cellulose ethers, hydrophilic acrylic polymers, ammonium alginate, sodium alginate, potassium alginate, calcium alginate, propylene glycol alginate, alginicacid, polyvinyl alcohol, povidone (PVP), carbomer, potassium pectate, potassium pectinate, and protein derived materials. Of these polymers, the cellulose ethers, especially hydroxyalkylcelluloses and carboxyalkylcelluloses are preferred. The oraldosage form may contain between 10% and 80% w / w, preferably from 20% to 70%, more preferably from 30% to 60%, of at least one hydrophilic polymer.

[0070] b) Hydrophobic polymers include but are not limited to ethyl cellulose, hydroxyethylcellulose, hydrophobic acrylic polymers and polyvinylacetate (PVAc) based polymers. Other hydrophobic materials which may be employ are digestible, long chain (C8C50, especially C12-C40), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols such as cetostearyl alcohol, stearyl alcohol; cetyl alcohol myristyl alcohol etc, fatty acids, mineral and vegetable oils and waxes such as beeswax, carnauba wax, microcrystalline wax, and ozokerite. Hydrocarbons having a melting point of between 25° and 90 °C are preferred. Of these long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The oral dosage form may contain up to 55-60% w / w of at least one digestible, long chain hydrocarbon. (c) Polyalkylene glycols. The oral dosage form may contain up to 60% w / w of at least one polyalkylene glycol.

[0071] In some embodiments, the dienogest: matrix forming agent weight ratio may be about 1: 2.5, about 1:5, about 1:10, about 1:12.5, about 1:15, about 1:20, about 1:25, about 1:30, about 1 :35, about 1 :40, about 1 :45 or about 1 :50. In preferred embodiments, is of 1 :20 to 1 :30, such as about 1:20, about 1:21, about 1:22, about 1:23, about 1:24, about 1:25, about 1:26, about 1 :27, about 1 :28, about 1 :29 or about 1 :30.

[0072] The at least one hydroxyalkyl cellulose is preferably a hydroxy (C1 to C6) alkyl cellulose, preferably selected from hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethyl cellulose, more preferably said hydrophilic polymer is HMPC. Preferably, HPMC in controlled-release (CR) grade. Typical HPMC products used in controlled release matrices are METHOCEL (HPMC) K100 Premium LV, K4M Premium, K15M Premium, K100M Premium, E4M Premium, and E10M Premium CR. All of these products are available in controlled-release (CR) grades, which are specially produced, ultra-fine particle size materials. These grades differ primarily in viscosity and methoxyl substitution type.

[0073] The viscosity of the matrix forming agents (e.g. HPMC) may be of 2 to 150,000 mPa.s in a 2% by weight aqueous solution at 20°C (determined using a Pharm. Eu. capillary viscosimeter). In a particular embodiment, said composition comprises as polymeric matrix forming agent, a HPMC with a viscosity of 80000-120000 cP, such as HPMC K100M. In a preferred embodiment the composition comprises as matrix forming agent a HPMC with a viscosity of 80-120 mPa s, such as HPMC K100 Premium LV. The viscosity ranges provided herein correspond to apparent viscosity at 2% in water at 20°C (determined using a Pharm. Eu. capillary viscosimeter).The amount of the at least one hydroxyalkyl cellulose in the present oral dosage form will be determined, inter alia, by the precise rate of EE, and preferably EE and DNG, release required. In preferred embodiments, said hydrophilic polymer, preferably a hydroxy (01 to 06) alkyl cellulose, or the preferred embodiments described herein above, is at a concentration from 25% to 60% w / w, such as from 30% to 50% w / w, including about 30%, about 40% and about 50%, or from 45% to 55% w / w, more preferably around 50% w / w.

[0074] Acrylic polymers such as polymethacrylates are pharmacologically inactive and have good compatibility with the skin and mucosal membranes. Eudragit is a trade name of copolymers derived from esters of acrylic and methacrylic acids. Eudragit grades differ in their proportion of neutral, alkaline or acid groups resulting in different physicochemical properties. In preferred embodiments of the present invention, the gastroinsoluble polymethacrylate grade (Eudragit RL / RS) is preferred. More preferably, this acrylic resin is Eudragit RS PO.

[0075] The amount of the at least one acrylic polymer in the present oral dosage form will be determined, inter alia, by the precise rate of EE, and preferably EE and DNG, release required. In preferred embodiments, said acrylic resin is found at 10% w / w to 40% w / w, preferably at 20% w / w to 30% w / w.

[0076] In some embodiments, said matrix composition further contains a glidant. A variety of agents may be incorporated as glidant agent (e.g., fumed silicon dioxides, Aerosil™, Aerosil™ COK84, Aerosil™ 200, etc.). Glidants enhance the pharmaceutical formulations of the invention by increasing the viscosity of solutions complementing the action of cellulose ethers (e.g., HPMCs).

[0077] In addition to the above ingredients, a sustained-release matrix may also contain suitable quantities of other excipients, e.g., diluents, lubricants, binders, granulating aids, colorants, flavourings and glidants that are conventional in the pharmaceutical art.

[0078] Suitable diluents, also known as fillers, include corn starch, microcrystalline cellulose, powdered cellulose, silicified cellulose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, sucrose, fructose, dextrose, and / or mixtures thereof. Preferably, lactose monohydrate and mannitol are used. Diluents may be presents in an amount from about 20% to about 95% by weight, preferably from 30% to 90% by weight, and more preferably from 35% to 80% by weight, even more preferably from 30% to 60%, including about 40%, about 45%, about 50%, about 55% and about 60% by weight of the total weight of the composition.

[0079] The dosage form according to the invention may also comprise a binder. The binding agent can be selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, calcium carboxymethyl cellulose, and / or mixtures thereof. Preferably polyvinylpyrrolidone (e.g. Povidone K30) is used. Binders may be present in an amount from about 0.5% to about 20% by weight, preferably from 1 % to 10% by weight, and more preferably from 2-7 % by weight, preferably about 5% by weight of the total weight of the composition. The dosage form according to the invention can also comprise a disintegration agent. Disintegrating agents may be selected from the group consisting of low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crospovidone, sodium croscarmellose, and / or mixtures thereof. Disintegrating agents may be present in an amount from about 2% to about 50% by weight, preferably from about 5% to about 45% by weight, and more preferably from 10% to 40% by weight of the total weight of the composition.

[0080] Lubricants may be selected from the group consisting of talc, alkaline earth salts of stearic acid, especially magnesium and calcium stearate, stearic acid, glycerine palmitostearate, stearyl fumarate, and / or mixtures thereof. In preferred embodiments, the lubricant is magnesium stearate. The lubricant may be present in an amount from about 0% to 5% by weight, preferably from about 1 % to about 3% (e.g., about 2%) based of the total weight of the composition.

[0081] Examples

[0082] Example 1. Coagulation Hemostatic and fibrinolytic parameters associated with the administration of dienogest 2.00 mg / ethinyl estradiol 0.02 mg controlled release formulation.

[0083] Tested product is Dienogest 2.0mg / Ethinyl Estradiol 0.02mg, controlled-release tablets, which composition is described in table 2:

[0084] Table 2. Dienogest 2.0mg / Ethinyl Estradiol 0.02mg, controlled-release tablet composition

[0085]

[0086]

[0087] Sub-analysis of a randomized double-blind trial, involving forty-four patients who received Dienogest 2.0mg / Ethinyl Estradiol 0.02mg, controlled-release tablets, as test product, in a regime intake of 24 days followed by four placebos, and forty-seven patients who received a COC with 0.02 mg EE / 3 mg DRSP (immediate release formulation) as comparator, with the same dosing regimen during nine complete cycles of 28 days, with a follow-up visit scheduled 7-10 days after the last dose of the study drug. These patients were a subgroup of 716 patients receiving the prolonged-release formulation with 2 mg DNG / 0.02 mg EE and 288 patients receiving 3 mg DRSP / 0.02 mg EE of the overall trial. The initial patients’ data before and after were obtained for 28 cases for the 0.02 mg EE / 2 mg DNG and 30 cases for the control group, respectively.

[0088] The trial was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and the relevant European Commission directives and laws of each country. All participants gave written informed consent prior to enrolment. Trial registration was at EudraCT: 2019-001877-97.

[0089] It is currently well established that the estrogens in combined hormonal contraceptives are responsible for the elevated risk of thromboembolic events. The use of combined contraceptives results in an acceleration of coagulation and fibrinolysis, by an increase of various markers of haemostasis and fibrin turnover.

[0090] This is induced by the marked action of EE on hepatic and vascular function. Progestins with pronounced androgenic properties, e.g., LNG, may counteract the estrogen-induced changes in the hepatic synthesis of hematological factors, unlike other progestogens with anti-androgenic properties such as DNG or with neutral androgenic properties may not.

[0091] Haemostatic markers are not the only parameters that influence the occurrence of thrombotic events, but they represent a critical component that influences this clinical event. For any 10 ILI / dL increment of factor VIII, the risk for a single or recurrent episode of venous thrombosis increases by 10% and 24%, respectively.

[0092] The following haemostatic parameters were evaluated, before and after treatment: Antithrombin III (AT III), activated protein C (APC) resistance ratio, D-Dimer, and clotting factors VII and VIII, and reactive Protein C.Results

[0093] The only significant difference between the beginning of the treatment and the end of treatment was found for AT III. At baseline, the geometric mean values for AT III were 0.88 for the controlled release formulation and 0.87 for the comparator (SD, 95% confidence interval [Cl], 0.83-0.94) and (SD, 95% Cl, 0.81-0.92). At the end of the study, the following geometric mean values were observed: 1.06 (SD, 95% Cl, 0.98-1.15) for the DNG / EE formulation and 1.04 SD (95% Cl, 0.96-1.12) for the comparator. The differences between before and after for AT III were significant, with a p value of 0.0006 and 0.0009, respectively. There were no intergroup differences between the two groups regarding the geometric mean ratios, before or after treatment.

[0094] When looking over the APC resistance ratio, no significant change from baseline to end of treatment was observed for both arms. The geometric mean value in the DNG / EE formulation was 2.61 (SD, 95% Cl, 2.33- 2.93) before treatment and 2.50 (SD, 95% Cl, 2.15-2.90) after nine months (p value = 0.6212). Similar results were observed in the comparator group. A geometric mean value of 2.82 (SD, 95% Cl, 2.57-3.10) before treatment and a geometric mean of 2.83 (SD, 95% Cl, 2.50-3.21) after treatment was observed (p value = 0.9629).

[0095] D-dimer, very often used as a surrogate marker for evaluating the risk of VTE, also showed no change in either group before or after treatment. In the DNG / EE group, the values were 276.62 (SD, 95% Cl, 228.92-334.26) ng / mL before treatment, with a slight reduction to 243.98 (SD, 95% Cl, 192.45-309.31) ng / mL after nine months. The comparator group displayed a slight rise in the values from 246.46 (95% Cl, 205.44-295.66) ng / mL to 275.30 (SD, 95% Cl, 219.21- 345.75) ng / mL. This difference was only a non-significant trend (p = 0.4520).

[0096] For all the other three analysed factors, no significant differences could be observed before and after the 9-month treatment for both groups. Also, the in-between comparative geometric mean values were also not significantly different. The only significant difference between the beginning of the treatment and the end of treatment was found for ATI II. Table 3 depicts all the analysed values.

[0097] Table 3. Effect before and after over coagulation and fibrinolysis parameters according to used formulation: DNG / EE (a) or DRSP / EE (b)

[0098]

[0099]

[0100] p value significant for the AT III differences before and after treatment for both formulations. In conclusion, the COC with 2 mg DNG / 0.02 mg EE was not associated with any meaningful changes in the analysed hemostatic parameters indicating that a prolonged release formulation does not impact on these factors.

[0101] Example 2. Double-blind, randomised clinical trial to assess the efficacy and safety of dienogest 2.00 mg / ethinyl estradiol 0.02 mg formulation in the treatment of polycystic ovary syndrome (PCOS) versus placebo during 9 cycles

[0102] Tested product is Dienogest 2.0mg / Ethinyl Estradiol 0.02mg, controlled-release tablets as disclosed in Example 1.

[0103] Methods

[0104] Trial design

[0105] This was a multicentre, multinational, double-blind, placebo-controlled trial for women 2-years post-menarche, 14-40 years old, with a diagnosis of PCOS and an adapted modified Ferriman- Gallwey score (mFG) of >7 at screening and a score of 28 was considered the most severe. The trial was registered at EudraCT (2021-002178-17) and formed part of a paediatric investigational plan (EMEA-002229-PIP02-21).

[0106] Ethics and consent

[0107] The trial protocol, as well as written materials provided to participants and any recruitment advertisements were approved by the relevant Independent Ethics Committee for each trial centre. The trial was performed in compliance with Good Clinical Practices and International Council for Harmonisation guidelines and in accordance with all national laws of participating countries and the Declaration of Helsinki (2008). Written informed consent / assent was received from all participants and parents of adolescents prior to enrolment into the trial. Participants

[0108] All participants had a PCOS diagnosis and hirsutism (adapted mFG score >7), and were in good physical and mental health, with a body mass index (BMI) 18-<35 kg / m2 and systolic / diastolic blood pressure of <140 / 90 mmHg at screening. Women who were pregnant, wishing to get pregnant or breastfeeding were not eligible to enrol, neither were current smokers >36 years and / or with a BMI >30 kg / m2at screening. Patients with abnormal gynaecological examination findings, poorly controlled diabetes (haemoglobin A1C >6.5%),anaemia (haemoglobin <10 g / dL), or the presence or risk of venous or arterial thromboembolism were also not eligible for enrolment.

[0109] Randomisation, trial drugs and masking

[0110] Participants were randomised (4:1 ; stratified by age and centre) to receive either a prolonged-release oral formulation of DNG 2 mg / EE 0.02 mg (active treatment) or placebo. Each participant was allocated a randomization number using a validated interactive web response system (GxP brain GmbH, Berlin, Germany).

[0111] One treatment cycle comprised 24 active or placebo white tablets followed by 4 green placebo tablets (24 / 4-day regimen) in identical blister packs. The participants were asked to take the trial medication at approximately the same time each day for nine consecutive 28-day cycles. If a tablet was missed, the participant was asked to take it as soon as remembered, even if that meant taking two tablets concurrently if more than 24 hours had lapsed since the missed tablet. If more than two consecutive tablets were missed within a cycle, the participant was instructed to resume taking the tablets leaving the missed tablets in the pack. All blister packs were returned for auditing missed tablets. If vomiting occurred within 3-4 hours after taking a white tablet, a replacement tablet was to be taken as soon as possible.

[0112] Randomisation codes were not revealed until after all data had been collected, all protocol deviations had been documented and the trial databased had been locked. The trial safety manager (who was not involved with any other aspect of the trial) was aware of the trial drug allocation in case of a safety emergency.

[0113] Trial procedures

[0114] For the duration of the trial participants were not permitted to take medications that may interfere with the efficacy of hormonal contraceptives or blood pressure regulation, serum lipids or carbohydrate metabolism.

[0115] Each participant could decide whether to shave her hairs during the trial, but she was required to shave exactly 15 days before each adapted mFG assessment, and the shaving regime had to be identical throughout the trial. Any plucked hairs were kept and photographed by the investigators using a smart phone with a pre-installed app provided by the sponsor, as were body areas assessed using the adapted mFG scoring system.

[0116] Laboratory evaluations

[0117] All laboratory evaluations were performed centrally by the Laboratorium fur Klinische Forschung GmbH, Hamburg, Germany.Outcomes

[0118] The dual primary endpoints were the change from baseline in the mean adapted mFG score at the end of Cycle 9 or at the early discontinuation visit (EDV) and proportion of responders, defined as participants with an adapted mFG score reduction of 50% from baseline to the end of Cycle 9 / EDV. The adapted mFG score was completed by each investigator based on seven body areas (chest, upper abdomen, lower abdomen, thighs, back, arm, and buttocks).

[0119] Secondary efficacy endpoints comprised change in laboratory parameters from baseline to the end of Cycle 9 / EDV for serum concentrations of free and total testosterone, androstenedione, 17a-Hydroxyprogesterone (17OHP), dehydroepiandrosterone sulphate (DHEAS) and SHBG. Changes from baseline to end of Cycle 9 / EDV in insulin resistance were assessed using the homeostatic model assessment for insulin resistance (HOMA2-IR) based on fasting serum glucose and insulin levels. Serum lipid profiles were assessed at baseline and the trial end for total cholesterol, high- and low-density lipoprotein (HDL and LDL) cholesterol and triglycerides. Adverse events were monitored throughout the trial. Other safety assessments included changes from baseline to the end of the trial for vital signs, clinical laboratory parameters, electrocardiogram, gynaecological examination cervical cytology and bodyweight. Bleeding patterns (self-reported using an e-diary) and quality of life based on the polycystic ovarian syndrome questionnaire (PCOSQ; 26 items measuring five domains: emotions [8 items], body hair [5 items], weight [5 items], infertility problems [4 items] and menstrual problems [4 items]; uses a 7-point Likert-type scale in which 7 represents optimal function and 1 the poorest function) were also assessed.

[0120] Statistical analysis

[0121] Sample size determination

[0122] The mFG scoring system quantifies and standardises hirsutism based on nine body areas (chest, upper abdomen, lower abdomen, thighs, back, arm, buttocks, upper lip and chin), allowing for data comparison and is currently used as a screening tool. At the time of planning the trial, we calculated the sample size using the duel primary endpoints. Our assumptions were that the mFG score (using nine body areas) relative reductions (the first primary endpoint) would be 50% and 30% in the DNG / EE and placebo groups, respectively, with a standard deviation of 25%. For the responder rates (the second primary endpoint), 60% and 20% were expected to be responders (defined as a mFG score reduction of 50% from baseline to the end of Cycle 9 / EDV) in the DNG / EE and placebo groups, respectively. Based on these assumptions, in addition to an expected drop-out rate of 35%, a sample size of 255 evaluable adult subjects (DNG / EE, n=204; placebo, n=51) was required to provide an overall power of -90%. An additional 20 adolescents were also randomised to fulfil the regulatory requirements for drugs used for adolescent patients.Primary analysis

[0123] A Bonferroni adjustment was applied to test the duel primary endpoints and kept the overall significance level at 5%, resulting in a 2.5% type I error for each test.

[0124] For the first primary endpoint, defined as the change in adapted mFG score, a t-test approach was assumed since prior knowledge of the influence of the baseline covariate was unavailable. The primary analysis was based on a mixed model repeated measure (MM RM) analysis with visit and treatment as factors and baseline-adapted mFG score as a covariate. Each participant was included as a random effect. The MMRM analysis was repeated for BMI subgroups (<30 or >30 kg / m2) and for post-hoc analyses for additional subgroups, including the adapted mFG total score at baseline (adapted mFG total score of <14, 14-19 or >19), the relative change of the adapted mFG total score from baseline (XX XX), and for the trial completers. The least squares (LS) mean associated with treatments were presented overall at the end of Cycle 9 / EDV with 97.5% confidence intervals (Cis) and corresponding p-values. Treatment differences at the end of Cycle 9 / EDV were presented with a one-sided 98.75% Cl and p-value. Multiple imputation methods dealt with missing primary endpoint values, assuming that data was missing at random. The statistical analysis plan (SAP) defined all further analyses due to the different intercurrent event strategies and the sensitivity analyses. For the post-hoc analyses, any intercurrent event occurrences were ignored.

[0125] A two-group Chi-Square test was used for the second primary endpoint. The one-sided testing was performed at a 1.25% one-sided significance level using Fisher's exact test. The primary analysis was repeated for BMI subgroups and as post-hoc analyses for the newly defined subgroups, including the adapted mFG total score at baseline and the trial completers. The response rates and 97.5% Cis were presented for treatment groups. The difference in the response rates was demonstrated with 98.75% Cl, and the p-value of Fisher's exact test was determined.

[0126] The primary analysis was conducted using the full analysis set (FAS), and supportive analyses were repeated on the per-protocol set (PPS).

[0127] Secondary efficacy endpoints were analysed based on the FAS with appropriate statistical methods in an exploratory manner and by BMI subgroup. A post-hoc analysis of trial completers was performed for the change from baseline to end of Cycle 9 for serum testosterone levels (free and total), and serum SHBG levels.

[0128] Further post-hoc analysis included the relationship between the change from baseline to end of Cycle 9 / EDV in the adapted mFG total score and the change of PCOSQ scores (in eachdomain and the total score). This analysis was based on Pearson's correlation coefficient r-values with 95% confidence limits.

[0129] Results

[0130] Patient disposition

[0131] Between November 02, 2021 and December 05, 2023, 500 patients were screened across 46 sites in Czech Republic, Hungary, Lithuania, Poland, Serbia, Slovakia, Spain and Ukraine, of whom 305 provided consent and were randomized. Two-hundred and two participants completed the trial (DNG / EE, n=168; placebo, n=34). A total of 291 participants were included in the safety set (DNG / EE, n=234; placebo, n=57), 256 in the full analysis set (FAS; DNG / EE, n=209; placebo, n=47) and 233 in the per-protocol set (DNG / EE, n=188; placebo, n=45). Demographics and baseline characteristics were similar in both groups but there were some group differences regarding the severity of hirsutism (Table 4). The mean ± standard deviation (SD) adapted mFG scores at baseline were 10.6 ± 3.15 and 11.7 ± 4.75 for the DNG / EE and placebo groups, respectively. Most participants (207 / 256 [80.9%)] had an adapted mFG score of <14 indicating mild hirsutism.

[0132] Table 4. Demographics and baseline characteristics (safety set)

[0133] < >

[0134]

[0135] >

[0136] < >

[0137]

[0138] mass index; DBP = diastolic blood pressure; mFG = modified Ferriman-Gallwey; PCOS = polycystic ovary syndrome; SBP = systolic blood pressure; VTE = venous thromboembolism. Exposure

[0139] The mean ± SD number of treatment days was 228.2 ± 59.22 days for the DNG / EE group and 215.2 ± 67.55 days for the placebo group (FAS). Mean exposure for the safety set was slightly shorter than for the FAS (211.6 ± 75.81 days versus 193.8 ± 81.36 days, respectively).

[0140] Changes in hirsutism severity in response to treatment

[0141] For the first primary endpoint, the adapted mFG score mean ± SD absolute changes from baseline to the end of Cycle 9 / EDV were -3.8 ± 3.37 and -1.7 ± 2.28 in the DNG / EE and placebo groups, respectively (FAS), with mean scores of 6.8 ± 3.39 and 9.5 ± 5.22, respectively. The LS mean treatment group difference at the end of Cycle 9 / EDV was -2.24 (98.75% Cl: -1.14; p<0.0001) in favour of the DNG / EE group (MMRM analysis, FAS, Figure 1) Similar treatment group differences were observed for the mild and moderate hirsutism severity subgroups. The more severe the category of adapted mFG total scores atbaseline (mild, moderate or severe) in the LPRI-424 group, the larger was the LS mean adapted mFG total score change from baseline (-3.13, -6.11 and -12.15, respectively) as can be seen in Table 5.

[0142] Table 5. Change of adapted mFG score at the end of Cycle 9 / EVD by severity subgroup in Baseline (FAS).

[0143]

[0144] The mean ± SD relative change in adapted mFG score from baseline to the end of Cycle 9 / EDV was also significantly greater in the DNG / EE group (-34.5 ± 29.09%) versus the placebo group (-16.6 ± 28.34%; p<0.001).

[0145] For the second dual primary endpoint, participants with a 50% reduction in their adapted mFG score from baseline to the end of Cycle 9 were defined as treatment responders; 31.3% vs 15.9% were responders in the DNG / EE and placebo groups, respectively (treatment difference 15.5%; 98.75% Cl -3.8, °°; p=0.0271). The per-protocol analysis demonstrated similar trends supporting the primary full analysis set.

[0146] Similar trends for were observed for both BM I subgroups for both primary endpoints. In women with a BMI <30 or >30 kg / m2, the LS mean treatment group differences were -3.8 and -3.7 for DNG / EE-treated participants, and -1.9 and -0.6 for placebo, respectively; the LS mean treatment group differences were -1.92 (98.75% Cl -«, -0.66; p =0.0004) and -3.14 (98.75% Cl -«, -0.89; p=0.0011;) respectively (MM RM analysis, FAS).

[0147] Table 6: Analysis of adapted mFG score change from baseline at Cycle 9 / EDV by baseline lirsutism severity subgroup (full analysis set; post-hoc analysis)

[0148] <

[0149]

[0150] >

[0151]

[0152] The number of patients with a mFG score <7 (no hirsutism) at the end of Cycle 9 was 95 (45,5%) and 14 (28.9%) in the DNG / EE group and placebo respectively.

[0153] Table 7: Change in hirsutism severity based on the adapted modified Ferriman-Gallwey scoring system (post-hoc analysis; full analysis set)

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[0155] <

[0156]

[0157] All data are n (%). DNG, dienogest; EE, ethinyl estradiol; EDV, early discontinuation visit. Changes in serum hormone levels, metabolism and serum lipids

[0158] Secondary efficacy analyses included the changes in serum hormone and metabolism laboratory parameters from baseline to the end of Cycle 9 / EDV. Favourable mean serum hormone changes were observed for the DNG / EE group for free testosterone, androstenedione, 17-OH-progesterone, dehydroepiandrosterone sulphate, and SHBG (Table 8). Similar changes were not observed for the placebo group. Neither group showed a negative impact on insulin resistance with all mean HOMO2-IR values below 2. At baseline and at the end of Cycle 9 / EDV, all mean serum lipid ranges were within normal ranges in both groups, and there were no changes to the mean ratios of LDLHDL and total cholesterokHDL.Table 8. Summary of exploratory serum laboratory parameters (full analysis set)

[0159]

[0160] Quality of life

[0161] Participant self-reported quality of life was assessed using the PCOSQ. At baseline, the total mean PCOSQ scores were 19.23 and 17.30, for the DNG / EE and placebo groups, respectively; a lower score indicates worse function. Mean domain scores improved across all domains (emotions, body hair, weight, infertility problems and menstrual problems) from baseline to the end of Cycle 9 / EDV for both groups; however, the DNG / EE group showed the greatest improvements (table 1 and Figure 2). As a post-hoc analysis, we found for the DNG / EE group at the end of Cycle 9 / EDV a negative linear correlation between the adapted mFG score and the PCOSQ total score (r=-0.247; 95% Cl -0.373, -0.0113; p=0.0004) as well with the PCOSQ body hair domain (r=-0.313; 95% Cl -0.432, -0.183; p < 0.0001). Similar negative linear correlations were also found between the adapted mFG score and the PCOSQ emotions and menstrual problems domains. The correlation estimates for the placebo group were not significant for the adapted mFG score and either the PCOSQ total score (r=— 0.171 ; 95% Cl -0.440, 0.125; p=0.2511) nor the PCOSQ body hair domain (r=-0.199; 95% Cl -0.463, 0.096; p=0.1802), nor any other of the PCOSQ domains.

[0162] Bleeding profile

[0163] A higher proportion of participants in the DNG / EE group reported scheduled bleeding / spotting during all reference periods compared with the placebo group (p<0.005 for each reference period). For the DNG / EE group the overall proportion of participants with no bleeding / spotting increased each cycle from 10.0% (24 / 228) in Cycle 1 to 23.3% (37 / 159) in Cycle 9, but there was no clear pattern in the placebo group with the lowest proportion of 27.7% (10 / 46) in Cycle 4 and the highest proportion of 44.2% (23 / 52) in Cycle 2. The mean ± SD duration of bleeding / spotting episodes during Cycles 2-9 was 4.1 ±2.82 days for the DNG / EE group (1632 bleeding episodes for 234 participants and 4.7 ± 3.24 days for the placebo group (253 bleeding episodes for 57 participants). Three women prematurely discontinued from the trial due to intermenstrual bleeding in the DNG / EE group.

[0164] Safety profile

[0165] The proportion of women with treatment-emergent adverse events (TEAEs) were similar in both treatment groups: 166 (70.9%) participants in the DNG / EE group and 42 (73.7%) participants in the placebo group. The most frequent TEAEs were headache (49 participants, 16.8%), intermenstrual bleeding (41 participants, 14.1%), nasopharyngitis (33 participants, 11.3%), and diarrhoea (25 participants, 8.6%) with similar proportions of women in both treatment groups. Most of TEAEs were of mild or moderate intensity. No deaths occurred among the participants during the trial. Serious TEAEs were reported for six participants (2.1%): five participants (2.1%) in the DNG / EE group (2 cases of abdominal pain, pain inextremity, hypoaesthesia and pulmonary embolism) and one participant (1.8%) in the placebo group (vestibular neuronitis). The investigators assessed all serious TEAEs as unrelated or unlikely to be related to trial medication, except for the pulmonary embolism of severe intensity, which was considered related to treatment with DNG / EE. The participant who developed the pulmonary embolism approximately 3 months after starting DNG / EE had other risk factors for pulmonary embolism, including prior COVID-19 infection, a BMI ~30 kg / m2 and while at hospital untreated type 2 diabetes mellitus was diagnosed. The trial medication was withdrawn, antithrombotic treatment started, and the patient prematurely discontinued the trial. Poorly controlled diabetes was a trial exclusion criterion as it is associated with a hypercoagulable state that may increase the risk of thromboembolism. One patient in the DNG / EE group developed insulin resistance which the investigator reported as possibly related to the trial medication. There were no clinically relevant changes in vital signs, electrocardiogram, gynaecological examination cervical cytology or bodyweight.

[0166] Discussion

[0167] This prospective, randomised controlled trial assessed treatment responses to oral prolonged-release DNG 2 mg / EE 0.2 mg in a 24 / 4 regimen versus placebo for the management of hirsutism in women with PCOS for up to 9 cycles. The trial demonstrated that DNG / EE significantly improved hirsutism severity, assessed using an adapted mFG score at the end of Cycle 9 / EDV, compared with placebo. Favourable mean serum hormone changes were observed for the DNG / EE group versus the placebo group. There were minor changes to glucose, insulin or lipid metabolism among the DNG / EE group, most of which were not clinically relevant. Participants in the DNG / EE group showed greater mean improvements across all domains of the PCOSQ versus the placebo group. There was a significant negative correlation between total PCOSQ score and adapted mFG score for participants in the DNG / EE group, but not the placebo group. Significantly more participants in the DNG / EE group had regular scheduled bleeding compared with the placebo group. No new safety concerns occurred, and the safety profile of DNG / EE was similar to a previous trial of the same prolonged-release formulation. One patient with multiple risk factors, including undiagnosed type 2 diabetes developed a pulmonary embolism. Insulin resistance plays a central role in the development of both PCOS and cardiovascular disease. Patients with PCOS also have altered coagulation factors. As with all COCs, the decision to treat an obese patient needs to be balanced between the potential benefit and harms. The trial discontinuation rate (33.8%) was in line with the anticipated rate (35%).

[0168] The FG or mFG scores evaluate clinical hirsutism. The original method uses 11 body areas (upper lip, chin, chest, upper and lower back, upper and lower abdomen, upper arms, forearms,thighs, and leg) to assess hair growth. The modified method excludes forearms and legs. Here, an adapted mFG score was used which assessed hair growth at the chest, upper abdomen, lower abdomen, thighs, back, arm, and buttocks (minimum score 0; maximum score 28). The facial areas stipulated in the FG and mFG scores were not included. If the facial regions had been included as part of the mFG assessment, enrolment may have been affected (hair removal treatments or shaving was prohibited for at least 15 days prior to each assessment). Nevertheless, this is the first time this adapted score system has been used to monitor treatment responses for the management of PCOS-associated hirsutism. The assumptions made for the sample size calculation were based on the mFG, and at the time, there was a lack of published information so were chosen as a ‘best guess’, which helps explain why the responder rates based on the adapted mFG oppose to the mFG score did not quite reach the prespecified level of significance of p<0.025. Moreover, most participants had mild hirsutism at baseline, making it was more challenging to detect a notable reduction in the adapted mFG score than would be expected in a population with hirsutism of moderate or severe intensity. Although widely used, the FG, and mFG scoring systems have limitations, which include their subjective nature, the failure to account for a locally high score that does not disproportionally skew the total score, and the lack of consideration of such androgen sensitive areas such as the sides of the face from the hairline to below the ear (sideburns) and buttocks. Moreover, the upper lip and chin, have androgen sensitivity for hair growth and were not included in the adapted mFG score. As two out of four essential androgen-sensitive regions were not assessed in our trial, we may have seen a greater treatment response if the lip and chin facial areas had been included. Caution should be made about applying our results to other patient populations as mFG scores and hirsutism severity vary considerably.

[0169] Other clinical trials have measured improvements in PCOS-associated hirsutism using FG or mFG score reductions; however, these have used different score cut-off values, treatment durations, doses of EE and progestogens and divergent trial populations. A recent Cochrane review found that among 473 women from 10 trials comparing metformin versus oral contraceptive pill reporting hirsutism using the FG score, found that there was substantial heterogeneity in mean study BMI as well as treatment response. Nevertheless, there appears to be an additive effect of bodyweight to increased hair growth in women with PCOS, with the maximum mFG scores observed in women with high BMI compared with women with a low BMI. In our trial, reductions in mean adapted mFG scores were observed with DNG / EE regardless of BMI subgroup but we observed a greater treatment difference in LS mean (MMRM analysis) adapted mFG score at the end of Cycle 9 / EDV for the BMI >30 versus <30 kg / m2subgroups (adapted mFG score, -3.14 vs -1.92, respectively). The placebo effect seemed to be lower among participants with a BMI >30 kg / m2, possibly because lifemodification measures are less effective in this subgroup of women. Obesity exerts a significant impact on the PCOS phenotype, particularly on the metabolic associations and complications of the syndrome, including increasing the risk for metabolic syndrome and its constellation of cardiovascular risk factors in these women.

[0170] DNG has powerful antiandrogenic properties, reviewed in a meta-analysis of 56 clinical studies (2266 women treated). The Hershberger test evaluating the antiandrogenic effect of various progestins indicates that DNG has about 40% of the potency of cyproterone acetate, the most potent antiandrogenic progestin. By using prolonged-release formulation of DNG / EE, the peak of exposure is reduced compared to immediate-release formulations and delayed by a few hours. This leads to a similar total systemic exposure with reduced peak intensity, and therefore reduced fluctuations in systemic blood levels of the active ingredients. Reduced hormonal fluctuations result in a better bleeding profile which is a desirable feature for women with PCOS. In our current trial, favourable changes in circulating hormone levels were observed for participants in the DNG / EE group from baseline to the end of Cycle 9 / EDV for free testosterone, testosterone, androstenedione, and free androgen index (FAI), as well as an increase in mean serum SHBG levels, which were not seen for the placebo group. Moreover, significant favourable decreases were observed for 17-OHP and DHEAS in the DNG / EE group compared with the placebo group. It has been shown that the combination of DNG / EE reduced the androgen levels, increased SHBG levels, and significantly decreased total testosterone and free testosterone levels. Therefore, the DNG / EE combination has strong antiandrogenic potential and usefulness in treating the conditions of hirsutism, polycystic ovarian syndrome, hirsutism associated with PCOS, hyperandrogenism, hyperandrogenism associated with PCOS, menstrual cycle irregularities, and / or menstrual cycle irregularities associated with PCOS, acne or seborrhea, and / or the symptoms of these conditions in women. COCs have a possible harmful impact on metabolic markers like lipids and carbohydrates; however, like other low-dose oral contraceptives, DNG / EE has a minor influence on lipid and carbohydrate metabolism, adrenal hormones, and blood pressure parameters and appears to have a balanced effect on the haemostatic system. DNG / EE in healthy women may cause a slight increase in serum insulin levels and insulin resistance. In our trial, although mean serum levels remained within normal ranges, there was a trend towards small increases in mean concentrations of blood lipids (i.e., total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol) and insulin fasting in the DNG / EE group, although LDLHDL and total cholesterokHDL ratios remained unchanged. These findings are aligned with the results showed in example 1 for healthy woman.Available data indicate that using COCs increases the risk of VTE in the general population. However, most studies addressing the topic have not evaluated all potential confounding factors and may be subject to bias. It remains controversial whether COCs create an additional risk of VTE among women with PCOS, a prothrombotic condition. Careful assessments of patients and ruling out additional risk factors before starting treatment with COCs would be the best measure to prevent VTEs both in the general population and in women with PCOS. In conclusion, the results of this trial show that oral DNG 2 mg / EE 0.2 in a 24 / 4 treatment regimen for up to 9 cycles is an effective treatment for hirsutism for women with PCOS, with no additional safety signals, and was generally well-tolerated.

[0171] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

[0172] For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:

[0173] 1. A controlled release composition comprising a combination of dienogest (DNG) and ethinyl estradiol (EE) for the use in treating hirsutism, hyperandrogenism and menstrual irregularities in a subject in need thereof.

[0174] 2. The composition according to clause 1 for the use in treating hirsutism associated to polycystic ovarian syndrome (PCOS).

[0175] 3. The composition according to clause 1 or clause 2 for a once daily administration. 4. The composition according to any of clauses 1 to 3 comprising 2 mg of DNG and 0.02 mg of EE.

[0176] 5. The composition according to clauses 1 or 2, for use in treating mild, moderate and / or severe hirsutism.

[0177] 6. The composition according to clause 1, wherein the subject is a human subject with a body mass index < 30 and / or a body mass index > 30.

[0178] 7. The composition according to clause 1 , wherein the subject in need thereof is a woman with hyperandrogenism.

[0179] 8. The composition according to clause 1, wherein the composition is administered once daily for 24 days, followed by administration of a placebo for 4 days.

[0180] 9. The composition according to clause 8, wherein the composition is administered over a period of at least 4 months, preferably over a period of at least 9 months.

[0181] 10. A controlled release composition comprising a combination of DNG and EE for the use in treating hirsutism, polycystic ovarian syndrome, hirsutism associated with PCOS, hyperandrogenism, hyperandrogenism associated with PCOS, menstrual cycleirregularities, and / or menstrual cycle irregularities associated with PCOS in a subject in need thereof.

[0182] 11. A combination of DNG and EE for the use in treating hirsutism in a subject in need thereof.

[0183] 12. The combination according to clause 11, wherein DNG and EE are administered together or subsequently one after another.

[0184] 13. The combination according to clause 11 for the use in treating hirsutism associated to PCOS.

[0185] 14. A controlled release composition comprising a combination of dienogest (DNG) and ethinyl estradiol (EE) for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof.

[0186] 15. The composition according to clause 14 for the use in treating hirsutism associated to polycystic ovarian syndrome (PCOS).

[0187] 16. The composition according to clause 14 or clause 15 for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof, wherein the composition is administered once daily.

[0188] 17. The composition according to any of clauses 14 to 16 for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof, the composition comprising 2 mg of DNG and 0.02 mg of EE.

[0189] 18. The composition according to clause 14 or 15, for use in treating mild, moderate and / or severe hirsutism.

[0190] 19. The composition according to clause 14 for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof, wherein the subject is a human subject with a body mass index < 30 and / or a body mass index > 30.

[0191] 20. The composition according to clause 14 for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof, wherein the subject in need thereof is a woman with hyperandrogenism.

[0192] 21. The composition according to clause 14 for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof, wherein the composition is administered once daily for 24 days, followed by administration of a placebo for 4 days.

[0193] 22. The composition according to clause 21 for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof, wherein the composition is administered over a period of at least 4 months, preferably over a period of at least 9 months.The composition according to clause 14 for the use in treating hirsutism, polycystic ovarian syndrome, hirsutism associated with PCOS, hyperandrogenism, hyperandrogenism associated with PCOS, menstrual cycle irregularities, menstrual cycle irregularities associated with PCOS, acne associated with hyperandrogenism, and / or acne associated with PCOS in a subject in need thereof.

[0194] The composition for use according to clause 14, for use in improving the quality of life of in patients suffering from hirsutism, hirsutism associated with PCOS, hyperandrogenism, hyperandrogenism associated with PCOS, or polycystic ovarian syndrome, wherein quality of life is determined by the polycystic ovary syndrome questionnaire (PCOSQ).

[0195] The controlled release composition comprising a combination of dienogest (DNG) and ethinyl estradiol (EE) for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof according to clause 14, wherein the subject is suffering from mild, moderate or severe hirsutism.

[0196] The controlled release composition comprising a combination of dienogest (DNG) and ethinyl estradiol (EE) for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof according to clause 14, wherein the subject has a body mass index (BMI) of > 30 kg / m2.

[0197] The controlled release composition comprising a combination of dienogest (DNG) and ethinyl estradiol (EE) for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof, wherein the subject has a BMI of < 30 kg / m2.

Claims

36CLAIMS1. A controlled release composition comprising a combination of dienogest (DNG) and ethinyl estradiol (EE) for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof.

2. The composition according to claim 1 for the use in treating hirsutism associated to polycystic ovarian syndrome (PCOS).

3. The composition according to claim 1 or claim 2 for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof, wherein the composition is administered once daily.

4. The composition according to any of claims 1 to 3 for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof, the composition comprising 2 mg of DNG and 0.02 mg of EE.

5. The composition according to claim 1 or 2, for use in treating mild, moderate and / or severe hirsutism.

6. The composition according to claim 1 for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof, wherein the subject is a human subject with a body mass index < 30 and / or a body mass index > 30.

7. The composition according to claim 1 for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof, wherein the subject in need thereof is a woman with hyperandrogenism.

8. The composition according to claim 1 for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof, wherein the composition is administered once daily for 24 days, followed by administration of a placebo for 4 days.

9. The composition according to claim 8 for the use in treating hirsutism, hyperandrogenism and menstrual cycle irregularities in a subject in need thereof, wherein the composition is administered over a period of at least 4 months, preferably over a period of at least 9 months.

10. The composition according to claim 1 for the use in treating hirsutism, polycystic ovarian syndrome, hirsutism associated with PCOS, hyperandrogenism, hyperandrogenism associated with PCOS, menstrual cycle irregularities, menstrual cycle irregularities associated with PCOS, acne associated with hyperandrogenism, and / or acne associated with PCOS in a subject in need thereof.

11. A controlled release composition comprising a combination of dienogest (DNG) and ethinyl estradiol (EE) for use in improving the quality of life of in patients suffering from37hirsutism, hirsutism associated with PCOS, hyperandrogenism, hyperandrogenism associated with PCOS, or polycystic ovarian syndrome, wherein quality of life is determined by the polycystic ovary syndrome questionnaire (PCOSQ).

12. A controlled release composition comprising a combination of dienogest (DNG) and ethinyl estradiol (EE) for use in treating polycystic ovarian syndrome.

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