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US-12616703-B2 - Methods of contraception using nomegestrol acetate and estradiol

US12616703B2US 12616703 B2US12616703 B2US 12616703B2US-12616703-B2

Abstract

Provided are methods of contraception using as a first line combined oral contraceptive (COC), a COC composition comprising nomegestrol acetate (NOMAC) and estradiol or an ester thereof. Said COC compositions are associated with a lower risk of venous thromboembolism (VTE) as compared to other CHCs. The compositions may also be used in methods of treatment in women having conditions linked to menstruation and/or fertility.

Inventors

  • Mitra BOOLELL

Assignees

  • Theramex HQ UK Limited

Dates

Publication Date
20260505
Application Date
20211012
Priority Date
20201016

Claims (19)

  1. 1 . A method of contraception, comprising: (i) identifying a woman desirous of contraception as suitable for receiving a combined hormonal contraceptive (CHC); (ii) selecting a CHC, wherein the selected CHC has been identified as a CHC associated with lowest risk of venous thromboembolism (VTE), wherein the selected CHC is a combined oral contraceptive (COC) composition comprising nomegestrol acetate and estradiol or an ester thereof; and (iii) providing the COC composition comprising nomegestrol acetate and estradiol or an ester thereof to the woman desirous of contraception; wherein the woman desirous of contraception is selected from at least one of the following: a woman who has been pregnant within the past 3 months, a woman who has or has had cancer, a woman who is having or has had chemotherapy treatment, and a woman who has an increased genetic risk of VTE, and wherein the woman desirous of contraception achieves a risk of VTE that is reduced by at least about 10% compared to a reference risk of VTE for a COC containing levonorgestrel.
  2. 2 . The method according to claim 1 , further comprising step (i-a) between steps (i) and (ii), wherein step (i-a) comprises: (i-a) identifying a group of one or more CHCs associated with lowest risk of VTE, wherein the identified group of CHCs associated with lowest risk of VTE comprises: a COC composition comprising nomegestrol acetate and estradiol or an ester thereof; and wherein the selection in step (ii) is made from the group identified in step (i-a); optionally wherein in step (i-a) the CHCs identified as CHCs associated with lowest risk of VTE are the CHCs in the group comprising: a COC composition comprising nomegestrol acetate and estradiol or an ester thereof, and one or more of a COC composition comprising levonorgestrel, a COC composition comprising norgestimate, and a COC composition comprising norethisterone; and wherein the selection in step (ii) is made from the group identified in step (i-a); and further optionally wherein in step (i-a) the CHCs identified as CHCs associated with lowest risk of VTE are the CHCs in the group comprising: a COC comprising nomegestrol acetate and estradiol or an ester thereof; a COC comprising levonorgestrel; a COC comprising norgestimate; and a COC comprising norethisterone.
  3. 3 . The method of claim 1 , wherein in step (i) the woman desirous of contraception is identified as suitable for receiving a CHC based on a determination of the VTE risk of the woman.
  4. 4 . The method of claim 1 , wherein prior to step (i), the method comprises the step of determining the VTE risk of the woman desirous of contraception.
  5. 5 . The method of claim 1 , wherein in step (i) the woman desirous of contraception is identified as suitable for receiving a CHC based on a determination of the unintended pregnancy risk of the woman; optionally wherein prior to step (i), the method comprises the step of determining the unintended pregnancy risk of the woman desirous of contraception.
  6. 6 . The method of claim 1 , wherein the woman desirous of contraception has not been administered a COC for at least 2 months; and/or wherein the woman desirous of contraception has not been administered a CHC for at least 2 months.
  7. 7 . The method of claim 1 , wherein the woman desirous of contraception has not previously been administered a COC; and/or wherein the woman desirous of contraception has not previously been administered a CHC.
  8. 8 . The method of claim 1 , wherein the woman desirous of contraception is at increased risk of unintended pregnancy.
  9. 9 . The method of claim 1 , wherein the woman desirous of contraception is 35 years of age or above.
  10. 10 . The method of claim 1 , wherein the woman desirous of contraception has a body mass index in excess of 30 kg/m 2 and/or has diabetes; and/or wherein the woman desirous of contraception has a body mass index of 30 kg/m 2 or less.
  11. 11 . The method of claim 1 , wherein the woman desirous of contraception does not have any condition selected from the group consisting of: systemic lupus erythematosus; hemolytic uremic syndrome; chronic inflammatory bowel disease; Crohn's disease; ulcerative colitis; and sickle cell disease; or wherein the woman desirous of contraception has a condition selected from the group consisting of: cancer; systemic lupus erythematosus; hemolytic uremic syndrome; chronic inflammatory bowel disease Crohn's disease; ulcerative colitis; and sickle cell disease.
  12. 12 . The method of claim 1 , wherein the nomegestrol acetate and estradiol or ester thereof are present in the COC composition in a weight ratio of approximately 1.67 to 1; and/or wherein the nomegestrol acetate is present in the COC in an amount ranging from about 1.5 mg to about 3.75 mg; and/or wherein the estradiol or ester thereof is present in the COC in an amount ranging from about 0.5 mg to about 3 mg.
  13. 13 . The method of claim 1 , wherein the estradiol is 17β-estradiol, optionally in hemihydrate form.
  14. 14 . The method of claim 1 , wherein the nomegestrol acetate is present in the COC in an amount of about 2.5 mg and the estradiol is present in the COC in an amount of about 1.5 mg.
  15. 15 . The method of claim 1 , wherein the COC composition is provided for administration daily for a period of 21 to 28 days or for a period of 24 consecutive days; and/or wherein the COC composition is provided as a pharmaceutical kit comprising a plurality of dosage units and optionally at least one placebo.
  16. 16 . The method of claim 1 , wherein the COC composition is in the form of a plain or a film-coated tablet, a sugar-coated tablet, a soft gelatin capsule, a wafer capsule, a pill, a cachet or a powder.
  17. 17 . The method of claim 1 , wherein the COC composition further comprises at least one excipient selected from the group consisting of: lactose monohydrate; microcrystalline cellulose (E460); crospovidone (E1201); talc (E553b); magnesium stearate (E572); and colloidal anhydrous silica; or any combination thereof; and/or wherein the COC composition comprises: 2.5 mg nomegestrol acetate; 1.5 mg 17β-estradiol; 57.7 mg lactose monohydrate; 14 mg microcrystalline cellulose; 2.4 mg crospovidone; 0.7 mg talc; 0.7 mg magnesium stearate; and 0.44 mg colloidal anhydrous silica.
  18. 18 . The method of claim 1 , wherein the woman desirous of contraception is less than 35 years of age.
  19. 19 . The method according to claim 1 , wherein the woman desirous of contraception has an increased genetic risk of VTE, and wherein the woman has at least one of the following: Factor V Leiden variant, Protein S deficiency and Protein C deficiency.

Description

RELATED APPLICATIONS The instant application is a 35 U.S.C. § 371 filing of International Patent Application No. PCT/IB2021/059354, filed Oct. 12, 2021, which claims priority to Great Britain Patent Application Nos. 2105398.8, filed Apr. 15, 2021, 2105401.0, filed Apr. 15, 2021, and 2016428.1, filed Oct. 16, 2020, the entire contents of which are incorporated herein by reference for all purposes. FIELD OF THE INVENTION The present invention relates to methods of contraception comprising at least the step of selecting a combined oral contraceptive (COC) composition comprising nomegestrol acetate (NOMAC) and estradiol or an ester thereof as a first line combined oral contraceptive. Said compositions are associated with a lower risk of venous thromboembolism (VTE) as compared to other CHCs. The compositions may also be used in methods of treatment in women having conditions linked to menstruation and/or fertility. BACKGROUND TO THE INVENTION Combined hormonal contraceptives (CHCs), are used to control the menstrual cycle of women by the use of a variety of different means such as transdermal patches, vaginal rings and oral contraceptives. CHC use in women typically prevents ovulation, and is thus a means to prevent pregnancy. One type of CHC known as combined oral contraceptives (COCs) are a popular form of birth control taken by over 100 million women worldwide. CHCs are also used in a clinical setting to treat a range of disorders or conditions linked to menstruation and fertility. Examples include the reduction of heavy menstrual bleeding, regulation of the menstrual cycle, alleviation of dysmenorrhea, treatment of polycystic ovary syndrome, treatment of hirsutism and treatment of premenstrual syndrome (Carey and Allen, The Obstetrician & Gynaecologist 2012; 14:223-228). CHCs (e.g. COCs) typically include an estrogen and a progestogen. A variety of different combinations of estrogens and progestogens are used in different CHCs. Examples of different progestogens used in CHCs currently on the market are levonorgestrel, norethisterone, desogestrel, gestodene, cyproterone acetate, drospirenone, dienogest and nomegestrol acetate. Examples of different estrogens used in CHCs currently on the market are ethinylestradiol, mestranol, estradiol valerate and estradiol. A significant problem associated with the use of CHCs is increased risk of venous thromboembolism (VTE); VTE is one of the most serious adverse events (AEs) associated with CHC use (World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception, The Lancet. (1995) 346: 1575-82; Practice Committee of the American Society for Reproductive Medicine, Fertility and Sterility. (2016) 107(1): 43-51; Dragoman et al., Int. J. Gynaecol Obstet. (2018) 141(3): 287-294; see also: https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/combined-hormonal-contraceptives). VTE is characterised by a series of events whereby a blood clot or “thrombus” forms in a vein, a portion of the clot breaks away and is carried in the circulation to a distal site where it lodges and causes a blockage in a blood vessel. A pulmonary embolism describes blockage in one of the pulmonary arteries in the lungs caused by a blood clot that has travelled from a vein at a distal site, typically a deep vein of the legs. In view of the VTE risks associated with CHCs (e.g. COCs) in general, it is important that CHCs having the lowest associated risk of VTE are used as first line CHCs. That is, for women who have not previously used a CHC or for whom there has been a significant hiatus in their use of CHCs, it is important that the first CHC regimen they receive is associated with the lowest risk of VTE. To date, only a small number of CHCs associated with the lowest risk of VTE are available, thus limiting patient and physician choice. There is therefore a need to identify further CHC compositions associated with the lowest risk of VTE, such that the choice of first line CHC contraception is increased. SUMMARY OF INVENTION One example of a CHC already in clinical use is “NOMAC-E2”, a COC marketed by Theramex HQ UK Limited as ZOELY®. NOMAC-E2 is a monophasic oral contraceptive containing a fixed dose of nomegestrol acetate (2.5 mg) and 17β-estradiol (1.5 mg). NOMAC-E2 pills are typically taken by women for 24 days followed by 4 days of placebo. The progestogen contained in NOMAC-E2, nomegestrol acetate or “NOMAC”, is a derivative of 19-norprogesterone and is thus structurally very similar to the naturally-occurring progesterone produced by the human body. It has a strong affinity for the progesterone receptor and has strong anti-gonadotropic activity and progesterone receptor-mediated anti-estrogenic activity. It also has moderate anti-androgenic activity, and is devoid of estrogenic, androgenic, glucocorticoid or mineralocorticoid activity. The estrogen contained in NOMAC-E2 is 17β-estradiol or “E2”. E2 is a synthetically pro