MÉTODO E DISPOSITIVO PARA PROPORCIONAR CONTRACEPÇÃO EFICAZ

Abstract

The present invention relates to levonorgestrel for use in a method for providing contraception in a female subject, comprising continuous intravaginal administration of levonorgestrel of from about 60 µg / day to about 100 µg / day. The invention further relates to levonorgestrel for use in a method for treating endometriosis, endometriosis associated pelvic pain (EAPP) and / or dysmenorrhea comprising continuously administering about 60 µg / day to about 160 µg / day of levonorgestrel. Delivery devices, preferably, intravaginal rings for putting the methods in practice are also envisaged.

Description

[0001] The present invention pertains to the field of women's health and, more specifically, to levonorgestrel for use in a method to provide contraception while at the same time providing optimal estrogen suppression. A method for treating endometriosis and endometriosis-related diseases is also provided, as well as a drug delivery device, such as an intravaginal ring, suitable for putting these methods into practice. BACKGROUND OF THE INVENTION

[0002] Levonorgestrel (LNG) is a synthetic progestin that does not exhibit significant estrogenic activity and is highly progestational. It inhibits follicular stimulation and ovulation and reduces the permeability of cervical mucus to sperm. Levonorgestrel is used as a progestogen component in numerous contraceptive products registered worldwide. Currently, it is one of the most widely used progestogens in combined oral contraceptives (COCs). Cerazet® is an effective progestin-only pill (POP) containing 75 pg of desogestrel in film-coated tablets (1). Its mechanism of action focuses on inhibiting ovulation. Traditional POP pills work by thickening cervical mucus, delaying egg transport and providing an endometrium hostile to implantation. Cerazet® has been shown to inhibit ovulation as effectively as a COC pill.A POP pill dosage containing 0.075 mg of desogestrel is high enough to inhibit ovulation in at least 98% of cycles, compared to only 72% of cycles with 0.030 mg of LNG (2,3,4). This is probably due to the consistent inhibition of ovulation that is considered. Petition 870250084815, dated 09 / 19 / 2025, page 7 / 146 2 / 117 the most robust mechanism of action of a POP, the contraceptive efficacy of desogestrel 0.075 mg is greater than that of LNG 0.030 mg and other low-dose POPs, and comparable to the efficacy of COCs. (5,6). Although Cerazet® is a widely used product with an extensive safety database, individuals receiving this treatment have reported adverse drug reactions, such as bleeding irregularities. There is therefore a need for alternative progestin-only contraceptives.

[0003] Long-lasting implants containing only LNG have also proven to be an effective form of contraception. For example, in multicenter clinical studies with the Jadelle® implant, involving 1393 women, 8 pregnancies occurred in the 5 years following placement (8,9).

[0004] Ovulation inhibition is directly related to steady-state plasma levonorgestrel concentration. However, the minimum threshold level of circulating LNG required for contraceptive efficacy is still uncertain. Based on initial studies of Norplant® (Wyeth, Pfizer, NY), a subdermal contraceptive implant, a plasma LNG concentration of 0.3 to 0.4 ng / mL is often mentioned as a threshold level below which contraceptive efficacy decreases. Several weeks after implant insertion, mean plasma LNG levels stabilized between 0.3 and 0.4 ng / mL and slowly decreased to a mean level of 0.28 ng / mL after 5 years of use; by the eighth year, levels were around 0.22 ng / mL (range, 0.02-0.35 ng / mL). LNG concentrations associated with unwanted pregnancies were therefore reported to be 0.21 ± 0.06 ng / mL.

[0005] With regard to ovulation inhibition provided by levonorgestrel implants, ovulation is inhibited in more than 85% of cycles in the first year of use, when the levo release rate Petition 870250084815, dated 09 / 19 / 2025, page 8 / 146 3 / 117 norgestrel is the highest (10). The percentage of ovulation inhibition decreases to around 65% of cycles in years 2 and 3, while luteal activity occurs in about 50% of cycles in the last 2 years of use. Mean serum estradiol levels during the 5-year Norplant period were similar to those of the control group, around 400 to 500 pmol / L (109 to 136 pg / mL).

[0006] The levonorgestrel implant exerts its contraceptive action by causing changes in cervical mucus, inhibiting ovulation and promoting ovulatory dysfunction. In case of contraceptive failure, a pregnancy that occurs while using the levonorgestrel implant is more likely to be ectopic than pregnancies conceived with other contraceptives. Due to the high contraceptive efficacy of the levonorgestrel implant, the absolute rate of ectopic pregnancies in users of Jadelle® (new trade name for Norplant®) is very low.

[0007] Higher dose LNG-POPs were tested with the aim of obtaining an estrogen-free contraceptive with high contraceptive reliability and an acceptable bleeding pattern (7). The investigational dosages were Levonorgestrel 0.095, 0.115 and 0.135 mg per day, administered to three groups of 30 patients for 56 days. It was concluded that Levonorgestrel 0.115 mg per day was the lowest effective dose for consistent inhibition of ovulation. Levonorgestrel, when administered orally, is known to be completely absorbed after oral administration, leading to a bioavailability of almost 100% and is not subject to first-pass metabolism, as demonstrated, for example, for a commercial COC comprising levonorgestrel and ethinylestradiol (Seasonique®).

[0008] A multicenter, open-label, single-arm study (NCT02403401) was conducted to investigate the contraceptive efficacy and safety of LNG (40 pg / day) delivered via an intravaginal ring (IVR). The delivery rate and dose of LNG for the IVR in this study were es Petition 870250084815, dated 09 / 19 / 2025, page 9 / 146 4 / 117 were harvested in order to achieve exposure similar to that of the approved low-dose LNG POP (NorgestonVR / MicrolutVR, 30 μg / day) and LNG implant (Norplant IIVR / JadelleVR) after a 2-year period of use. However, the study was terminated prematurely after approximately one-third of the planned exposure due to the high number of pregnancies.

[0009] Therefore, although the safety profile of LNG is well characterized and there is experience in the use of various doses, pharmaceutical formulations and delivery systems, the contraceptive efficacy of LNG as monotherapy administered in a vaginal delivery system has not been demonstrated to date.

[0010] Another problem associated with progestogen-only contraceptives is menstrual irregularity due to the lack of estrogen administration. In fact, this is the most common reason (45%) for discontinuation of the levonorgestrel implant (11).

[0011] Although the bleeding mechanism associated with progestin-only contraceptives is still poorly understood, it is known that the bleeding pattern associated with progestin-only contraceptives depends on the degree of suppression of ovarian activity. In general, if normal ovulation occurs consistently, a woman will experience menstrual bleeding with a frequency characteristic of her normal cycle. If both ovulation and follicular development are completely suppressed, it may result in amenorrhea. If ovulation or follicular development (and therefore sufficient estrogen secretion to stimulate endometrial growth) occurs irregularly, bleeding will be erratic and unpredictable (12).

[0012] Therefore, there is a need for progestin-only contraceptives that provide high contraceptive efficacy by inhibiting ovulation while at the same time providing a Petition 870250084815, dated 09 / 19 / 2025, page 10 / 146 5 / 117 good bleeding profile.

[0013] Increasing the dosage of Levonorgestrel in dosage forms will result in consistent inhibition of ovulation; however, it is desirable to achieve complete inhibition of ovulation to improve contraceptive efficacy while administering the minimum dose of the drug to avoid or reduce side effects.

[0014] One of the main side effects is caused by estrogen suppression due to the administration of progestogen-only preparations, which can lead to the occurrence of undesirable hypoestrogenic side effects, in particular bone loss. Although tissues vary in their sensitivity to estradiol, an average estradiol concentration between 30 and 45 pg / ml is considered sufficient to prevent bone loss (13).

[0015] The reduction in plasma estradiol levels is also related to the improvement of other conditions, such as premenstrual syndrome, hypermenorrhea, and also the improvement of other pathologies considered estrogen-dependent, such as uterine fibroids and subserosal endometrial polyps.

[0016] Estrogen suppression also has a direct influence on the development of endometriosis. Endometriosis is a chronic, estrogen-dependent disease characterized by the presence of endometrial tissue outside the uterus, including the ovaries and other pelvic structures. These lesions cause a chronic inflammatory reaction, which can lead to the generation of scar tissue and adhesions. Women with endometriosis frequently experience symptoms of dysmenorrhea, premenstrual pain, dyspareunia, and chronic fatigue, (14) as well as the less common symptoms of ovulation pain, constipation, and painful urination (15). In addition, the presence of ectopic endometrium can also cause infertility, which may be the case in up to 50% of women with endometriosis (16). Estradiol levels in utero. Petition 870250084815, 19 / 09 / 2025, p. 11 / 146 6 / 117 doses of 40-60 pg / ml were suggested in the previous technique for the treatment of endometriosis.

[0017] Currently, there is no cure for endometriosis. Women with endometriosis still require ongoing and collaborative management of their condition, as well as an understanding of the significant impact the condition can have on their quality of life. The main goals of treatment are to relieve pain and other symptoms, reduce endometriotic lesions, and improve the quality of life of affected individuals.

[0018] Current hormonal treatments for pain associated with endometriosis focus on systemic or local estrogen suppression, inhibition of tissue proliferation and inflammation, or both. Combined oral contraceptives (COCs) are widely used as first-line treatment for dysmenorrhea or chronic pelvic pain with or without presumed endometriosis, particularly in adolescents with endometriosis (17). However, estrogens have a stimulatory effect on the metabolic activity of the endometrial mucosa. Thus, the administration of COCs could result in estrogen dominance, with the potential risk of lesion progression (18).

[0019] Progestogen-only treatment is also used as first-line therapy for pelvic pain associated with endometriosis and to suppress the extension of endometriotic lesions.An FDA-approved progestogen for the treatment of endometriosis, secondary amenorrhea, and abnormal uterine bleeding is norethisterone acetate (NETA) (5 mg tablets). Although, in principle, NETA may also provide ovulation inhibition from a dosage of 0.35 mg / day when administered continuously for 28 days, it is not approved for contraceptive use, since the high dosage required for the treatment of endometriosis (5 to 15 mg / day) is more than 10 times higher than the dosage required for other conditions. Petition 870250084815, dated 09 / 19 / 2025, page 12 / 146 7 / 117 ovulation inhibition (0.35 mg / day). Therapy may be maintained at this high dosage level for a maximum of six to nine months, or until breakthrough bleeding necessitates temporary interruption of treatment. Furthermore, at such high doses, NETA may produce androgenic side effects such as acne, hirsutism, weight gain, and mild voice changes in some women.

[0020] Another approved progestogen, Dienogest (DNG), is a synthetic progestogen currently used for the clinical treatment of endometriosis in Europe at a dose of 2 mg per day (Visanne® 2 mg tablets). DNG, being devoid of androgenic activity, is better tolerated than NETA. DNG 2 mg per day provides ovulation inhibition, but ovarian activity is not completely suppressed; therefore, it has not been approved as a contraceptive (19). Thus, users are formally encouraged to adopt barrier contraception or other non-hormonal alternatives (20) when using DNG in the treatment of endometriosis.

[0021] Currently approved treatments for endometriosis-associated pain are not indicated for contraception. Furthermore, the concomitant use of hormonal contraceptives with some FDA- or European-approved medications for endometriosis (e.g., GnRH antagonists such as the recently approved Elagolix or progestogens such as dienogest) is not permitted. The need for barrier contraception may limit adherence to these products and may increase the discontinuation rate. Thus, there is a definite need for therapies that treat endometriosis-associated pelvic pain (EAPP) in women seeking hormonal contraception.

[0022] It was therefore an objective of the present invention to provide a contraceptive with a very high ovulation inhibition efficacy, while at the same time limiting estrogen suppression to Petition 870250084815, dated 09 / 19 / 2025, page 13 / 146 8 / 117 an optimal level, such as levels corresponding to an early follicular phase, and thus avoiding the commonly known side effects caused by prior art contraceptives that contain levonorgestrel as an active ingredient.

[0023] It is a further objective of the invention to provide a contraceptive with a very high ovulation inhibition efficacy, which is at the same time suitable for the treatment of endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea and other related estrogen-dependent diseases. SUMMARY OF THE INVENTION

[0024] The present invention, therefore, relates in one aspect to levonorgestrel for use in a method for providing contraception in a female individual, comprising administering levonorgestrel to said individual continuously, wherein the daily amount of levonorgestrel administered is from about 60 pg / day to about 100 pg / day, wherein the route of administration is vaginal administration.

[0025] In one embodiment, the present invention relates to levonorgestrel for use in a method for providing contraception in a female individual, comprising administering levonorgestrel to said individual continuously, wherein the average daily amount of levonorgestrel administered is about 75 pg / day, wherein the route of administration is vaginal administration.

[0026] In another aspect, the present invention relates to levonorgestrel for use in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea in a female individual, comprising administering levonorgestrel to said individual continuously, wherein the daily amount of levonorgestrel administered is from about 60 pg / day to about 160 pg / day, preferably wherein the route of administration is by administration Petition 870250084815, dated 09 / 19 / 2025, p. 14 / 146 9 / 117 vaginal.

[0027] In one embodiment, the present invention relates to levonorgestrel for use in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea in a female individual, comprising administering levonorgestrel to said individual continuously, wherein the average daily amount of levonorgestrel administered is from about 75 pg / day to about 150 pg / day, preferably wherein the route of administration is vaginal administration.

[0028] In one embodiment, the present invention relates to levonorgestrel for use in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea in a female individual, comprising administering levonorgestrel to said individual continuously, wherein the average daily amount of levonorgestrel administered is about 75 pg / day, about 125 pg / day or about 150 pg / day, preferably where the route of administration is vaginal administration.

[0029] In one embodiment, the present invention relates to levonorgestrel for use in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea as described above, wherein said treatment also provides contraception.

[0030] In one embodiment of the methods of the present invention, no additional contraceptive ingredient is administered to the female subject at the same time, preferably no estrogen is administered to the female subject at the same time.

[0031] In a preferred embodiment of the methods of the present invention, no additional antiviral agent is administered to the female subject at the same time.

[0032] In a preferred embodiment of the methods of the present Petition 870250084815, dated 09 / 19 / 2025, page 15 / 146 10 / 117 invention, no tenofovir is administered to the female individual at the same time.

[0033] In one embodiment of the methods of the present invention, said administration of Levonorgestrel also induces amenorrhea.

[0034] In a further aspect, the present invention relates to the use of Levonorgestrel as a contraceptive, comprising the continuous administration of Levonorgestrel in an amount of about 60 pg / day to about 200 pg / day to a female individual, wherein the route of administration is vaginal administration.

[0035] In one embodiment of the aforementioned aspect, the present invention relates to the use of Levonorgestrel as a contraceptive, comprising the continuous administration of Levonorgestrel in an average amount of between about 75 pg / day and about 150 pg / day to a female individual, preferably where the route of administration is vaginal administration.

[0036] In one embodiment of the aforementioned aspect, the present invention relates to the use of Levonorgestrel as a contraceptive, comprising the continuous administration of Levonorgestrel in an average amount of about 75 pg / day, about 125 pg / day, or about 150 pg / day to a female individual, preferably where the route of administration is vaginal administration.

[0037] In a preferred embodiment, the route of administration is transmucosal, preferably vaginal.

[0038] In a further embodiment of the use of the present invention, no additional contraceptive ingredient, preferably no estrogen, is administered to the female subject at the same time.

[0039] In one embodiment of the use of the present invention, said administration of Levonorgestrel also induces amenorrhea.

[0040] In one embodiment of the use of the present invention, none Petition 870250084815, dated 09 / 19 / 2025, p. 16 / 146 11 / 117 an additional antiviral agent is administered to the female individual at the same time.

[0041] In one embodiment of the use of the present invention, no tenofovir is administered to the female subject at any one time.

[0042] In a further aspect, the present invention relates to a drug delivery device comprising (a) a core comprising a polymer; (b) a sheath substantially or completely surrounding said core; the sheath referred to comprising a polymer; (c) Levonorgestrel dissolved or dispersed in said core and / or said sheath, wherein the total amount of Levonorgestrel present in said core and / or said sheath is between about 9 mg and about 11 mg.

[0043] In a preferred embodiment, the total amount of levonorgestrel present in said core and / or said sheath is approximately 10 mg.

[0044] In one embodiment, the core polymer is a polyurethane and the sheath polymer is an ethylene-vinyl acetate copolymer.

[0045] In one embodiment, the ethylene-vinyl acetate copolymer of the sheath comprises a vinyl acetate content of between 10 and 40% w / w, preferably 15 to 30% w / w.

[0046] In a further embodiment, the release device comprises (a) a core comprising a polyurethane; (b) a sheath substantially or completely enclosing said core, said sheath comprising ethylene vinyl acetate copolymer with a vinyl acetate content between Petition 870250084815, dated 09 / 19 / 2025, p. 17 / 146 12 / 117 at around 10 to 40% w / w, preferably around 15 to 30% w / w; (c) Levonorgestrel dissolved or dispersed in said core and / or said sheath, wherein the total amount of Levonorgestrel present in said core and / or said sheath is about 10 mg.

[0047] In a further embodiment, the release device comprises (a) a core comprising a polyurethane; (b) a sheath substantially or completely enclosing said core, said sheath comprising ethylene vinyl acetate copolymer with a vinyl acetate content of about 18% w / w (c) Levonorgestrel dissolved or dispersed in said core and / or said sheath, wherein the total amount of Levonorgestrel present in said core and / or said sheath is about 10 mg.

[0048] In one embodiment of said drug delivery device, the device releases Levonorgestrel at a constant rate for 28 days after it has been administered to the female subject.

[0049] In one embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein said device releases: - not more than about 150 pg, preferably not more than about 130 pg, of levonorgestrel during an initial 24-hour release period, - approximately 60 pg to 90 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period, when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2. Petition 870250084815, dated 09 / 19 / 2025, page 18 / 146 13 / 117

[0050] In one embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein said device releases: - approximately 70 pg to approximately 150 pg, preferably approximately 70 pg to approximately 130 pg of levonorgestrel during an initial release period of 24 hours, and - approximately 60 pg to 90 pg, preferably approximately 60 pg to approximately 80 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period, when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2 medium.

[0051] In some embodiments, the average daily release of levonorgestrel over the 28-day treatment cycle, including the initial 24-hour release period and the subsequent 27 days after the initial 24-hour release period, is about 60 pg to about 100 pg, preferably about 70 pg to about 80 pg, more preferably about 75 pg per day.

[0052] In one embodiment, the daily release of levonorgestrel during the 28-day treatment cycle, including the initial 24-hour release period and the subsequent 27 days after the initial 24-hour release period, is no less than approximately 56 pg per day on any day.

[0053] In a further embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein said device releases: - no more than approximately 250 pg of levonorgestrel during an initial 24-hour release period, - approximately 90 pg to 150 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period Petition 870250084815, dated 09 / 19 / 2025, page 19 / 146 14 / 117 when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2.

[0054] In a further embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein said device releases: - approximately 100 pg to approximately 200 pg, preferably approximately 110 pg to approximately 170 pg of levonorgestrel during an initial release period of 24 hours, - approximately 90 pg to 150 pg, preferably approximately 90 pg to 140 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2 medium.

[0055] In some embodiments, the average daily release of levonorgestrel over the 28-day treatment cycle, including the initial 24-hour release period and the subsequent 27 days after the initial 24-hour release period, is about 90 pg to about 160 pg, preferably about 105 pg to about 140 pg, more preferably about 125 pg per day.

[0056] In one embodiment, the daily release of levonorgestrel during the 28-day treatment cycle, including the initial 24-hour release period and the subsequent 27 days after the initial 24-hour release period, is no less than approximately 87 pg per day on any given day.

[0057] In a further embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein said device releases: - no more than about 300 pg of levonorgestrel during Petition 870250084815, dated 09 / 19 / 2025, p. 20 / 146 15 / 117 an initial release period of 24 hours, - approximately 110 μg to 180 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2.

[0058] In one mode, the aforementioned device releases: - no more than about 250 pg, preferably about 170 μg to about 220 pg of levonorgestrel during an initial release period of 24 hours, - 110 pg to 180 pg, preferably about 120 μg to about 170 μg of levonorgestrel per day for at least 27 days after the initial 24-hour release period when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2 medium.

[0059] In one embodiment, the average daily release of levonorgestrel over the 28-day treatment cycle, including the initial 24-hour release period and the subsequent 27 days after the initial 24-hour release period, is about 120 pg to about 200 μg, preferably about 150 pg per day.

[0060] In one embodiment, the daily release of levonorgestrel during the 28-day treatment cycle, including the initial 24-hour release period and the subsequent 27 days after the initial 24-hour release period, is no less than about 105 μg per day.

[0061] In one embodiment, the release of levonorgestrel from the delivery device as described herein, in this patent application, follows zero-order kinetics after the initial 24-hour release period, i.e., the amount of levonorgestrel released each day Petition 870250084815, dated 09 / 19 / 2025, page 21 / 146 16 / 117 is constant.

[0062] In a preferred embodiment, levonorgestrel is administered continuously for 28 days via the delivery device after the device has been placed in the individual.

[0063] In a preferred embodiment, the delivery device according to the present invention does not comprise an additional active ingredient.

[0064] In a preferred embodiment, the delivery device according to the present invention does not comprise an additional contraceptive ingredient.

[0065] In a preferred embodiment, the delivery device according to the present invention does not comprise an antiviral agent.

[0066] In a preferred embodiment, the delivery device according to the present invention does not comprise tenofovir.

[0067] In another preferred embodiment, the delivery device does not comprise estrogen.

[0068] In one embodiment of the drug delivery device of the present invention, levonorgestrel is present in the core at a concentration of 0.20 to 1.00% by weight based on the total weight of the core.

[0069] In an additional embodiment, the sheath has a thickness between 5 and 500 pm, preferably between 50 and 200 pm.

[0070] In one embodiment, the drug delivery device of the present invention provides a mean Cmax value for levonorgestrel of less than 1 ng / ml after a 28-day treatment cycle and less than 0.7 ng / ml after two 28-day treatment cycles, and a mean AUC (0.-t) value of less than 350 h*ng / ml after a 28-day treatment cycle and less than 370 h*ng / ml after two treatment cycles. Petition 870250084815, dated 09 / 19 / 2025, page 22 / 146 17 / 117 treatment of 28 days each in a female individual, after the delivery device had been placed intravaginally inside the individual's body.

[0071] In another embodiment, the drug delivery device of the present invention provides a mean Cmax value for levonorgestrel of less than 1.6 ng / ml after a 28-day treatment cycle and less than 1 ng / ml after two 28-day treatment cycles, and a mean AUC (0-t) value of less than 580 h*ng / ml after a 28-day treatment cycle and less than 540 h*ng / ml after two 28-day treatment cycles in a female subject, after the delivery device has been placed intravaginally inside the subject's body.

[0072] In another embodiment, the drug delivery device of the present invention provides a mean Cmax value for levonorgestrel of less than 1.5 ng / ml after a 28-day treatment cycle and less than 1 ng / ml after two 28-day treatment cycles, and a mean AUC (0-t) value of less than 480 h*ng / ml after a 28-day treatment cycle and less than 540 h*ng / ml after two 28-day treatment cycles.

[0073] In one embodiment, the drug delivery device of the present invention has a shape selected from either a spiral (helical) shape or a ring shape, preferably wherein the drug delivery device has a ring shape. In a preferred embodiment, the device is a vaginal ring. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: In vitro elution profile of the drug delivery system for Levonorgestrel Vaginal 75 μg / day. Figure 2: In vitro elution profile of the drug delivery system for Levonorgestrel Vaginal 125 μg / day. Figure 3: In vitro elution profile of the delivery system. Petition 870250084815, dated 09 / 19 / 2025, page 23 / 146 18 / 117 of Levonorgestrel Vaginal drug 150 μg / day. Figure 4: Estradiol Level by Visit and Body Mass Index. Average estradiol levels are shown for each treatment cycle and by BMI category for all treatment groups. Figure 5: Pharmacokinetic parameters for LNG. Mean concentration-time profiles of LNG and participants in the LNG VDS 75, 125, and 150 treatment groups. Figure 6: Pharmacokinetic parameters for SHBG. Mean concentration-time profiles of LNG and SHBG, respectively, of participants in the LNG VDS 75, 125, and 150 treatment groups. Figure 7: Pharmacokinetic parameters for LNG by Body Mass Index. Mean concentration-time profiles of LNG and participants in the LNG VDS 75, 125, and 150 treatment groups categorized by BMI. Figure 8: Pharmacokinetic parameters for SHBG by Body Mass Index. Mean concentration-time profiles of LNG and SHBG, respectively, of participants in the LNG VDS 75, 125, and 150 treatment groups categorized by BMI. Figure 9: Schematic representation of two forms of drug delivery devices A) ring-shaped, B) spiral (helical)-shaped. Figure 10: Mean concentration vs. time curves of SHBG after vaginal administration of the Levonorgestrel Vaginal Delivery System (LVDS) during 2 treatment cycles of 28 days each (release rate of 75 μg / day) by BMI subgroup (BMI subgroup 1: 30 < BMI > 35; BMI subgroup 2: BMI > 35), linear graph. Figure 11: Mean plasma concentration vs. time curves after vaginal administration of the Levonorgestrel Vaginal Delivery System (LVDS) during 2 treatment cycles of 28 days each. Petition 870250084815, dated 09 / 19 / 2025, page 24 / 146 19 / 117 (release rate of 75 pg / day) by BMI subgroup (BMI subgroup 1: 30 < BMI > 35, N = 12; BMI subgroup 2: BMI > 35, N = 16), linear graph, PPS. DETAILED DESCRIPTION OF THE INVENTION

[0074] As described above, it was an object of the present invention to provide a contraceptive with a very high ovulation inhibition efficacy, while at the same time limiting estrogen suppression to an optimum level, such as levels corresponding to an early follicular phase, and thus avoiding the generally known side effects caused by prior art contraceptives comprising levonorgestrel as an active ingredient.

[0075] The inventors therefore resolved to develop a delivery device with the desired properties and conducted a multicenter, phase 2, open-label, randomized clinical trial to evaluate ovulation inhibition by levonorgestrel (LNG) delivered at three different dosage potencies (75 pg / day, 125 pg / day and 150 pg / day) from an LNG vaginal delivery system (LNG VDS) for 28 days on a continuous regimen versus desogestrel (Cerazet®) administered orally in healthy female subjects aged 18 to 35 years.

[0076] The study consisted of four phases: a screening phase of at least 4 weeks and at most 8 weeks (in case a washout cycle was necessary), a 28-day pre-treatment cycle, a treatment cycle (TC) consisting of 56 days of treatment (2 cycles TC1 and TC2, each with 28 days per cycle), and a 28-day post-treatment cycle.

[0077] Ovulation inhibition was measured by assessing ovarian activity, studying follicular growth, and serum estradiol and progesterone concentrations in patients.

[0078] In addition, the influence was evaluated during this trial. Petition 870250084815, dated 09 / 19 / 2025, page 25 / 146 20 / 117 cia of LNG VDS on cervical mucus, endometrial thickness, return of ovulation in the post-treatment cycle, the impact of LNG VDS on blood levels of sex hormones, and the safety and tolerability of LNG VDS.

[0079] Overall, 268 individuals were screened, of whom 137 were randomized and 130 started the study treatment. Efficacy was assessed in a total of 128 participants comprising the full analysis set or FAZ, and in 118 participants comprising the per protocol set or PP. For the PK / PD analysis, 55 participants comprised the PK population (14 of them had a BMI > 30 kg / m2 and 41 had a BMI between >18 and <30 kg / m2).

[0080] It can be shown that a total of 127 / 128 (99.2%) participants experienced ovulation inhibition during TC1. The only participant who did not experience ovulation inhibition belonged to the BMI >18 and <30 kg / m2 group and was treated with Cerazet. During TC2, all participants surprisingly achieved total ovulation inhibition (125 / 125 [100%]).

[0081] The numbers and percentages of participants who presented no ovarian activity or minimal ovarian activity (Hoogland score 1-2) were 19 (57.6%), 17 (56.7%), 26 (76.5%) and 26 (83.9%) in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively, in TC1 and 15 (48.4%), 19 (63.3%), 28 (84.8%) and 27 (87.1%) in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively, in TC2. The numbers and percentages of participants who presented residual ovarian activity (Hoogland score 3-4) were 13 (39.4%), 13 (43.3%), 8 (23.5%), and 5 (16.1%) in the Cerazet, LNG VDS 75, 125, and 150 treatment groups, respectively, in TC1, and 16 (51.6%), 11 (36.7%), 5 (15.2%), and 4 (12.9%) in the Cerazet, LNG VDS 75, 125, and 150 treatment groups, respectively, in TC1. Petition 870250084815, dated 09 / 19 / 2025, page 26 / 146 21 / 117 TC2.

[0082] Only 1 (0.8%) participant had a positive result on the Landgren test during TC1. This participant was treated with Cerazet. No positive results on the Landgren score were observed in TC2 in either group.

[0083] In summary, the data from this clinical study convincingly show that levonorgestrel administered via a delivery device according to the present invention effectively inhibited ovulation at all three release rates, namely 75 pg / day, 125 pg / day and 150 pg / day, regardless of the individual's BMI.

[0084] In addition, the safety profile of LNG VDS was acceptable, and no serious treatment-emergent adverse events were observed during the trial.

[0085] The present invention, therefore, relates in one aspect to levonorgestrel for use in a method for providing contraception in a female individual, comprising administering levonorgestrel to said individual continuously, wherein the daily amount of levonorgestrel administered is from about 60 pg / day to about 100 pg / day, wherein the route of administration is vaginal administration.

[0086] In one embodiment, the average daily amount of levonorgestrel administered is approximately 75 pg / day, where the route of administration is vaginal administration.

[0087] As described above, previous studies have shown that Levonorgestrel 115 pg / day was the lowest effective dose for consistent inhibition of ovulation when administered orally. Levonorgestrel, when administered orally, is known to be completely absorbed after oral administration, leading to a bioavailability of almost 100% and is not subject to metabolism. Petition 870250084815, dated 09 / 19 / 2025, page 27 / 146 22 / 117 first pass.

[0088] Surprisingly, it has now been found that the very low dose of Levonorgestrel of 75 pg / day, when administered vaginally, completely or substantially completely inhibited ovulation.

[0089] It is known that ovarian suppression is dose-dependent; the higher the doses of LNG, the greater the ovarian suppression and the lower the estradiol levels achieved. Surprisingly, with a lower dose of levonorgestrel, such as 75 pg / day of levonorgestrel, 100% inhibition of ovulation is observed in all study groups, including individuals with a BMI > 30 kg / m2. Administering such a low dose of levonorgestrel is highly advantageous, as fewer side effects are expected.

[0090] As described above, one of the main side effects is caused by estrogen suppression, due to the administration of progestogen-only preparations, which can lead to the occurrence of undesirable hypoestrogenic side effects, in particular bone loss. Although tissues vary in their sensitivity to estradiol, an average estradiol concentration between 30 and 45 pg / ml is considered sufficient to prevent bone loss. (13).

[0091] Thus, it is essential to ensure a good balance between estrogen suppression and the contraceptive effect, because estradiol levels must be maintained within a certain safe range in order to avoid the undesirable side effect of bone density loss.

[0092] It was found that estrogen suppression caused by administering approximately 75 pg / day of LNG after two treatment cycles is within the desirable safety range, i.e., above 30 pg / ml.

[0093] The clinical study data showed that the concentration Petition 870250084815, dated 09 / 19 / 2025, p. 28 / 146 23 / 117 mean (SD) estradiol was 97.1 (84.3) pg / mL, 59.3 (40.2) pg / mL, 37.3 (21.2) pg / mL and 32.1 (12.1) pg / mL in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively, in TC1, and 66.5 (41.6) pg / mL, 48.0 (21.4) pg / mL, 30.4 (10.4) pg / mL and 26.8 (8.2) pg / mL in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively, in TC2.

[0094] Serum estradiol levels observed for the three doses of levonorgestrel IVR after two cycles of administration tested resulted in the lowest dose of Levonorgestrel 75 μg / day of LNG after two cycles of treatment leading to less estrogen suppression than the higher doses of 125 pg / day and 150 μg / day and therefore less effect on bone loss.

[0095] In another modality, the reduction in plasma estradiol levels is also related to the improvement of other conditions, such as premenstrual syndrome, hypermenorrhea, and also the improvement of other pathologies that are considered estrogen-dependent, such as uterine fibroids and subserosal endometrial polyps.

[0096] In particular, estrogen suppression is directly related to the improvement of endometriosis. Estrogens play a fundamental role in the pathophysiology of endometriosis, as they promote the implantation of endometrial tissue in the peritoneum, have proliferative and anti-apoptotic effects on endometrial cells, and stimulate local and systemic inflammation (21, 22). Barbieri explained that estradiol levels should be around 40 to 60 pg / ml to treat endometriosis (13).

[0097] It was found that estrogen suppression caused by administering approximately 75 pg / day of LNG after two treatment cycles is within the desirable range for treating endometriosis, i.e., 40 to 60 pg / ml, as explained above. Petition 870250084815, dated 09 / 19 / 2025, page 29 / 146 24 / 117 DEFINITIONS

[0098] As used herein in this patent application, the term “amenorrhea” refers to the absence / lack of bleeding / breakthrough bleeding for at least 56 days or two administration cycles in a female individual, preferably a woman of reproductive age.

[0099] As used herein in this patent application, the term explosive release refers to a release rate over time of an active pharmaceutical ingredient in which the rate is not uniform but is generally higher over a given period of time, typically immediately after placement of the device containing the active pharmaceutical ingredient on the tissue.

[00100] As used herein in this patent application, the term complete ovulation inhibition refers to 100% inhibition of ovulation in an individual. The term substantially complete ovulation inhibition should be understood as being 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% inhibition of ovulation in an individual.

[00101] As used herein in this patent application, a contraceptive method or method for providing contraception refers to a method for preventing pregnancy.

[00102] As used herein in this patent application, the term “dysmenorrhea” refers to the medical term for painful menstrual periods, which are caused by uterine contractions. Primary dysmenorrhea refers to recurrent pain, while secondary dysmenorrhea results from disorders of the reproductive system.

[00103] The term dispersed, as used herein in this patent application, means that one or more active pharmaceutical ingredients form a dispersion in the core polymer or in the sheath polymer, such that they are partially or completely in the form of Petition 870250084815, dated 09 / 19 / 2025, p. 30 / 146 25 / 117 solid particles suspended and surrounded by a continuous phase.

[00104] As used herein in this patent application, the term dissolved means that one or more active pharmaceutical ingredients form a solution in the core polymer or sheath polymer, such that they are distributed in the core polymer or sheath polymer forming a homogeneous phase.

[00105] As used herein in this patent application, the terms “endometriosis” and “endometriosis-associated pelvic pain (EAPP)” refer to a chronic, estrogen-dependent disease characterized by the formation of endometriotic lesions outside the uterus, including the ovaries and other pelvic structures, and one of its most common symptoms, which is reported as pelvic pain, respectively. All subtypes of endometriosis are included, including superficial, cystic, deep infiltrating, abdominal wall, and catamenial endometriosis. The effectiveness of the management of endometriosis-associated pelvic pain (EAPP) can be assessed using different rating scales, such as the visual analog scale (VAS) or the numerical rating scale (NRS), as is generally known to specialists in the field (see, for example, Gerlinger et al. (2010) and Breivik et al. (2008)).Depending on the rating scale, for example, a difference of at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, at least 3.0 on an NRS scale of 0-10 for placebo can be considered clinically significant and as providing a real benefit to the patient.

[00106] As used herein in this patent application, the term “estrogen(s)” defines a group of steroid hormones that promote Petition 870250084815, dated 09 / 19 / 2025, page 31 / 146 26 / 117 comes the development and maintenance of the female characteristics of the body. Synthetic estrogens are widely known and are commonly used in oral contraceptives or to treat menopausal and menstrual disorders.

[00107] As used herein in this patent application, the term “levonorgestrel” or “LNG” refers to levonorgestrel itself, that is, the chemical entity identified by CAS Registry Number 797-63-7, levonorgestrel solvates, and levonorgestrel derivatives or prodrugs.

[00108] As used herein in this patent application, the term post-treatment cycle or post-treatment refers to the 28 days following the TC, beginning from day 1 after removal of the LNG VDS or day 1 without oral administration of Cerazet.

[00109] As used herein in this patent application, progestogen-only contraceptive or progestogen-only pill (also known as POP) means a pill or contraceptive comprising progestogens as the sole active contraceptive ingredients and not comprising any estrogen.

[00110] As used herein in this patent application, a therapeutically effective amount refers to an amount effective in dosages and for periods of time required to achieve the desired therapeutic outcome, such as one or more of the following therapeutic outcomes, such as a significant delay in the onset or progression of the disease; or a significant reduction in the severity of one or more symptoms. A therapeutically effective amount is also typically one in which any toxic or harmful effect of the active ingredient or pharmaceutical composition is outweighed by the therapeutically beneficial effects.

[00111] As used herein in this patent application, the term treatment cycle (TC) refers to a total of 56 treatment days. Petition 870250084815, dated 09 / 19 / 2025, page 32 / 146 27 / 117 continuous. Treatment Cycle 1 (TC1) refers to the first cycle consisting of 28 days and Treatment Cycle 2 (TC2) to the second cycle consisting of 28 days.

[00112] As used herein in this patent application, treatment, treating, or treating refers to: (i) preventing or delaying the occurrence of a disease, disorder, or condition in an individual who 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, that is, halting or delaying its development or progression; and / or (iii) alleviating the disease, disorder, or condition, that is, causing regression of the disease, disorder, and / or condition. In certain embodiments, the term refers to the improvement or eradication of a disease or symptoms associated with a disease.

[00113] As used herein in this patent application, vaginal administration and intravaginal administration may be used interchangeably. They refer to the administration of a compound, preferably levonorgestrel, through the vaginal mucosa. It should be understood that vaginal administration does not include intrauterine administration, such as, for example, through an intrauterine device (IUD), which is inserted into the uterus. Vaginal administration may be carried out through a device, such as, for example, an intravaginal ring (IVR), which is placed inside the vaginal canal.

[00114] As used herein in this patent application, zero order or near zero order means that a substantially constant amount or a constant amount of drug per unit of time is released during a given period of time. For the purposes of the invention, the term substantially constant amount is as defined by Higuchi's formula, see Journal Pharmaceutical Sciences 1963, vol. 52, 1145-1149. Petition 870250084815, dated 09 / 19 / 2025, p. 33 / 146 28 / 117 METHODS OF THE PRESENT INVENTION

[00115] The present invention relates in one aspect to levonorgestrel for use in a method for providing contraception in a female individual, comprising administering levonorgestrel to said individual continuously, wherein the daily amount of levonorgestrel administered is from about 60 pg / day to about 100 pg / day.

[00116] In one embodiment, the present invention relates to levonorgestrel for use in a method for providing contraception in a female individual, comprising administering levonorgestrel to said individual continuously, wherein the average daily amount of levonorgestrel administered is about 75 pg / day, wherein the route of administration is vaginal administration.

[00117] It has been surprisingly demonstrated that the average dose of 75 pg / day, when administered intravaginally, provides complete or substantially complete inhibition of ovulation. At the same time, the dose of 75 pg / day, when administered intravaginally, provides less estrogen suppression than the higher doses tested after two cycles of administration, thus decreasing the undesirable side effects caused by estrogen suppression, such as bone loss.

[00118] It was also found that the estrogen suppression caused by the average administration of about 75 pg / day of LNG after two treatment cycles is within the desirable range for treating endometriosis, i.e., 40 to 60 pg / ml, as explained above.

[00119] Therefore, the present invention, in another aspect, relates to levonorgestrel for use in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea in a female individual, comprising administering levonorgestrel to said individual continuously, wherein the daily amount Petition 870250084815, dated 09 / 19 / 2025, p. 34 / 146 29 / 117 The dose of levonorgestrel administered is approximately 60 pg / day to approximately 160 pg / day, preferably where the route of administration is vaginal administration.

[00120] In one embodiment, the present invention relates to levonorgestrel for use in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea in a female individual, comprising administering levonorgestrel to said individual continuously, wherein the average daily amount of levonorgestrel administered is from about 75 pg / day to about 150 pg / day.

[00121] In one embodiment, the present invention relates to levonorgestrel for use in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea in a female individual, comprising administering levonorgestrel to said individual continuously, wherein the average daily amount of levonorgestrel administered is about 75 pg / day, about 125 pg / day or about 150 pg / day, preferably where the route of administration is vaginal administration.

[00122] In one embodiment, the average daily amount of levonorgestrel administered is about 75 pg / day to about 125 pg / day.

[00123] In an additional preferred embodiment, said treatment also provides contraception. As described in more detail above, administration of all three dosages in the clinical study provided complete or substantially complete inhibition of ovulation.

[00124] In a preferred embodiment of the methods of the present invention, the route of administration is transmucosal, preferably vaginal administration.

[00125] In a further embodiment of the method of the present invention, no additional contraceptive ingredient is administered to Petition 870250084815, dated 09 / 19 / 2025, page 35 / 146 30 / 117 female individuals at the same time.

[00126] In a preferred embodiment of the method of the present invention, no estrogen is administered to the female subject at the same time.

[00127] In one embodiment of the method of the present invention, the administration of levonorgestrel as described above herein, in this patent application, induces amenorrhea.

[00128] The present invention, in another aspect, relates to levonorgestrel for use in a method for treating other pathologies considered estrogen-dependent, such as uterine fibroids and subserosal endometrial polyps. USES

[00129] In a further aspect, the present invention relates to the use of Levonorgestrel as a contraceptive, comprising the continuous administration of Levonorgestrel in an amount of about 60 pg / day to about 200 pg / day to a female individual, wherein the route of administration is vaginal administration.

[00130] In one embodiment thereof, the present invention relates to the use of Levonorgestrel as a contraceptive, comprising the continuous administration of Levonorgestrel in an average amount of between about 75 pg / day to 150 pg / day to a female individual, wherein the route of administration is vaginal administration.

[00131] In one embodiment of the aforementioned aspect, the present invention relates to the use of Levonorgestrel as a contraceptive, comprising the continuous administration of Levonorgestrel in an average amount of about 75 pg / day, about 125 pg / day, or about 150 pg / day to a female individual, preferably where the route of administration is vaginal administration.

[00132] In a further embodiment of the use of the present invention, no additional contraceptive ingredient, preferably Petition 870250084815, dated 09 / 19 / 2025, p. 36 / 146 31 / 117 no estrogen is administered to the female individual at the same time.

[00133] In one embodiment of the use of the present invention, said administration of Levonorgestrel also induces amenorrhea.

[00134] In a preferred form of levonorgestrel for use in a method or with the use of levonorgestrel, ovulation is recovered in more than 80% of female subjects within 28 days post-treatment. In contrast, in the Cerazet treatment group, ovulation is recovered in only 69.7% of female subjects within 28 days post-treatment. DEVICE

[00135] In a further aspect, the present invention relates to a drug delivery device comprising (a) a core comprising a polymer; (b) a sheath substantially or completely surrounding said core; the sheath referred to comprising a polymer; (c) Levonorgestrel dissolved or dispersed in said core and / or said sheath, wherein the total amount of Levonorgestrel present in said core and / or said sheath is between about 9 mg and about 11 mg.

[00136] In one embodiment, the total amount of levonorgestrel present in said core and / or said sheath is approximately 10 mg.

[00137] In one embodiment of the aforementioned aspect, the polymer is selected from low-density polyethylene, ethylene vinyl acetate copolymers, styrene-butadiene-styrene copolymers, polyurethanes, poly(dimethyl siloxane), or silicone polyether amide copolymer, silicone, silicone-poly(carbonate urethane), poly(carbonate urethane), and silicone-poly(ether urethane), or combinations thereof. Petition 870250084815, dated 09 / 19 / 2025, p. 37 / 146 32 / 117

[00138] In one embodiment, the core polymer is a polyurethane and the sheath polymer is an ethylene-vinyl acetate copolymer.

[00139] In one embodiment, the ethylene-vinyl acetate copolymer of the sheath comprises a vinyl acetate content of between 10 and 40% w / w, preferably 15 to 30% w / w.

[00140] In one embodiment, the present invention relates to a drug delivery device comprising (a) a core comprising a polyurethane; (b) a sheath substantially or completely enclosing said core, said sheath comprising ethylene vinyl acetate copolymer (EVA) with a vinyl acetate content of between 10 and 40% w / w, preferably 15 to 30% w / w; (c) Levonorgestrel dissolved or dispersed in said core and / or said sheath, wherein the total amount of Levonorgestrel present in said core and / or said sheath is about 10 mg.

[00141] In a further embodiment, the release device comprises (a) a core comprising a polyurethane; (b) a sheath substantially or completely enclosing said core, said sheath comprising ethylene vinyl acetate copolymer with a vinyl acetate content of about 18% w / w; (c) Levonorgestrel dissolved or dispersed in said core and / or said sheath, wherein the total amount of Levonorgestrel present in said core and / or said sheath is about 10 mg. Petition 870250084815, dated 09 / 19 / 2025, p. 38 / 146 33 / 117

[00142] The core of the device comprises a polyurethane. Polyurethane (PU) is a polymer composed of a chain of organic units linked by carbamate (urethane) bonds. Examples of suitable polyurethanes which can be used as core polymers include, without limitation, aliphatic polyether-based thermoplastic polyurethanes, hydrophilic aliphatic polyether-based thermoplastic polyurethanes, aromatic polyether-based thermoplastic polyurethanes, aliphatic polycarbonate-based thermoplastic polyurethanes, aromatic polycarbonate-based thermoplastic polyurethanes, aromatic polyether-based polyurethane elastomers, thermoplastic polyether poly(urethanes), thermoplastic polyether silicone polyurethanes, thermoplastic polycarbonate silicone polyurethanes and hydrophilic thermoplastic polyurethane elastomers, or combinations thereof.Suitable commercially available polyurethanes include, without limitation, Tecophilic®, Tecoflex®, Tecothane®, Carbothane®, Chronothane®, Elasthane®, Pursil®, Hydrothane® and PATHWAY®. Hydrothane® AL25 80A and PATHWAY® PY-PT80AE25 polyurethanes are preferred.

[00143] PATHWAY PY-PT80AE25 is an aliphatic thermoplastic polyurethane, based on polyether, supplied by LUBRIZOL.

[00144] Hydrothane® AL25 80A is as disclosed in the Patent US9872829 B2.

[00145] In one embodiment, the core polymer comprises at least 50% polyurethane. In one embodiment, the core comprises at least 60% polyurethane. In one embodiment, the core comprises at least 70% polyurethane. In one embodiment, the core comprises at least 80% polyurethane. In one embodiment, the core comprises at least 90% polyurethane. In one embodiment, the core comprises at least 95% polyurethane. In one embodiment, the core consists essentially of polyurethane, that is, the core comprises from 50 to 100%, more particularly 75 to 100% polyurethane. Petition 870250084815, dated 09 / 19 / 2025, p. 39 / 146 34 / 117 no. The percentages above refer to percentages by weight (weight of polyurethane relative to the weight of the core).

[00146] The core may additionally comprise one or more of the following additives: release-modifying substances, including, without limitation, polyethyleneglycerol, glucose, glycine, ascorbic acid, hydroxyethylcellulose, croscarmellose, lactose; fillers, including, without limitation, high surface area fumed and precipitated silicas, clays such as kaolin, ground quartz, diatomaceous earth, calcium carbonate, barium sulfate, iron oxide, titanium dioxide and carbon black; antioxidants, including, without limitation, octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (Irganox®), ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), citric acid (CA), butylated hydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), and propyl gallate 30 (PG) and alpha-tocopherol; lubricants, including, without limitation, irgawax, talc, aerosil and stearates, such as magnesium stearate;and excipients, including, without limitation, water-soluble or water-swelling polysaccharides such as croscarmellose (cross-linked carboxymethylcellulose) or hydroxyethylcellulose, glucose, lactose or other mono- or disaccharides, or their water-soluble salts, proteins such as gelatin, non-ionic surfactants, bile salts, organic solvents such as ethoxydiglycol, polyethylene glycol and fatty acid esters, or combinations thereof.

[00147] As used herein in this patent application, the expression "a sheath substantially enclosing the core" means that at least 90% of the surface area of ​​the core, more particularly 95%, more particularly 100%, is enclosed by the sheath. In a preferred embodiment, the ethylene vinyl acetate copolymer sheath completely encloses the core.

[00148] As mentioned above, the device sheath comprises ethylene vinyl acetate copolymer (EVA). EVA is a Petition 870250084815, dated 09 / 19 / 2025, p. 40 / 146 35 / 117 semicrystalline copolymer of ethylene and vinyl acetate (VA) monomers. The specific ethylene vinyl acetate copolymer of the sheath to be used will depend on the desired drug flow and can be any commercially available ethylene vinyl acetate copolymer. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the sheath comprises an EVA copolymer with a vinyl acetate (VA) content between 1 and 50% w / w, more particularly from 10 to 40% w / w, and even more particularly from 15 to 30% w / w. In a preferred embodiment, the EVA sheath copolymer has a vinyl acetate content of 15 to 20% w / w, more preferably about 18% w / w.

[00149] For the purposes of the invention, vinyl acetate content refers to the vinyl acetate content by weight based on the total weight of the ethylene vinyl acetate copolymer.

[00150] Commercially available suitable ethylene vinyl acetate copolymers include products available under the trade names: Elvax®, VitalDose®, Evatane®, Lupolen V®, Movriton®, Ultrathene®, Ateva®, Vestypar®, Dupont 760, Equistar UE637-000, Huntsman PE1903, and F 100309 (Exxon Mobil).

[00151] In one embodiment, the sheath comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of ethylene vinyl acetate. In another embodiment, the sheath consists essentially of ethylene vinyl acetate, that is, the sheath comprises from 50 to 100%, more particularly from 75 to 100% of ethylene vinyl acetate. The percentages above refer to percentages by weight (weight of ethylene vinyl acetate relative to the weight of the sheath).

[00152] The sheath may additionally comprise one or more of the following additives: some release-modifying substances Petition 870250084815, dated 09 / 19 / 2025, p. 41 / 146 36 / 117 tion, including, without limitation, polyethyleneglycerol, glucose, glycine, ascorbic acid, hydroxyethylcellulose, croscarmellose, lactose; fillers, including, without limitation, high surface area fumed and precipitated silicas, clays such as kaolin, ground quartz, diatomaceous earth, calcium carbonate, barium sulfate, iron oxide, titanium dioxide and carbon black; antioxidants, including, without limitation, octadecyl-3(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (Irganox®), ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), citric acid (CA), butylated hydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), propyl gallate (PG) and alpha-tocopherol; lubricants, including, without limitation, irgawax, talc, aerosil and stearates such as magnesium stearate;and excipients, including, without limitation, water-soluble or water-swelling polysaccharides such as croscarmellose (cross-linked carboxymethylcellulose) or hydroxyethylcellulose, glucose, lactose or other mono- or disaccharides, or their water-soluble salts, proteins such as gelatin, non-ionic surfactants, bile salts, organic solvents such as ethoxydiglycol, polyethylene glycol and fatty acid esters, or combinations thereof.

[00153] In a particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, the core weight represents 70 to 95% by weight of the total weight of the device, and the sheath weight represents 5 to 30% by weight of the total weight of the device, the total weight of the device being 100%.

[00154] In a preferred embodiment, LNG is present in the core. In a more preferred embodiment, LNG is present in the core at a concentration lower than its saturation concentration at 25 °C.

[00155] Levonorgestrel has been found to be very soluble in the core polymer, particularly at the concentrations mentioned below. Petition 870250084815, dated 09 / 19 / 2025, p. 42 / 146 37 / 117 of the. Thus, the LNG is present at a concentration lower than its saturation concentration, and therefore there is no tendency for the LNG to crystallize over time, at any practical temperature. As a result, the devices of the invention are stable when stored at room temperature for long periods of time, in particular for at least 6 months. This has the advantage that the devices do not require expensive storage and transport below room temperature.

[00156] In a preferred embodiment of the drug delivery device of the present invention, the core comprises a hydrophilic thermoplastic polyurethane, preferably PATHWAY® PYPT80AE25 and levonorgestrel at a concentration of 0.46% w / w 0.51% w / w and an EVA polymer sheath with a vinyl acetate content of 18% (w / w).

[00157] It has been found that when the devices of the invention, in particular the devices mentioned above, are subjected to tissue or in vitro delivery media, levonorgestrel is eluted in zero or near-zero order, thereby minimizing potential peak / trough fluctuations and side effects, while maximizing the amount of time that drug concentrations remain within the therapeutic window (efficacy). By zero or near-zero order, it is indicated here in this patent application that a substantially constant amount or a constant amount of drug per unit of time is released during a given period of time. For the purposes of the invention, the term substantially constant amount is as defined by Higuchi's formula, see Journal Pharmaceutical Sciences 1963, vol. 52, 1145-1149.

[00158] Additionally, the aforementioned devices also exhibit low initial explosive release. The term explosive release refers to a release rate over time of a Petition 870250084815, dated 09 / 19 / 2025, page 43 / 146 38 / 117 active pharmaceutical ingredient where the rate is not uniform, but is generally higher over a given period of time, typically immediately after placement of the device containing the active pharmaceutical ingredient in the tissue.

[00159] In one embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein said device releases: - no more than about 150 pg, preferably no more than about 130 pg of levonorgestrel during an initial 24-hour release period, - approximately 60 pg to 90 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2.

[00160] In one embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein said device releases: - approximately 70 pg to 150 pg, preferably approximately 70 pg to 130 pg of levonorgestrel during an initial 24-hour release period, - approximately 60 pg to 90 pg, preferably approximately 60 pg to 80 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2 medium.

[00161] In one mode, the device releases - approximately 90 pg to 140 pg of levonorgestrel during an initial 24-hour release period, Petition 870250084815, dated 09 / 19 / 2025, page 44 / 146 39 / 117 - approximately 65 pg to 80 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2.

[00162] In one aspect of the above modalities, at least 56 pg, preferably around 56 pg to around 90 pg of levonorgestrel are released on day 28.

[00163] In one aspect of the above preferred modalities, the daily release of levonorgestrel during the 28-day treatment cycle, including the initial 24-hour release period and the subsequent 27 days after the initial 24-hour release period, is not less than about 56 pg per day.

[00164] It is further preferred that the average daily release of levonorgestrel over the 28-day treatment cycle, including the initial 24-hour release period and the subsequent 27 days after the initial 24-hour release period, be from about 60 pg to about 100 pg, preferably from about 70 pg to about 80 pg, more preferably about 75 pg per day.

[00165] In a preferred embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein said device releases: - no more than 250 pg of levonorgestrel during an initial 24-hour release period, - approximately 90 pg to 150 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2.

[00166] In a further embodiment, the present invention refers Petition 870250084815, dated 09 / 19 / 2025, page 45 / 146 40 / 117 refers to a drug delivery device comprising levonorgestrel, wherein said device releases: - approximately 100 pg to approximately 200 pg, preferably approximately 110 pg to approximately 170 pg of levonorgestrel during an initial release period of 24 hours, - approximately 90 pg to 150 pg, preferably approximately 90 pg to 140 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2 medium.

[00167] In a preferred mode, the device releases: - no more than 220 pg of levonorgestrel during an initial 24-hour release period, - approximately 105 pg to 135 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2.

[00168] In one aspect of the above preferred modalities, more than about 85 pg to 95 pg of levonorgestrel. In one aspect of the above preferred modalities, more than about 28.

[00169] In one aspect of the above preferred modalities, the daily release of levonorgestrel during the 28-day treatment cycle, including the initial 24-hour release period and the subsequent 27 days after the initial 24-hour release period, is not less than about 87 pg per day.

[00170] It is additionally preferred that the average daily release of levonorgestrel over the 28-day treatment cycle, including the initial 24-hour release period and the subsequent 27 days Petition 870250084815, dated 09 / 19 / 2025, pp. 46 / 146 41 / 117 after the initial 24-hour release period, either from about 90 pg to about 160 pg, preferably from about 105 pg to about 140 pg, more preferably about 125 pg per day.

[00171] In a preferred embodiment, the present invention relates to a drug delivery device comprising levonorgestrel, wherein said device releases: - no more than 300 pg of levonorgestrel during an initial 24-hour release period, - approximately 110 pg to 180 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2.

[00172] In a preferred mode, the aforementioned device releases: - no more than 250 pg, preferably around 170 pg to around 220 pg of levonorgestrel during an initial 24-hour release period, - approximately 110 pg to 180 pg, preferably approximately 120 pg to approximately 170 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2 medium.

[00173] In one aspect of the above preferred modalities, more than about 100 pg to 110 pg, preferably more than about 105 pg of levonorgestrel are released on day 28.

[00174] In one embodiment, the daily release of levonorgestrel during the 28-day treatment cycle, including the initial 24-hour release period and the subsequent 27 days after the period of Petition 870250084815, dated 09 / 19 / 2025, page 47 / 146 42 / 117 initial 24-hour release, on no day is less than approximately 105 pg per day.

[00175] It is further preferred that the average daily release of levonorgestrel over the 28-day treatment cycle, including the initial 24-hour release period and the subsequent 27 days after the initial 24-hour release period, be from about 120 pg to about 200 pg, preferably about 150 pg per day.

[00176] In a preferred embodiment, the release of levonorgestrel from the delivery device as described herein, in this patent application, follows zero-order kinetics after the initial 24-hour release period, i.e., the amount of levonorgestrel released each day is constant.

[00177] In one embodiment, constant release means that the amount of levonorgestrel released per day can vary up to a maximum of 20 to 25%.

[00178] In a preferred embodiment, the intravaginal ring according to the present invention does not comprise an additional active ingredient.

[00179] In one embodiment of the drug delivery device of the present invention, levonorgestrel is present in the core at a concentration of about 0.20 to 1.00% by weight based on the total weight of the core.

[00180] In a further embodiment, the sheath has a thickness between about 5 to 500 pm, preferably between about 50 to 200 pm.

[00181] In one embodiment, the drug delivery device of the present invention provides a mean Cmax value for levonorgestrel of less than 1 ng / ml after a 28-day treatment cycle and less than 0.7 ng / ml after two 28-day treatment cycles, and a mean AUC (0.-t) value of less than 350 ng / ml after a cycle of Petition 870250084815, dated 09 / 19 / 2025, pp. 48 / 146 43 / 117 28-day treatment and less than 370 h*ng / ml after two 28-day treatment cycles in a female subject, after the delivery device had been placed intravaginally inside the subject's body.

[00182] In another embodiment, the drug delivery device of the present invention provides a mean Cmax value for levonorgestrel of less than 1.6 ng / ml after a 28-day treatment cycle and less than 1 ng / ml after two 28-day treatment cycles, and a mean AUC (0-t) value of less than 580 h*ng / ml after a 28-day treatment cycle and less than 540 h*ng / ml after two 28-day treatment cycles in a female subject, after the delivery device has been placed intravaginally inside the subject's body.

[00183] In another embodiment, the drug delivery device of the present invention provides an average Cmax value for levonorgestrel of less than 1.5 ng / ml after a 28-day treatment cycle and less than 1 ng / ml after two 28-day treatment cycles, less than (0-t) less than 480 h*ng / ml after a 28-day treatment cycle and less than 540 h*ng / ml after two 28-day treatment cycles each.

[00184] In one embodiment, the drug delivery device of the present invention has a shape selected from a spiral shape (helical shape) or a ring shape, preferably wherein the drug delivery device has a ring shape. The various shapes are represented in Figure 9 A) and B). In a preferred embodiment, the device is a vaginal ring. More particularly, the ring-shaped device has an outer diameter between 50 and 60 mm, more particularly from 52 to 56 mm, and an inner diameter of 40 to 48 mm, more particularly from 44 to 48 mm, and has a cross-sectional diameter between 2.5 and 8 mm, preferably 4 mm. Petition 870250084815, dated 09 / 19 / 2025, page 49 / 146 44 / 117

[00185] Preferably, this dosage form should not contain any estrogen which, although beneficial for the contraceptive effect, may be harmful for any estrogen-induced diseases.

[00186] It is contemplated that any features described herein in this patent application may optionally be combined with any embodiment of any medical or contraceptive use, composition, kit, contraceptive methods, treatment methods or method of manufacture of the invention; and any embodiment discussed in this specification may be implemented with respect to any of these. It will be understood that the particular embodiments described herein in this patent application are shown by way of illustration and not as limitations of the invention.

[00187] All publications and patent applications are incorporated herein, to this patent application, by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

[00188] The use of the word one or an may mean one, but is also consistent with the meaning of one or more, at least one, and one or more of one. The use of the term other may also refer to one or more. The use of the term or in the claims is used to mean and / or, unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive.

[00189] As used in this specification and claim(s), the words comprising (and any form of comprising, such as comprise and comprise), having (and any form of having, such as has and have), including (and any form of including, such as includes and include) or containing (and any form of containing, such as contains and contain) are inclusive or open-ended and do not exclude additional elements or method steps not mentioned. The term “comprises” also encompasses and expressly discloses Petition 870250084815, dated 09 / 19 / 2025, p. 50 / 146 45 / 117 The terms consist of and essentially consist of. As used herein in this patent application, the expression essentially consisting of limits the scope of a claim to the materials or steps specified and those that do not materially affect the basic and novel feature(s) of the claimed invention. As used herein in this patent application, the expression consisting of excludes any element, step, or ingredient not specified in the claim, except, for example, impurities normally associated with the element or limitation.

[00190] The term or combinations thereof, as used herein in this patent application, refers to all permutations and combinations of the listed items preceding the term. For example, A, B, C or combinations thereof is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, combinations containing repetitions of one or more items or terms are expressly included, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. Those skilled in the art will understand that there is typically no limit to the number of items or terms in any combination unless the contrary is apparent from the context.

[00191] As used herein in this patent application, approximation words such as, without limitation, about, around, approximately refer to a condition which, when so modified, is understood not necessarily to be absolute or perfect, but would be considered sufficiently close by those with ordinary skill in the art to warrant designation of the condition as being present. The extent to which the description may vary will depend on how great a change may be instituted and yet have a person skilled in the art recognize the modified feature. Petition 870250084815, dated 09 / 19 / 2025, page 51 / 146 46 / 117 remains as still having the required characteristics and capabilities of the unmodified characteristic. In general, but subject to the preceding discussion, a numerical value here in this patent application, which is modified by an approximation word such as approximately, may vary from the stated value by ±1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%. Consequently, the term approximately may mean the stated value ± 5% of its value, preferably the stated value ± 2% of its value, most preferably the term approximately means exactly the stated value (± 0%).

[00192] The following examples serve to illustrate the present invention and should not be interpreted as limiting its scope. EXAMPLES Example 1:

[00193] Vaginal delivery systems (VDS) comprise the following composition: Table 1: Formulation for the three different VDS comprising different dosage potencies. Ingredients Function Composition Quantity 150 pg / day 125 pg / day 75 pg / day % mg % mg % mg Levonorgestrel Active substance 0.51 10.80 0.51 10.80 0.46 9.72 Polyurethane Carrier polymer 94.31 1994.03 92.59 1952.90 86.73 1813.41 Ethylene vinyl acetate 18% vinyl acetate Release Control Polymer 5.18 109.60 6.98 145.40 12.81 267.75 Total 100.0 2114.4 100.0 2109.1 100.0 2090.9 Manufacturing process:

[00194] The VDS were manufactured using a process comprising the following steps: Petition 870250084815, dated 09 / 19 / 2025, page 52 / 146 47 / 117 1) Polymer drying: Drying of the thermoplastic polyurethane elastomer, PY-PT80AE25, for at least 6 hours in an air dryer at 80 °C. 2) Mixing: A GlenMills T2F turbula mixer was used to homogeneously mix the materials. The following materials were added to the container in the following order: a) Fraction A of the thermoplastic polyurethane elastomer, b) Micronized levonorgestrel, c) Fraction B of the thermoplastic polyurethane elastomer and mixed for 30 minutes at 13 rpm. 3) Compounding: A Leistritz ZSE18 twin-screw extruder was used to compound the LNG into the thermoplastic polyurethane elastomer. The dry-mixed LNG and polymer were fed into the extruder via a gravimetric feeder and extruded through a filament die with a circular orifice. The extruder's process zones were set to 130–150 °C and the screw speed to 120–180 rpm. The extruded filaments were cooled in a water bath and fed directly into the pelletizing unit. 4) Benchtop pelleting: The cooled fiber was pulled directly through the pelletizing unit and pelletized into 3.0 mm long pellets. 5) Drying of the pellets: The polymer pellets loaded with API were dried for at least 4 hours in an air dryer at 80 °C. 6) Mixing: the dry pellets were mixed for 5 minutes at 13 rpm. 7) Co-extrusion: The API-loaded polymer pellets were extruded as the core material with ethylene-vinyl acetate copolymer pellets (VA content of 18% w / w) as the skin material through a coaxial extrusion configuration. Petition 870250084815, dated 09 / 19 / 2025, p. 53 / 146 The 48 / 117 coaxial extrusion system comprises two extruders, two melt pumps, a co-extrusion die, and connecting pipes. The core extruder process temperatures were set to 130–150 °C. The core material output was controlled by a melt pump set to 42%. The skin extruder process temperatures were set to 120–150 °C. The skin material output was controlled by a melt pump set to 30 rpm. The core sheath fiber exited the co-extrusion die and was cooled in a vertical water bath. The water temperature was set to 9 °C. 8) Filament cutting: The fiber was pulled at 3.8 m / min by a drag conveyor before being cut into 157 mm segments / filaments. The fiber diameter of 4 mm was continuously monitored by a laser gauge. 9) Welding: the two ends of the filament were thermally joined. In the welding equipment, the edges of the 157 mm filaments are fused, forcing the fiber to assume a toroidal shape, resulting in an intravaginal core sheath ring with an outer diameter of 54 mm, an inner diameter of 46 mm, and a cross-sectional diameter of 4 mm.

[00195] Figures 1, 2, and 3 and Tables 2 to 4 below show the in vitro elution profile for levonorgestrel intravaginal rings above 75, 125, and 150 mg / day. The in vitro release rate of levonorgestrel for example 1 was determined by immersing the samples in 200 mL (for day 1) and 100 mL (for days 2-28) of 0.2M aqueous sodium acetate buffer solution with 1.0% sodium lauryl sulfate (SLS) surfactant and adjusted to pH 4.2 at 37 °C under continuous stirring at 60 rpm. The levonorgestrel concentration was determined daily by HPLC using a Waters XBridge C18, flow rate of 1.0 mL / min, and an injection volume of 25 μL. The detection was performed using UV detection at 240 nm. Petition 870250084815, dated 09 / 19 / 2025, page 54 / 146 Table 2: Individual Data, In vitro Elution Profile, LVDS 75 pg / day LNG 0.075 mg / day Vaginal Delivery System LNG Time (pg) Released Day V1 V2 V3 V4 V5 V6 Average Min Max SD 1 103 107 114 110 101 102 106 101 114 5.2 2 71 72 76 74 70 70 72 70 76 2.6 3 64 67 71 68 67 68 67 64 71 2.2 4 68 69 74 72 67 68 70 67 74 2.7 5 69 70 72 71 67 69 70 67 72 1.8 6 69 68 74 70 67 66 69 66 74 2.7 7 69 69 73 71 67 69 70 67 73 1.9 8 69 68 74 72 66 68 70 66 74 2.9 9 68 69 72 72 66 66 69 66 72 2.7 10 69 68 73 71 69 68 70 68 73 2.0 11 68 68 74 70 67 66 69 66 74 2.9 12 67 68 73 70 69 67 69 67 73 2.3 13 67 66 73 69 67 67 68 66 73 2.7 14 66 66 71 69 65 66 67 65 71 2.5 15 65 67 72 70 66 64 67 64 72 2.9 16 66 68 72 70 66 65 68 65 72 2.7 17 67 67 72 68 65 64 67 64 72 2.6 18 66 67 71 70 66 65 67 65 71 2.3 49 / 117 Petition 870250084815, dated 09 / 19 / 2025, page 55 / 146 Table 2: -continued LNG 0.075 mg / day Vaginal Delivery System LNG Time (pg) Released Day V1 V2 V3 V4 V5 V6 Average Min Max DP 19 65 67 71 69 66 67 68 65 71 2.1 20 66 67 71 68 67 65 68 65 71 2.0 21 69 67 71 69 69 65 68 65 71 2.2 22 65 67 71 70 65 63 67 63 71 3.2 23 65 65 70 67 65 65 66 65 70 2.1 24 64 66 72 69 64 64 66 64 72 3.3 25 67 65 70 69 67 66 67 65 70 2.1 26 65 63 69 66 61 61 64 61 69 3.1 27 63 63 69 67 63 64 65 63 69 2.6 28 65 65 69 67 65 64 66 64 69 2.0 Day 1 103 107 114 110 101 102 106 101 114 5.2 Day 2-27 67 67 72 70 66 66 68 66 72 2.4 Day 28 65 65 69 67 65 64 66 64 69 2.0 50 / 117 Petition 870250084815, dated 09 / 19 / 2025, page 56 / 146 Table 3: Individual Data, In vitro Elution Profile, LVDS 125 pg / day LNG 0.125 mg / day Vaginal Delivery System LNG Time (pg) Released Day V1 V2 V3 V4 V5 V6 Average Min Max DP 1 148 146 148 156 151 146 149 146 156 3.8 2 128 127 127 130 126 124 127 124 130 2.1 3 127 126 124 128 127 122 126 122 128 2.4 4 126 124 123 130 127 124 126 123 130 2.4 5 122 125 124 126 126 123 124 122 126 1.5 6 122 124 124 129 123 124 124 122 129 2.4 7 123 125 123 128 126 122 125 122 128 2.3 8 123 124 122 129 127 122 125 122 129 2.7 9 121 123 121 127 124 121 123 121 127 2.3 10 123 122 122 127 124 121 123 121 127 2.1 11 122 123 122 128 124 122 124 122 128 2.5 12 121 124 121 125 123 121 123 121 125 1.5 13 122 124 121 128 123 121 123 121 128 2.4 14 120 121 118 123 120 116 120 116 123 2.4 15 120 118 119 122 121 118 120 118 122 1.7 16 118 121 117 125 120 118 120 117 125 2.7 17 116 118 116 123 120 117 118 116 123 2.9 51 / 117 Petition 870250084815, dated 09 / 19 / 2025, p. 57 / 146 Table 3: -continued- LNG 0.125 mg / day Vaginal Delivery System Time LNG (pg) Released Day V1 V2 V3 V4 V5 V6 Average Min Max SD 18 117 120 119 122 120 117 119 117 122 2.2 19 117 117 119 122 118 117 118 117 122 1.9 20 116 115 115 119 115 117 116 115 119 1.7 21 111 112 113 114 114 113 113 111 114 1.0 22 110 111 110 118 113 109 112 109 118 3.2 23 109 112 110 113 111 108 110 108 113 1.9 24 106 109 106 110 108 108 108 106 110 1.5 25 106 107 105 111 106 106 107 105 111 2.1 26 105 106 104 108 106 104 106 104 108 1.8 27 102 103 107 109 104 104 105 102 109 2.5 28 99 101 102 106 101 101 102 99 106 2.4 Day 1 148 146 148 156 151 146 149 146 156 3.8 Day 2-27 117 118 117 122 119 117 119 117 122 1.9 Day 28 99 101 102 106 101 101 102 99 106 2.4 52 / 117 Petition 870250084815, dated 09 / 19 / 2025, page 58 / 146 Table 4: Individual Data, In vitro Elution Profile, LVDS 150 pg / day LNG 0.150 mg / day Vaginal Delivery System LNG Release Time (μg) Day V1 V2 V3 V4 V5 V6 Mean Min Max SD 1 202 193 192 192 206 187 195 187 206 7.2 2 183 178 176 190 187 172 181 172 190 6.8 3 181 175 170 173 179 165 174 165 181 6.0 4 182 176 173 188 185 168 179 168 188 7.6 5 185 174 177 185 183 164 178 164 185 8.3 6 180 172 173 172 182 162 174 162 182 7.0 7 178 174 174 184 178 165 176 165 184 6.1 8 178 167 166 168 174 163 169 163 178 5.6 9 170 165 162 168 172 160 166 160 172 4.9 10 166 159 162 177 173 157 166 157 177 8.0 11 169 157 164 171 167 155 164 155 171 6.3 12 166 159 158 169 166 153 162 153 169 6.2 13 164 155 156 154 165 153 158 153 165 5.0 14 150 144 145 157 155 140 148 140 157 6.5 15 155 148 152 160 154 144 152 144 160 5.6 16 152 148 146 150 152 144 149 144 152 3.3 17 150 144 146 154 150 139 147 139 154 5.4 18 147 139 140 154 148 138 144 138 154 6.3 53 / 117 Petition 870250084815, dated 09 / 19 / 2025, page 59 / 146 Table 4: -continued LNG 0.150 mg / day Vaginal Delivery System Time LNG (pg) Released Day V1 V2 V3 V4 V5 V6 Average Min Max DP 4.1 21 140 137 138 140 144 131 138 131 144 4.1 22 139 131 134 144 140 129 136 129 144 5.6 23 135 135 133 173 73 133 127 137 4.0 24 134 128 131 134 137 126 132 126 137 4.1 25 132 124 129 136 134 126 130 124 136 136 126 126 128 129 118 124 118 129 4.5 27 125 120 120 124 127 127 121 124 120 127 3.0 28 123 118 119 126 126 128 119 12 12 18 Dia 202 193 192 192 206 187 195 187 206 7.2 Days 2-27 157 150 151 158 158 146 153 146 158 5.0 Days 28 123 118 198 121 218 216 118 128 4.1 54 / 117 Petition 870250084815, of 19 / 09 / 2025, p. 60 / 146 55 / 117 Example 2:

[00196] A multicenter, phase 2, open-label, randomized clinical trial to evaluate the ovulation inhibition of 3 potencies of levonorgestrel (LNG) vaginal delivery system (VDS) dosage, releasing over 28 days on a continuous regimen, versus desogestrel (Cerazet®) was conducted as further detailed below: 1. Study Design 1.1. Objectives Primary Objective: • To evaluate the inhibition of ovulation measured by ovarian activity (follicular growth, serum estradiol and progesterone concentrations) of the levonorgestrel (LNG) vaginal delivery system (VDS) in treatment cycles (TCs) 1 and 2 compared to (Cerazet). Secondary Objectives: • To evaluate the influence of LNG VDS on cervical mucus and endometrial thickness. • To evaluate the impact of LNG VDS on blood levels of sex hormones. • To evaluate the safety and tolerability of LNG VDS, and the return of ovulation in a post-treatment cycle. 1.2. Methodology

[00197] Multicenter, open-label, randomized, phase 2 clinical trial to evaluate ovulation inhibition of 3 different dosage potencies (75 pg / day, 125 pg / day and 150 pg / day) of LNG VDS released over 28 days in a continuous regimen versus desogestrel (Cerazet) in healthy female subjects aged 18–35 years.

[00198] The study consists of 4 phases: • Screening phase (minimum of 4 weeks and maximum of 8 weeks if a washout cycle was necessary). Petition 870250084815, dated 09 / 19 / 2025, p. 61 / 146 56 / 117 • Pre-treatment cycle (28 days) and randomization. • Treatment cycle consisting of 56 days of treatment (2 cycles, 28 days per cycle). • Treatment cycle consisting of 56 days of treatment (2 cycles, 28 days per cycle) (28 days).

[00199] Overall, 268 individuals were screened, of whom 137 were randomized and 130 initiated study treatment (safety analysis set or SAS). Efficacy was assessed in a total of 128 participants comprising the full analysis set or FAS, and in 118 participants comprising the per-protocol set or PP. For the PK / PD analysis, 55 participants comprised the PK population (14 of them had a BMI > 30 kg / m2 and 41 had a BMI between >18 and <30 kg / m2). 1.3. Test product, dose and method of administration

[00200] LNG VDS was used for vaginal administration. Each LNG VDS contained approximately 10 mg of LNG which was designed to release 75 pg / day, 125 pg / day, or 150 pg / day of LNG. One LNG VDS was intended to last 28 continuous days. 1.4. Duration of treatment

[00201] The treatment was carried out for 56 days, that is, two consecutive Treatment Cycles (TC1 and TC2) each of 28 days. 1.5. Reference therapy, dose and method of administration

[00202] As a reference, Desogestrel (Cerazet) 75 pg film-coated tablets were used, administered orally for 28 consecutive days in each cycle. 2. EVALUATION CRITERIA 2.1. Primary Efficacy

[00203] Ovulation inhibition was determined by calculating the Hoogland Score, which combined follicle size measurement in mm by TVU and serum progesterone / estradiol concentration in Petition 870250084815, dated 09 / 19 / 2025, page 62 / 146 57 / 117 nmol / L (in the case of ovulation being suspected sonographically in TC1 or TC2, it was confirmed by blood progesterone levels and reflected by the Landgren Score).

[00204] Analysis of the primary outcome: ovulation inhibition (Yes, No) was analyzed using a logistic regression model to compare ovulation inhibition between treatment groups, in which BMI was included as a covariate. Adjusted odds ratios (ORs) with their two-sided 95% CIs were calculated. No hypothesis testing was performed. 2.2. Secondary Efficacy • The Insler Score in the pre-cycle, TC1 and TC2, and post-treatment cycle was evaluated whenever follicles had a diameter >13 mm. • Endometrial thickness was monitored throughout all cycles by TVUs. • Serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), estradiol, progesterone, and SHBG were analyzed. • The return of ovulation was evaluated in one post-treatment cycle.

[00205] Secondary outcome analysis: Secondary efficacy parameters were described with appropriate descriptive statistics for dichotomous, categorical, or continuous variables by treatment group and cycle. No hypothesis testing was performed. 2.3. Safety • Vital signs • Laboratory analysis • Incidence of adverse events (AEs) • • The pattern of vaginal bleeding was assessed through daily records in the individuals' diaries, therefore evaluating the Petition 870250084815, dated 09 / 19 / 2025, page 63 / 146 58 / 117 cycle control and the occurrence of intermediate bleeding. 2.4. PK Analysis

[00206] LNG PK parameters were correlated with SHBG levels and ovulation inhibition within a randomized subgroup of LNG recipients, consisting of 12 individuals with BMI >18 and <30 kg / m2 and 7 individuals with BMI > 30 kg / m2 per treatment arm (75 pg / day, 125 pg / day or 150 pg / day). The pharmacokinetic parameters of LNG were determined to correlate them with ovulation inhibition and SHBG levels in a subgroup of 55 individuals using LNG VDS, comprising 41 individuals with a BMI >18 and <30 kg / m2 and 14 individuals with a BMI > 30 kg / m2. 3. STATISTICAL METHOD

[00207] The analysis in this study was exploratory and primarily used descriptive statistical methods. In addition, exploratory statistical tests and modeling were used to highlight interesting aspects of the data. The descriptive statistics presented for continuous variables (Landgren Score, Insler Score, endometrial thickness, pituitary hormones, bleeding pattern, demographics and baseline characteristics, as well as safety parameters) were the number of individuals (n), mean (mean), median (median), standard deviation (SD), minimum (min) and maximum (max) and 1-3 quantiles at each scheduled visit.

[00208] The analysis in this study was exploratory and primarily used descriptive statistical methods. In addition, exploratory statistical tests and modeling were used to highlight interesting aspects of the data. Descriptive statistics were presented for continuous variables (Landgren score, Insler score, endometrial thickness, pituitary hormones, bleeding pattern, demographics, and baseline characteristics, as well as follow-up parameters). Petition 870250084815, dated 09 / 19 / 2025, page 64 / 146 59 / 117 trança) were the number of individuals (n), mean (mean), median (median), standard deviation (SD), minimum (min) and maximum (max) and 1-3 quantiles in each scheduled visit. 4. RESULTS AND EFFECTIVENESS ANALYSIS 4.1. Primary Effectiveness Assessment 4.1.1. Ovulation Inhibition

[00209] The results obtained regarding ovulation inhibition by treatment cycle and by treatment group are presented in Table 5 for FAS. In TC1, 127 (99.2%) participants showed ovulation inhibition in all treatment groups, and only 1 participant with a BMI >18 and <30 kg / m2 who was treated with Cerazet did not show ovulation inhibition. In TC2, ovulation inhibition was confirmed for all participants, regardless of treatment group and BMI. Petition 870250084815, dated 09 / 19 / 2025, page 65 / 146 Table 5: Ovulation Inhibition per Treatment Cycle - Logistic Regression Model All (N = 128) All (N = 23) Total analyzed n (%) Individuals with ovulation inhibition n (%) [1] [2] Total analyzed n (%) by BMI >30 Individuals with ovulation inhibition n (%) by BMI >30 [1] [2] Treatment Cycle 1 128 127 (99.2%) 23 23 (100.0%) Cerazette 33 (25.8%) 32 (97.0%) 6 (26.1%) 6 (100.0%) LNG VDS 75 30 (23.4%) 30 (100.0%) 4 (17.4%) 4 (100.0%) LNG VDS 125 34 (26.6%) 34 (100.0%) 7 (30.4%) 7 (100.0%) LNG VDS 150 31 (24.2%) 31 (100.0%) 6 (26.1%) 6 (100.0%) BMI < 18 BMI <30 105 (82.0%) 104 (99.0%) BMI >30 23 (18.0%) 23 (100.0%) Treatment Cycle 2 125 125 (100.0%) 22 22 (100.0%) Cerazette 31 (24.8%) 31 (100.0%) 6 (27.3%) 6 (100.0%) LNG VDS 75 30 (24.0%) 30 (100.0%) 4 (18.2%) 4 (100.0%) LNG VDS 125 33 (26.4%) 33 (100.0%) 6 (27.3%) 6 (100.0%) LNG VDS 150 31 (24.8%) 31 (100.0%) 6 (27.3%) 6 (100.0%) 60 / 117 Petition 870250084815, dated 09 / 19 / 2025, page 66 / 146 Table 5: -continued- All (N = 128) All (N = 23) Total analyzed n (%) Individuals with ovulation inhibition n (%) [1] [2] Total analyzed n (%) by BMI >30 Individuals with ovulation inhibition n (%) by BMI >30 [1] [2] BMI 18< BMI <30 103 (82.4%) 103 (100.0%) BMI >30 22 (17.6%) 22 (100.0%) Grouped [3] 128 127 (99.2%) 23 23 (100.0%) Cerazette 33 (25.8%) 32 (97.0%) 6 (26.1%) 6 (100.0%) LNG VDS 75 30 (23.4%) 30 (100.0%) 4 (17.4%) 4 (100.0%) LNG VDS 125 34 (26.6%) 34 (100.0%) 7 (30.4%) 7 (100.0%) LNG VDS 150 31 (24.2%) 31 (100.0%) 6 (26.1%) 6 (100.0%) BMI 18< BMI <30 105 (82.0%) 104 (99.0%) BMI >30 23 (18.0%) 23 (100.0%) Adjusted Odds Ratio (95% CI) not applicable 61 / 117 Note: Parameters for the logistic regression model using BMI as a covariate. Adjusted Odds Ratio for Ovulation: Yes vs. No. Note: For each treatment cycle, the highest score result during the treatment was considered for the analysis. Petition 870250084815, dated 09 / 19 / 2025, page 67 / 146 62 / 117 [1]: Inhibition of ovulation assessed as a Hoogland score of 1-4 (both included) [2]: % calculated using the total number of individuals in each factor category. [3]: Pooled data includes results from Treatment Cycle 1 and Treatment Cycle 2. Pooled Hoogland score considered as ovulation whenever ovulation occurred in either cycle, regardless of the result of the other cycle (no ovulation / absent). Pooled Hoogland score considered as absent whenever there was missing data in both cycles. In the case of no ovulation in one cycle and missing data in the other, it was considered globally as no ovulation. 4.1.2. Hoogland and Landgren score

[00210] The number and percentage of participants who had no ovarian activity, had residual or high ovarian activity, by treatment group and by BMI group in each treatment cycle in FAS, are presented in Table 6. Petition 870250084815, dated 09 / 19 / 2025, page 68 / 146 Table 6: Hoogland Score by Treatment Cycle - Sensitivity Analysis by Body Mass Index (Proportional Odds Model) All (N=128) All BMI >30 (N=23) Total analyzed n (%) None n (%) [1] [2] Residual n (%) [1] [3] High n (%) [1] [4] Total analyzed n (%) None n (%) [1] [2] Residual n (%) [1] [3] High n (%) [1] [4] Treatment Cycle 1 128 88 (68.8%) 39 (30.5%) 1 (0.8%) 23 11 (47.8%) 12 (52.2%) 0 (0.0%) Cerazette Treatment 33 (25.8%) 19 (57.6%) 13 (39.4%) 1 (3.0%) 6 (26.1%) 1 (16.7%) 5 (83.3%) 0 (0.0%) LNG VDS 75 30 (23.4%) 17 (56.7%) 13 (43.3%) 0 (0.0%) 4 (17.4%) 2 (50.0%) 2 (50.0%) 0 (0.0%) LNG VDS 125 34 (26.6%) 26 (76.5%) 8 (23.5%) 0 (0.0%) 7 (30.4%) 3 (42.9%) 4 (57.1%) 0 (0.0%) LNG VDS 150 31 (24.2%) 26 (83.9%) 5 (16.1%) 0 (0.0%) 6 (26.1%) 5 (83.3%) 1 (16.7%) 0 (0.0%) BMI 18< BMI <30 105 (82.0%) 77 (73.3%) 27 (25.7%) 1 (1.0%) BMI >30 23 (18.0%) 11 (47.8%) 12 (52.2%) 0 (0.0%) Treatment Cycle 2 125 89 (71.2%) 36 (28.8%) 0 (0.0%) 22 15 (68.2%) 7 (31.8%) 0 (0.0%) Cerazette Treatment 31 (24.8%) 15 (48.4%) 16 (51.6%) 0 (0.0%) 6 (27.3%) 2 (33.3%) 4 (66.7%) 0 (0.0%) LNG VDS 75 30 (24,0%) 19 (63.3%) 11 (36.7%) 0 (0.0%) 4 (18.2%) 3 (75.0%) 1 (25.0%) 0 (0.0%) LNG VDS 125 33 (26.4%) 28 (84.8%) 5 (15.2%) 0 (0.0%) 6 (27.3%) 5 (83.3%) 1 (16.7%) 0 (0.0%) LNG VDS 150 31 (24.8%) 27 (87.1%) 4 (12.9%) 0 (0.0%) 6 (27.3%) 5 (83.3%) 1 (16.7%) 0 (0.0%), 63 / 117 Petition 870250084815, dated 09 / 19 / 2025, page 69 / 146 Table 6: -continued- All (N=128) All BMI >30 (N=23) Total analyzed n (%) None n (%) [1] [2] Residual n (%) [1] [3] Discharge n (%) [1] [4] Total analyzed n (%) None n (%) [1] [2] Residual n (%) [1] [3] Discharge n (%) [1] [4] Treatment Cycle 1 128 88 (68.8%) 39 (30.5%) 1 (0.8%) 23 11 (47.8%) 12 (52.2%) 0 (0.0%) BMI 18< BMI <30 103 (82.4%) 74 (71.8%) 29 (28.2%) 0 (0.0%) BMI >30 22 (17.6%) 15 (68.2%) 7 (31.8%) 0 (0.0%) Grouped [5] 128 79 (61.7%) 48 (37.5%) 1 (0.8%) 23 11 (47.8%) 12 (52.2%) 0 (0.0%) Cerazet Treatment 33 (25.8%) 14 (42.4%) 18 (54.5%) 1 (3.0%) 6 (26.1%) 1 (16.7%) 5 (83.3%) 0 (0.0%) LNG VDS 75 30 (23.4%) 15 (50.0%) 15 (50.0%) 0 (0.0%) 4 (17.4%) 2 (50.0%) 2 (50.0%) 0 (0.0%) LNG VDS 125 34 (26.6%) 24 (70.6%) 10 (29.4%) 0 (0.0%) 7 (30.4%) 3 (42.9%) 4 (57.1%) 0 (0.0%) LNG VDS 150 31 (24.2%) 26 (83.9%) 5 (16.1%) 0 (0.0%) 6 (26.1%) 5 (83.3%) 1 (16.7%) 0 (0.0%) BMI 18< BMI <30 105 (82.0%) 68 (64.8%) 36 (34.3%) 1 (1.0%) BMI >30 23 (18.0%) 11 (47.8%) 12 (52.2%) 0 (0.0%) 64 / 117 Adjusted Odds Ratio (95% CI) not applicable Note: Parameters for the multinomial proportional odds logistic regression model using BMI as a covariate. High ovarian activity, including ovulation, was the reference group for the Hoogland Score. Note: For each treatment cycle, the highest score result during the treatment was considered for the analysis. Petition 870250084815, dated 09 / 19 / 2025, page 70 / 146 65 / 117 [1]: % calculated using the total number of individuals in each factor category. [2]: No or minimal ovarian activity: Hoogland score 1 or 2. [3]: Residual ovarian activity: Hoogland score 3 or 4. [4]: High ovarian activity including ovulation: Hoogland score 5 or 6. [5]: Pooled data includes results from Treatment Cycle 1 and Treatment Cycle 2. Pooled Hoogland score considered as ovulation whenever ovulation occurred in either cycle, regardless of the result of the other cycle (no ovulation / absent). Pooled Hoogland score considered absent whenever there was missing data in both cycles. In the case of no ovulation in one cycle and missing data in the other, it was considered globally as no ovulation.

[00211] In TC1, a total of 88 (68.8%) participants had no ovarian activity or had minimal ovarian activity (Hoogland score of 1 or 2), corresponding to 19 (57.6%), 17 (56.7%), 26 (76.5%) and 26 (83.9%) participants treated with Cerazet, LNG VDS 75, 125 and 150, respectively; and 39 (30.5%) had residual ovarian activity (Hoogland score of 3 or 4), corresponding to 13 (39.4%), 13 (43.3%), 8 (23.5%), 5 (16.1%) participants treated with Cerazet, LNG VDS 75, 125 and 150, respectively.

[00212] There was only 1 (0.8%) participant, who was treated with Cerazet, who had high ovarian activity (Hoogland score of 5 to 6) during TC1.

[00213] In the ANCOVA model performed, the mean LS (95% CI) of the differences, considering Cerazet as the reference group, was -0.2 (0.30) (-0.8; 0.4) for LNG VDS 75, -0.6 (0.29) (-1.1; 0.0) for LNG VDS 125 and -0.7 (0.29) (-1.3; -0.2) for LNG VDS 150. Petition 870250084815, dated 09 / 19 / 2025, p. 71 / 146 66 / 117

[00214] The Hoogland score assessment by BMI group showed that no ovarian activity was observed or minimal ovarian activity was observed in 77 (73.3%) and 11 (47.8%) participants with BMI >18 and <30 kg / m2 and participants with BMI > 30 kg / m2, respectively, and residual ovarian activity was observed in 27 (25.7%) and 11 (47.8%) participants with BMI >18 and <30 kg / m2 and participants with BMI > 30 kg / m2, respectively.

[00215] In the ANCOVA model performed, the mean LS (95% CI) of the differences, considering the group of participants with BMI >18 and <30 kg / m2, was 0.8 (0.27) (0.2; 1.3) for participants with BMI > 30 kg / m2.

[00216] In the group of participants with BMI >30 kg / m2, 1 (16.7%), 2 (50.0%), 3 (42.9%) and 5 (83.3%) participants treated with Cerazet, LNG VDS 75, 125 and 150 had no ovarian activity or had minimal activity; and 5 (83.3%), 2 (50.0%), 4 (57.1%) and 1 (16.7%) participant(s) treated with Cerazet, LNG VDS 75, 125 and 150, respectively, had residual ovarian activity. There were no participants with BMI >30 kg / m2 who reported high ovarian activity during TC1.

[00217] In TC2, a total of 89 (71.2%) and 36 (28.8%) participants had no ovarian activity or had minimal activity (Hoogland score of 1 or 2) and residual ovarian activity (Hoogland score of 3 or 4), respectively.

[00218] By treatment group, 15 (48.4%), 19 (63.3%), 28 (84.8%), and 27 (87.1%) participants treated with Cerazet, LNG VDS 75, 125, and 150, respectively, had no ovarian activity or had minimal activity; and 16 (51.6%), 11 (36.7%), 5 (15.2%), and 4 (12.9%) participants treated with Cerazet, LNG VDS 75, 125, and 150, respectively, had residual ovarian activity. There were no participants who had high ovarian activity (Hoogland score of 5). Petition 870250084815, dated 09 / 19 / 2025, p. 72 / 146 67 / 117 to 6) during TC1.

[00219] In the ANCOVA model performed, the mean LS (95% CI) of the differences, considering Cerazet as the reference group, was 0.4 (0.29) (-0.9; 0.2) for LNG VDS 75, -0.8 (0.29) (-1.4; -0.3) for LNG VDS 125 and -1.0 (0.29) (-1.6; -0.5) for LNG VDS 150.

[00220] The Hoogland score assessment by BMI group showed that no ovarian activity was observed or minimal ovarian activity was observed in 74 (71.8%) and 15 (68.2%) participants with BMI >18 and <30 kg / m2 and participants with BMI >30 kg / m2, respectively, and residual ovarian activity was observed in 29 (28.2%) and 7 (31.8%) participants with BMI >18 and <30 kg / m2 and participants with BMI >30 kg / m2, respectively.

[00221] In the ANCOVA model performed, the mean LS (95% CI) of the differences, considering the group of participants with BMI >18 and <30 kg / m2, was 0.2 (0.27) (-0.4-0.7) for participants with BMI>30 kg / m2.

[00222] In the group of participants with BMI >30 kg / m2, 2 (33.3%), 3 (75.0%), 5 (83.3%) and 5 (83.3%) participants treated with Cerazet, LNG VDS 75, 125 and 150 had no ovarian activity or had minimal activity; and 4 (66.7%), 1 (25.0%), 1 (16.7%) and 1 (16.7%) participants treated with Cerazet, LNG VDS 75, 125 and 150, respectively, had residual ovarian activity. There were no participants with BMI >30 kg / m2 who reported high ovarian activity during TC1.

[00223] The Landgren test was performed on 43 (33.6%) participants (when ovulation was suspected by follicle size measured by TVU) of the FAS during TC1 and TC2 (10 [33.3%] participants in the LNG VDS 75 treatment group, 10 [29.4%] in the LNG VDS 125, 10 [32.3%] in the LNG VDS 150, and 13 [39.4%] in the Cerazet treatment group). However, this test was positive in only 1 (0.8%) participant in the Cerazet treatment group. There were no treated participants. Petition 870250084815, dated 09 / 19 / 2025, page 73 / 146 68 / 117 with LNG VDS who reported a positive Landgren test. 4.1.3. Follicle Size

[00224] Follicle size per treatment cycle was assessed in each treatment group (Table 4). During TC1, the mean (SD) size of the largest follicle was 10.2 (3.8) mm, assessed in 117 FAS participants. Numerical differences were observed between treatment groups: 11.7 (4.6) mm, 11.2 (4.2) mm, 9.4 (3.4) mm, and 8.6 (2.1) mm in the Cerazet, LNG VDS 75, 125, and 150 treatment groups, respectively.

[00225] In TC2, the mean size (SD) of the largest follicle was 9.8 (3.2) mm, assessed in 111 FAS participants. Numerical differences were also observed between treatment groups: 12.0 (4.1) mm, 10.4 (3.5) mm, 8.7 (1.8) mm and 8.2 (1.3) mm in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively.

[00226] Among participants with BMI >30 kg / m2 (Table 12), the mean size (SD) of the largest follicle during TC1 was 11.5 (4.2) mm (14.5 [5.5] mm, 11.0 [4.3] mm, 11.3 [3.2] mm and 9.2 [2.8] mm in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively), which was slightly higher compared to the total population. In TC2, the mean size (SD) of the largest follicle decreased to 9.8 (3.3) mm (12.5 [4.8] mm, 9.4 [3.1] mm, 8.8 [0.6] mm and 8.3 [1.4] mm in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively), which was very similar to the value obtained in the total population. Petition 870250084815, dated 09 / 19 / 2025, page 74 / 146 Table 7: Follicle Size per Treatment Cycle LNG VDS 75 (N=30 / n=4) LNG VDS 125 (N=34 / n=7) LNG VDS 150 (N=31 / n=6) Cerazet (N=33 / n=6) All (N=128 / n=23) Treatment cycle 1 Largest follicle size (mm) Number 26 32 29 30 117 Mean (SD) 11.2 (4.2) 9.4 (3.4) 8.6 (2.1) 11.7 (4.6) 10.2 (3.8) Median 9.8 8.6 7.8 10.5 9.0 Q1 : Q3 7.9 : 13.7 7.7 : 10.0 7.2 : 9.9 8.2 : 14.8 7.7 : 11.3 Min Max 6.4:22.0 4.7:21.6 5.7:14.7 6.8:21.8 4.7:22.0 Absent 4 2 2 3 11 Size of the largest follicle (mm) - BMI >30 Number 4 7 6 6 23 Mean (SD) 11.0 (4.3) 11.3 (3.2) 9.2 (2.8) 14.5 (5.5) 11.5 (4.2) Median 10.6 10.0 8.1 16.0 9.7 Q1 : Q3 7.5 : 4.4 8.6 : 15.4 7.5 : 9.7 8.6 : 18.4 8.3 : 15.4 Min : Max 6.4 : 16.1 8.3 : 16.1 7.2 : 14.7 7.3 : 20.9 6.4 : 20.9 Absent 0 0 0 0 0 69 / 117 Petition 870250084815, dated 09 / 19 / 2025, page 75 / 146 Table 7: Follicle Size per Treatment Cycle LNG VDS 75 (N=30 / n=4) LNG VDS 125 (N=34 / n=7) LNG VDS 150 (N=31 / n=6) Cerazet (N=33 / n=6) All (N=128 / n=23) Treatment cycle 2 Largest follicle size (mm) Number 25 29 29 28 111 Mean (SD) 10.4 (3.5) 8.7 (1.8) 8.2 (1.3) 12.0 (4.1) 9.8 (3.2) Median 9.4 8.7 7.8 11.0 9.0 Q1 : Q3 8.4 : 12.3 7.2 : 9.6 7.0 : 9.1 8.7 : 15.1 7.6 : 10.4 Min : Max 6.0 : 22.8 6.0 : 13.9 6.2 : 11.8 6.6 : 22.2 6.0 : 22.8 Absent 5 5 2 5 17 Size of the largest follicle (mm) - BMI >30 Number 4 5 6 6 21 Mean (SD) 9.4 (3.1) 8.8 (0.6) 8.3 (1.4) 12.5 (4.8) 9.8 (3.3) Median 8.9 8.8 7.7 14.0 8.8 Q1 : Q3 7.3 : 11.6 8.7 : 8.8 7.6 : 9.5 6.7 : 15.1 7.6 : 10.5 Min : Max 6.4 : 13.6 8.1 : 9.7 7.0 : 10.5 6.6 : 18.6 6.4 : 18.6 Absent 0 2 0 0 2 N: total number of individuals. n: number of individuals with BMI >30 70 / 117 Petition 870250084815, dated 09 / 19 / 2025, page 76 / 146 71 / 117 4.1.4. Serum Progesterone Levels

[00227] Serum progesterone levels were assessed from Day 3 to Day 27 every three days during TC1 and from Day 3 to Day 27 every three days and on Day 29 during TC2. Progesterone levels per visit and for each treatment group were assessed throughout the FAS and among participants with BMI >30 kg / m2, as well as in the PP set.

[00228] In TC1, higher serum progesterone levels were observed among participants treated with Cerazet compared with those treated with LNG VDS at any of its 3 release rates, mainly on Day 21 (2.3 [8.7] nmol / L, 0.9 [0.5] nmol / L, 0.7 [0.6] nmol / L and 0.6 [0.5] nmol / L in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively) and on Day 24 (1.7 [6.1] nmol / L, 0.9 [0.5] nmol / L, 0.8 [0.7] nmol / L and 0.6 [0.5] nmol / L in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively).

[00229] In TC2, mean progesterone levels were similar between treatment groups at all visits. In participants with BMI >30 kg / m2, no large variations were observed between treatment groups in either TC1 or TC2 per study visit, although serum progesterone levels were generally lower than those observed in the general population. 4.1.5. Serum Estradiol Levels

[00230] Serum estradiol levels were assessed from Day 3 to Day 27 every three days during TC1 and from Day 3 to Day 27 every three days and on Day 29 during TC2, see Table 8. Petition 870250084815, dated 09 / 19 / 2025, p. 77 / 146 Table 8: Estradiol Level per Treatment Cycle LNG VDS 75 (N=30 / n=4) LNG VDS 125 (N=34 / n=7) LNG VDS 150 (N=31 / n=6) Cerazet (N=33 / n=6) All (N=128 / n=23) Treatment Cycle 1 Average Estradiol (pg / mL) Number 30 34 31 33 128 Mean (SD) 59.3 (40.2) 37.3 (21.2) 32.1 (12.1) 97.1 (84.3) 56.6 (54.6) Median 44.8 32.8 29.1 56.4 38.1 Q1 : Q3 35.7 : 65.8 24.7 : 40.9 23.4 : 36.6 38.1 Average Estradiol (pg / mL) Number 30 34 31 33 128 <20 0 (0.0%) 4 (11.8%) 3 (9.7%) 0 (0.0%) 7 (5.5%) [20-30] 2 (6.7%) 10 (29.4%) 14 (45.2%) 1 (3.0%) 27 (21.1%) [30-50] 15 (50.0%) 16 (47.1%) 12 (38.7%) 13 (39.4%) 56 (43.8%) >50 13 (43.3%) 4 (11.8%) 2 (6.5%) 19 (57.6%) 38 (29.7%) Absent 0 0 0 0 0 72 / 117 Petition 870250084815, dated 09 / 19 / 2025, p. 78 / 146 Table 8: -continued- LNG VDS 75 (N=30 / n=4) LNG VDS 125 (N=34 / n=7) LNG VDS 150 (N=31 / n=6) Cerazet (N=33 / n=6) All (N=128 / n=23) Treatment Cycle 1 Average Estradiol (pg / mL) - BMI >30 Number 4 7 6 6 23 Mean (SD) 58.7 (25.9) 50.2 (17.0) 33.8 (20.3) 123.6 (74.9) 66.5 (53.1) Median 51.5 47.0 27.2 139.8 42.9 Q1 : Q3 40.0 : 77.4 39.1 : 60.1 23.8 : 28.2 36.5 : 163.6 34.0 : 83.8 Min : Max 37.2 : 94.8 34.0 : 83.8 21.5 : 74.8 34.4 : 222.2 21.5 : 222.2 Absent 0 0 0 0 0 Average Estradiol (pg / mL) - BMI >30 Number 4 7 6 6 23 <20 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) [20-30] 0 (0.0%) 0 (0.0%) 5 (83.3%) 0 (0.0%) 5 (21.7%) [30-50] 2 (50.0%) 5 (71.4%) 0 (0.0%) 2 (33.3%) 9 (39.1%) >50 2 (50.0%) 2 (28.6%) 1 (16.7%) 4 (66.7%) 9 (39.1%) Absent 0 0 0 0 0 73 / 117 Petition 870250084815, dated 09 / 19 / 2025, p. 79 / 146 Table 8: Estradiol Level per Treatment Cycle LNG VDS 75 (N=30 / n=4) LNG VDS 125 (N=34 / n=7) LNG VDS 150 (N=31 / n=6) Cerazet (N=33 / n=6) All (N=128 / n=23) Treatment cycle 2 Average Estradiol (pg / mL) Number 30 33 31 31 125 Mean (SD) 48.0 (21.4) 30.4 (10.4) 26.8 (8.2) 66.5 (41.6) 42.7 (28.7) Median 43.6 29.5 25.7 57.8 34.7 Q1 : Q3 29.2 : 58.8 23.7 : 35.7 19.3 : 33.6 36.0 : 89.3 25.4 : 45.7 Min : Max 22.6 : 110.2 5.5 : 57.7 14.6 : 42.3 22.5 : 218.8 5.5 : 218.8 Absent 0 1 0 2 3 Average Estradiol (pg / mL) Number 30 33 31 31 125 <20 0 (0.0%) 4 (12.1%) 8 (25.8%) 0 (0.0%) 12 (9.6%) [20-30] 8 (26.7%) 13 (39.4%) 13 (41.9%) 2 (6.5%) 36 (28.8%) [30-50] 12 (40.0%) 14 (42.4%) 10 (32.3%) 13 (41.9%) 49 (39.2%) >50 10 (33.3%) 2 (6.1%) 0 (0.0%) 16 (51.6%) 28 (22.4%) 74 / 117 Petition 870250084815, dated 09 / 19 / 2025, p. 80 / 146 Table 8: Estradiol Level per Treatment Cycle LNG VDS 75 (N=30 / n=4) LNG VDS 125 (N=34 / n=7) LNG VDS 150 (N=31 / n=6) Cerazette (N=33 / n=6) All (N=128 / n=23) Treatment cycle 2 Average Estradiol (pg / mL) - BMI >30 Number 4 6 6 6 22 Mean (SD) 44.6 (26.8) 35.4 (3.3) 28.4 (8.3) 75.5 (41.0) 46.1 (29.9) Median 36.8 35.5 25.9 83.5 34.8 Q1 : Q3 25.5 : 63.7 32.8 : 37.8 23.2 : 33.6 34.3 : 96.2 26.4 : 45.3 Min : Max 22.6 : 82.2 30.9 : 40.0 19.3 : 42.3 22.5 : 132.6 19.3 : 132.6 Absent 0 1 0 0 1 Average Estradiol (pg / mL) - BMI >30 Number 4 6 6 6 22 <20 0 (0.0%) 0 (0.0%) 1 (16.7%) 0 (0.0%) 1 (4.5%) [20-30] 2 (50.0%) 0 (0.0%) 3 (50.0%) 1 (16.7%) 6 (27.3%) [30-50] 1 (25.0%) 6 (100.0%) 2 (33.3%) 1 (16.7%) 10 (45.5%) >50 1 (25.0%) 0 (0.0%) 0 (0.0%) 4 (66.7%) 5 (22.7%) Absent 0 1 0 0 1 N: total number of individuals. n: number of individuals with BMI >30 75 / 117 Petition 870250084815, dated 09 / 19 / 2025, page 81 / 146 76 / 117

[00231] In TC1, the mean (SD) estradiol concentration in FAS was 56.6 (54.6) pg / mL (97.1 [84.3] pg / mL, 59.3 [40.2] pg / mL, 37.3 [21.2] pg / mL and 32.1 [12.1] pg / mL in the Cerazet, LNG treatment groups VDS 75, 125 and 150, respectively).

[00232] In the general population, 7 (5.5%) participants had a mean estradiol concentration <20 pg / mL (0 [0.0%], 0 [0.0%], 4 [11.8%] and [9.7%] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively) and 27 (21.1%) participants had a mean estradiol concentration >20 and <30 pg / mL (1 [3.0%], 2 [6.7%], 10 [29.4%], 14 [45.2%] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively).

[00233] In TC2, the mean (SD) estradiol concentration was 42.7 (28.7) pg / mL (66.5 [41.6] pg / mL, 48.0 [21.4] pg / mL, 30.4 [10.4] pg / mL and 26.8 [8.2] pg / mL in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively).

[00234] In the general population, 12 (9.6%) participants had a mean estradiol concentration <20 pg / mL (0 [0.0%], 0 [0.0%], 4 [12.1%] and 8 [25.8%] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively) and 36 (28.8%) participants had a mean estradiol concentration >20 and <30 pg / mL (2 [6.5%], 8 [26.7%], 13 [39.4%] and 13 [41.9%] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively).

[00235] In the group of participants with BMI >30 kg / m2 the mean (SD) estradiol concentration in TC1 was 66.5 (53.1) pg / mL (123.6 [74.9] pg / mL, 58.7 [25.9] pg / mL, 50.2 [17.0] pg / mL and 33.8 [20.3] pg / mL in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). There were no participants with mean estradiol concentration <20 pg / mL and there were 5 (21.7%) participants with mean estradiol concentration >20 and <30 pg / mL (0 [0.0%], 0 [0.0%], 0 [0.0%] and 5 [83.3%] in the Cerazet, LNG VDS 75 treatment groups, Petition 870250084815, dated 09 / 19 / 2025, p. 82 / 146 77 / 117 125 and 150, respectively).

[00236] In TC2, the mean (SD) estradiol concentration was 46.1 (29.9) pg / mL (75.5 [41.0] pg / mL, 44.6 [26.8] pg / mL, 35.4 [3.3] pg / mL and 28.4 [8.3] pg / mL in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). There was 1 (4.5%) participant with a mean estradiol concentration <20 pg / mL (0 [0.0%], 0 [0.0%], 0 [0.0%] and 1 [16.7%] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively) and 6 (27.3%) participants with a mean estradiol concentration >20 and <30 pg / mL (1 [16.7%], 2 [50.0%], 0 [0.0%] and 3 [50.0%] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively).

[00237] Mean estradiol levels in each treatment cycle and by BMI category for all treatment groups were presented in Figure 4. This figure shows how estradiol levels decreased from TC1 to TC2 in both BMI groups, although serum levels were higher in TC1 among participants with a BMI >30 kg / m2 compared to participants with a lower BMI. 4.2. Secondary Efficacy Assessment 4.2.1. Insler Score

[00238] Insler score results obtained per visit during pre-treatment, TC1, TC2, and post-treatment were assessed for each treatment group in the PP set and in the FAS. The Insler score was assessed in 38 FAS participants in both TCs.

[00239] In TC1, the mean maximum score (SD) obtained was 4.6 (2.1) (4.4 [1.8], 4.5 [1.8], 5.6 [2.7] and 3.5 [2.4] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). There were 9 (23.7%) participants with a maximum Insler score between 0 and 3 (3 [20.0%], 3 [27.3%], 2 [25.0%] and 1 [25.0%] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively) and 20 (52.6%) with a score Petition 870250084815, dated 09 / 19 / 2025, p. 83 / 146 78 / 117 maximum Insler score between 4 and 6 (9 [60.0%], 6 [54.5%], 2 [25.0%] and 3 [75.0%] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively).

[00240] In TC2, the mean maximum Insler score (SD) obtained was 4.1 (2.1) (4.2 [1.6], 3.7 [1.8], 5.0 [3.7] and 3.4 [2.7] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). There were 13 (34.2%) with a maximum score between 0 and 3 (5 [29.4%], 4 [36.4%], 2 [40.0%] and 2 [40.0%] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively) and 23 (60.5%) with a maximum score between 4 and 6 (11 [64.7%], 7 [63.6%], 2 [40.0%] and 3 [60.0%) in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively).

[00241] Among 12 participants with BMI >30 kg / m2 (Table 15), the mean maximum Insler score (SD) obtained was 5.8 (1.8) during TC1 (5.4 [1.5], 4.5 [0.7], 7.3 [1.7] and 4.0 [NA] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). None of these participants had a maximum score between 0 and 3 and 7 (58.3%) participants had a maximum Insler score between 4 and 6 (3 [60.0%], 2 [100.0%], 1 [25.0%] and 1 [100.0%] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively).

[00242] During TC2, the mean maximum score (SD) was 3.6 (2.0), which was assessed in only 8 participants (4.8 [0.5], 4.0 [NA], 5.0 [NA] and 0.5 [0.7] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). There were 2 (25%) participants with an Insler score between 0 and 3 (0 [0.0%], 0 [0.0%], 2 [100%] and 0 [0.0%] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively) and 6 (75.0%) participants with an Insler score between 4 and 6 (4 [100%], 1 [100%], 1 [100%] and 0 [0.0%] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). 4.2.2. Return of Ovulation

[00243] The return of ovulation, assessed in the FAS (Table 9), mos Petition 870250084815, dated 09 / 19 / 2025, page 84 / 146 79 / 117 showed that 104 (81.9%) of 127 participants experienced a return of ovulation during post-treatment (23 [69.7%], 24 [80.0%], 31 [93.9%], and 26 [83.9%] in the Cerazet, LNG VDS 75, 125, and 150 treatment groups, respectively): 86 (81.9%) of 105 participants with BMI >18 and <30 kg / m2 (20 [74.1%], 20 [6.9%], 25 [92.6%], and 21 [84.0%] in the Cerazet, LNG VDS 75, 125, and 150 treatment groups, respectively) and 18 (81.8%) of 22 participants with BMI >30 kg / m2 (3 [50.0%], 4 [100%], 6 [100%] and 5 [83.3%] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). Petition 870250084815, dated 09 / 19 / 2025, page 85 / 146 Table 9: Return of Ovulation (Complete Analysis Set) LNG VDS 75 (N=30) LNG VDS 125 (N=34) LNG VDS 150 (N=31) Cerazette (N=33) All (N=128) Return of ovulation Number 30 33 31 33 127 Yes 24 (80.0%) 31 (93.9%) 26 (83.9%) 23 (69.7%) 104 (81.9%) No 6 (20.0%) 2 (6.1%) 5 (16.1%) 10 (30.3%) 23 (18.1%) Absent 0 1 0 0 1 18 < BMI <30 Number 26 27 25 27 105 Yes 20 (76.9%) 25 (92.6%) 21 (84.0%) 20 (74.1%) 86 (81.9%) No 6 (23.1%) 2 (7.4%) 4 (16.0%) 7 (25.9%) 19 (18.1%) Absent 0 0 0 0 0 BMI >30 Number 4 6 6 6 22 Yes 4 (100.0%) 6 (100.0%) 5 (83.3%) 3 (50.0%) 18 (81.8%) No 0 (0.0%) 0 (0.0%) 1 (16.7%) 3 (50.0%) 4 (18.2%) Absent 0 1 0 0 1 80 / 117 Petition 870250084815, dated 09 / 19 / 2025, page 86 / 146 81 / 117

[00244] The same results were observed when the return of ovulation was evaluated in the PP set. Mean blood levels (SD) of progesterone evaluated during the post-treatment cycle (in FAS) were 17.3 (15.3) pg / mL in OV+2 (12.8 [11.0], 16.4 [13.5], 15.5 [12.3] and 24.7 [20.8] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively) and 29.9 (14.9) pg / mL in OV+4 (31.0 [13.5], 29.1 [17.7], 26.9 [11.7] and 33.4 [16.2] in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). Similar results were obtained in the evaluation of blood progesterone levels during the post-treatment cycle in the PP group. 4.2.3. Endometrial thickness

[00245] Endometrial thickness was assessed to determine any changes in the endometrial bed that were unsuitable for implantation. A thickness of <6 mm was considered to be an endometrium that was not suitable for pregnancy. It was measured as the distance between the double layer in longitudinal section of the uterus by TVUs at each visit.

[00246] Endometrial thickness was measured by TVU at pre-treatment, TC1, TC2, and post-treatment, at each study visit. The mean results obtained at each visit and by treatment group were analyzed for the entire population and for the group of participants with BMI >30 kg / m2.

[00247] In pre-treatment, the mean endometrial thickness (SD) was 7.8 (2.1) mm (8.2 [2.9], 7.2 [1.8], 7.9 [1.3] and 7.8 [1.9] mm in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively).

[00248] In TC1, the mean endometrial thickness (SD) was 4.1 (1.1) (4.3 [1.3], 3.7 [0.9], 4.1 [0.8] and 4.1 [1.1] mm in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively).

[00249] In TC2, the mean endometrial thickness (SD) was 3.8 (1.0) mm (3.9 [1.2], 3.3 [0.9], 3.9 [0.9] and 3.9 [1.0] mm in the groups of Petition 870250084815, dated 09 / 19 / 2025, page 87 / 146 82 / 117 treatment Cerazet, LNG VDS 75, 125 and 150, respectively).

[00250] In the post-treatment period, the mean endometrial thickness (SD) was 7.0 (1.6) mm (6.7 [2.0], 6.7 [1.6], 7.3 [1.5] and 7.4 [1.3] mm in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively).

[00251] In the group of participants with BMI >30 kg / m2 at pretreatment, the mean endometrial thickness (SD) in this group of participants was 7.8 (2.1) mm (9.1 [1.7], 7.2 [0.9], 8.0 [1.5] and 9.1 [2.7] mm in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). In TC1, the mean endometrial thickness (SD) was 4.1 (1.1) mm (5.6 [1.7], 3.6 [0.7], 4.0 [0.6] and 4.6 [1.2] mm in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). In TC2, the mean endometrial thickness (SD) was 3.8 (1.0) mm (4.9 [1.1], 3.9 [1.5], 3.6 [0.6] and 3.8 [1.4] mm in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). In the post-treatment period (Table 20), the mean endometrial thickness (SD) was 7.0 (1.6) mm (6.9 [1.5], 6.9 [0.6], 6.4 [1.8] and 6.9 [1.7] mm in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). 4.2.4. Bleeding Patterns

[00252] Vaginal bleeding was recorded daily in the participant's diary. The results regarding the presence or absence of bleeding and the bleeding episode are presented for all participants.

[00253] In TC1, 1 (0.8%) participant had no bleeding throughout the cycle (in the LNG VDS 75 treatment group). The mean (SD) number of days with any bleeding was 11.2 (6.0) (10.7 [4.9], 11.5 [6.4], 11.6 [6.4] and 11.3 [6.3] days in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively); the mean (SD) number of days with breakthrough bleeding was 6.2 (4.7) (5.5 [4.4], 6.8 [5.6], 5.9 [4.0] and 6.9 [5.0] days in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively) and the mean (SD) number of days Petition 870250084815, dated 09 / 19 / 2025, page 88 / 146 83 / 117 with mild bleeding was 3.4 (2.8) (3.2 [2.4], 2.8 [2.1], 4.6 [3.9] and 2.8 [1.8] days in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively).

[00254] In TC2, 22 (17.6%) participants had no bleeding (3 [9.7%], 8 [26.7%], 8 [24.2%] and 3 [9.7%] participants in the Cerazet, LNG VDS 75, 125 and 150 treatment groups). The mean (SD) number of days with any bleeding was 14.1 (8.9) (12.5 [6.7], 13.0 [8.2], 17.9 [9.7] and 13.2 [10.2] days in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively); The mean number (SD) of days with breakthrough bleeding was 9.2 (7.1) (7.4 [5.1], 9.3 [8.1], 10.3 [6.8] and 9.7 [8.1] days in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively) and the mean number (SD) of days with light bleeding was 5.8 (4.7) (5.1 [4.0], 3.3 [2.3], 8.0 [5.2] and 6.3 [5.6] days in the Cerazet, LNG VDS 75, 125 and 150 treatment groups, respectively). 5. CONCLUSION ON EFFECTIVENESS

[00255] A total of 128 participants were included in the FAS.

[00256] Analysis of the primary outcome showed that all participants treated with LNG VDS experienced ovulation inhibition in both CTs. All participants treated with Cerazet also experienced ovulation inhibition in both CTs, except for 1 participant (with BMI >18 and <30 kg / m2) who ovulated during CT1.

[00257] Ovarian activity measured by the Hoogland score during TC1 showed that 69% of participants had no ovarian activity or minimal activity, a percentage that was 84% ​​among participants treated with LNG VDS 150; 31% presented residual ovarian activity, a percentage that was higher among participants treated with LNG VDS 75 (43%). Similarly, more participants with BMI >18 and <30 kg / m2 showed no or minimal ovarian activity (73%) compared to participants with BMI >30 kg / m2 (48%), although this percentage was higher if the aforementioned participants were treated with LNG VDS 150 (83%). During TC2, the percentage of participants with no or minimal ovarian activity compared to TC1 was higher in the total population (71% vs 68%), as well as among participants with a BMI >30 kg / m2 (68% vs 48%).

[00258] The ANCOVA model showed with statistical significance that, during TC2, the Hoogland score differed by 1 point in participants treated with LNG VDS 150 and participants treated with Cerazet (1.8 vs 2.8, respectively) and by 0.7 between those treated with LNG VDS 125 and those treated with Cerazet (2.1 vs 2.8, respectively).

[00259] The Landgren score results confirmed that only 1 participant treated with Cerazet ovulated in TC1.

[00260] In TC1, the mean size (SD) of the largest follicle was 10.2 (3.8) mm, being larger in participants treated with Cerazet and LNG VDS 75 (11.7 [4.6] and 11.2 [4.2] mm, respectively) versus LNG VDS 125 and 150 (9.4 [3.4] and 8.6 [2.1] mm, respectively). The same trend was observed in TC2 with similar results.

[00261] In participants with a BMI>30 Kg / m2, a larger follicle size was obtained, although the same differences were observed between the treatment arms; however, the values ​​obtained in TC2 were very similar to those observed for the general population.

[00262] Serum progesterone concentrations were higher at TC1 in participants treated with Cerazet at the last visits of TC1 compared with the values ​​observed in the LNG VDS treatment groups, whereas no significant variations were observed during TC2, regardless of the treatment group.

[00263] In participants with a BMI >30 kg / m2, no observations were made. Petition 870250084815, dated 09 / 19 / 2025, pp. 90 / 146 85 / 117 of the large variations between treatment groups in both TC1 and TC2 per study visit, although serum progesterone levels were generally lower than those observed in the general population.

[00264] Regarding the mean estradiol concentration, the value obtained in TC1 was 56.6 (54.6) pg / mL, although this value was higher in the Cerazet treatment group (97.1 [84.3] pg / mL) compared to LNG VDS 75, 125 and 150 (59.3 [40.2], 37.3 [21.2] and 32.1 [12.1] pg / mL, respectively). The same trend was observed in TC2, although the reported values ​​were lower compared to TC1. It is important to highlight that the percentage of participants with estradiol concentrations <20 pg / mL and <30 pg / mL was notably higher among those treated with LNG VDS 125 and 150 compared to LNG VDS 75 and Cerazet. In participants with a BMI >30 kg / m2, the same trend was observed, although serum estradiol concentration was higher in all treatment arms in both CTs compared to the total population.

[00265] The mean maximum Insler score obtained was 4.6 in TC1 and 4.1 in TC2, and in both TCs, participants treated with LNG VDS 150 had a lower maximum score (3.5 in TC1 and 3.4 in TC2) compared to the other 3 treatment groups. No participant had good sperm ascent conditions (maximum Insler score of 10-12) in either TC, and only 1 participant (treated with Cerazet) had moderate sperm ascent conditions (maximum Insler score of 7-9) in TC2. Among participants with a BMI >30 kg / m2, the maximum Insler score in TC1 was higher compared to the total population (5.8), and no participant had an average score between 0 and 3. Among these, no participant had a maximum Insler score of 10-12 in any TC, and a maximum Insler score of 7-9 was achieved only by Petition 870250084815, dated 09 / 19 / 2025, pp. 91 / 146 86 / 117 and 2 participants treated with LNG VDS 125 and Cerazet, respectively, only in TC1.

[00266] In post-treatment, ovulation was recovered in more than 80% of participants (80.0%, 93.9% and 83.9% in the LNG VDS 75, 125 and 150 treatment groups vs 69.7% in the Cerazet treatment group). Pharmacokinetic Evaluation

[00267] LNG pharmacokinetic parameters and SHBG levels were determined in a subgroup of 55 participants using LNG VDS; 41 of them had a BMI between 18< and <30 kg / m2 (15, 14 and 12 participants for the LNG VDS 75, 125 and 150 treatment groups, respectively) and 14 of them had a BMI >30 kg / m2 (3, 7 and 4 participants for the LNG VDS 75, 125 and 150 treatment groups, respectively).

[00268] Figures 2 and 3 show the time-mean concentration profiles of LNG and SHBG, respectively, of participants in the LNG VDS 75, 125, and 150 treatment groups; and Figures 4 and 5 show the same parameters (time-mean concentration profiles of LNG and SHBG) categorized by BMI. 5.1. Pharmacokinetics of LNG in the LNG VDS 75, 125 and 150 Treatment Groups

[00269] After the insertion of LNG VDS at dose levels of 75, 125 and 150 μg / day, plasma LNG concentrations were evident from the first sampling (2 h post-insertion) in all individuals, in all cycles, at all dose levels.

[00270] In TC1, overall peak concentrations were observed at 116, 123, and 113 hours after dosing at 75, 125, and 150 pg / day, respectively. In the BMI >18 and <30 kg / m2 categories, the observed Tmax values ​​were 115, 110, and 98.667 hours after insertion at 75, 125, and 150 pg / day, respectively, and in participants Petition 870250084815, dated 09 / 19 / 2025, page 92 / 146 In individuals with a BMI >30 kg / m2 (87 / 117), the observed Tmax values ​​were 120, 151, and 156 hours after dosing at 75, 125, and 150 pg / day, respectively.

[00271] After peak plasma LNG concentrations at Tmax, plasma levels remained elevated with minimal peak-to-trough fluctuation, representative of prolonged LNG release during TC1 at all dose levels and in all BMI categories.

[00272] In TC1, the maximum observed plasma concentrations were generally 0.950, 1.548, and 1.426 ng / mL after dosing at 75, 125, and 150 pg / day, respectively. In participants with BMI >18 and <30 kg / m2, the Cmax values ​​were 1.011, 1.829, and 1.539 ng / mL, and in participants with BMI >30 kg / m2, the Cmax values ​​were 0.647, 0.987, and 1.090 after dosing at 75, 125, and 150 pg / day, respectively.

[00273] The exposure, assessed by AUC(0-t), observed overall in TC1 was 340, 571, and 468 h*ng / mL after dosing at 75, 125, and 150 pg / day. In the BMI >18 and <30 kg / m2 category, the AUC(0-t) values ​​were 357, 662, and 490 h*ng / mL, and in participants with BMI >30 kg / m2, the AUC(0-t) values ​​were 253, 389, and 403 after dosing at 75, 125, and 150 pg / day, respectively.

[00274] The clearance values ​​measured after extravascular LNG VDS dosing at 75, 125 and 150 pg / day in TC1 were 76,383, 96,103 and 106 mL / h in participants with BMI >18 and <30 kg / m2, the values ​​were 66,816, 84,964 and 101 mL / h, and where the BMI was >30 kg / m2, the values ​​determined were 119, 125 and 123 mL / h.

[00275] The volume of distribution measured after extravascular LNG VDS dosing at 75, 125 and 150 μg / day, the values ​​in TC1 were 101, 96,294, 103 L, and in participants with BMI >18 and <30 kg / m2, the values ​​were 99,117, 85,227 and 94,116 L, and where the BMI Petition 870250084815, dated 19 / 09 / 2025, p. 93 / 146 88 / 117 was >30 kg / m2, the values ​​determined were 111,991, 124,941 and 140,244 L.

[00276] In TC2, peak LNG concentrations were generally observed at 283, 192, and 192 hours after dosing at 75, 125, and 150 pg / day, respectively. In participants with BMI >18 and <30 kg / m2, the observed Tmax values ​​were 269, 156, and 199 hours after dosing at 75, 125, and 150 pg / day, respectively. In participants with BMI >30 kg / m2, the observed Tmax values ​​were 352, 276, and 174 hours after dosing at 75, 125, and 150 pg / day, respectively.

[00277] After peak plasma LNG concentrations at Tmax, plasma levels remained elevated with minimal peak-to-trough fluctuation, representative of prolonged LNG release during TC2 at all dose levels and in all BMI categories.

[00278] In TC2, the maximum observed plasma concentrations were generally 0.654, 0.987, and 0.925 ng / mL after dosing at 75, 125, and 150 pg / day, respectively. In participants with BMI >18 and <30 kg / m2, the Cmax values ​​were 0.695, 1.085, and 0.995 ng / mL, and in participants with BMI >30 kg / m2, the Cmax values ​​were 0.449, 0.757, and 0.842 ng / mL after dosing at 75, 125, and 150 pg / day, respectively.

[00279] In TC2, the exposure, assessed by AUC(0-t), observed overall was 363, 538, and 505 h*ng / mL after dosing at 75, 125, and 150 pg / day. In participants with BMI >18 and <30 kg / m2, the AUC(0-t) values ​​were 382, ​​584, and 517 h*ng / mL, and in participants with BMI >30 kg / m2, the AUC(0-t) values ​​were 269, 432, and 473 h*ng / mL after dosing at 75, 125, and 150 pg / day, respectively.

[00280] In TC2, the clearance values ​​measured after extravascular LNG VDS dosing at 75, 125 and 150 pg / day were 25,705, Petition 870250084815, dated 09 / 19 / 2025, pp. 94 / 146 89 / 117 75,382 and 62,028 mL / h, and in participants with BMI >18 and <30 kg / m2, the values ​​were 25,449, 57,623 and 52,200 mL / h, and where the BMI was >30 kg / m2, the values ​​determined were 27,240, 116,821 and 91,512 mL / h.

[00281] In TC2, the volume of distribution measured after extravascular LNG VDS dosing at 75, 125 and 150 pg / day, the values ​​were 138, 140 and 172 L, and in participants with BMI >18 and <30 kg / m2, the values ​​were 131, 118 and 167 L, and in participants with BMI >30 kg / m2, the values ​​determined were 177, 191 and 187 L.

[00282] In both TC1 and TC2, although terminal elimination half-life values ​​are reported, they do not represent the LNG elimination kinetics, since during the sampling period a constant input of LNG is provided by the VDS, therefore these values ​​are not interpreted or discussed.

[00283] In summary, in TC1, an increase in exposure (as determined by Cmax and AUC(0-t)) was generally observed across the dosage range, and participants with BMI >30 kg / m2 had lower exposure than participants with BMI >18 and <30 kg / m2.

[00284] In TC2, an increase in exposure (as determined by Cmax and AUC(0-t)) was generally observed between dose levels of 75 and 125 pg / day; however, no clear overall difference occurred between dose levels of 125 and 150 pg / day. Participants with BMI >30 kg / m2 tended to demonstrate lower exposure (as determined by Cmax and AUC(0-t)), lower clearance, and a larger volume of distribution than observed in participants with BMI >18 and <30 kg / m2. As observed overall and in both BMI categories, no clear difference in exposure was observed between dose levels of 125 and 150 pg / day. Plasma clearance observed in TC2 appeared to differ across dose levels, with lower clearance observed for both BMI categories. Petition 870250084815, dated 09 / 19 / 2025, pp. 95 / 146 90 / 117 BMI at 75 μg / day compared to dosages of 125 and 150 μg / day. Example 3:

[00285] A multicenter, phase 2, dose-finding, double-blind, randomized clinical trial to evaluate the efficacy and safety of the levonorgestrel (LNG) vaginal delivery system (VDS), delivering doses over 28 days on a continuous regimen of 75 mcg / day and 125 mcg / day, for the management of moderate to severe pain associated with endometriosis versus placebo after 4 medication cycles. Study design:

[00286] Multicenter clinical study in female subjects aged > 18 and < 45 years with surgically confirmed diagnosis of endometriosis and with endometriosis-associated pelvic pain (EAPP) of > 3 points on a numerical rating scale (NRS) during the last 3 months. The clinical study consists of a screening period (up to 100 days), a treatment period consisting of 4 double-blind, placebo-controlled medication cycles, and a follow-up period.

[00287] Individuals will be randomized to receive either LVDS 75 mcg / day, LVDS 125 mcg / day, or a placebo vaginal ring. Vaginal rings will be inserted at the site at Visit 1b and must be changed every 28 days (on Day 29). Subsequently, individuals will attend the site at Visit 2 on Day 20 (+6) of the 1st medication cycle. The end-of-treatment visit (Visit 3) will be conducted 1-3 days after the end of the 4th medication cycle (i.e., on the hypothetical Day 29 (+2) of the 4th medication cycle), or, in case of early discontinuation, (early discontinuation visit [EDV]) will be conducted up to 1-3 days after the last day of ring use. Study Objectives: Primary Objective: • To demonstrate the effectiveness of the vaginal delivery system of Petition 870250084815, dated 09 / 19 / 2025, pp. 96 / 146 91 / 117 levonorgestrel (LVDS) at two doses, LVDS 75 mcg / day and LVDS 125 mcg / day, compared with placebo for the management of endometriosis-associated pelvic pain (EAPP) as assessed on a numerical rating scale (NRS) Primary Outcome

[00288] Population: Premenopausal women aged > 18 and < 45 years with a surgically confirmed diagnosis of endometriosis and an EAPP score > 3 on an NRS for at least 3 months, who were randomized to receive LVDS 0.075 mg / day, LVDS 0.125 mg / day, or placebo. Women who used the respective LVDS at least once and have at least one post-baseline primary efficacy assessment (mITT set [modified ITT]) analyzed.

[00289] Variable: Changes from baseline in the endometriosis-associated pelvic pain score (EAPP) as assessed by the individual's self-reported pain score at an NRS in Week 16 (after 4 cycles of medication).

[00290] Intercurrent events (ICEs) and strategies: • Change in rescue medication during 16 weeks of treatment (4 medication cycles) compared to baseline • Non-compliance with treatment (< 80% or > 120%) • Discontinuation of treatment (due to lack of efficacy, adverse events (AEs), or safety concerns)

[00291] Population-level summary: Difference in mean values ​​of treatment groups (LVDS 0.075 mg / day, LVDS 0.125 mg / day, placebo) of changes in EAPP score at Week 16 (after 4 cycles of medication) compared with baseline (or the last individual cycle for those who discontinued). Secondary Objectives • Proportion of patients who meet the criteria for Petition 870250084815, dated 09 / 19 / 2025, pp. 97 / 146 92 / 117 patients with dysmenorrhea showed a mean reduction in NRS scores for dysmenorrhea after 16 weeks of treatment with LVDS 75 mcg and LVDS 125 mcg compared to placebo, achieving a mean reduction in NRS scores for dysmenorrhea of ​​50% compared to baseline. • Proportion of patients who met the response criteria for nonmenstrual pelvic pain (NMPP) after 16 weeks of treatment with LVDS 75 mcg and LVDS 125 mcg compared with placebo, achieving a mean reduction in NRS scores for nonmenstrual pelvic pain of 50% compared to baseline. • To determine the benefit in function as measured by the pain domain of the Endometriosis Health Profile-30. • To determine the benefit in function, as measured by the non-pain-related domain of the Endometriosis Health Profile-30, related to quality of life associated with endometriosis. • Determine the benefit in the average EAPP score in the NRS. • To determine the benefit in dysmenorrhea, non-menstrual pelvic pain, and dyspareunia based on NRS scores. • Determine the benefit in the Patient Global Assessment (PGA) for dysmenorrhea, NMPP, overall pain severity, and functional impairment. • Determine the Patient Global Impression of Change (PGIC) for dysmenorrhea, NMPP, and dyspareunia. • Determine the change in the use of rescue medication. Secondary Outcomes: • Change from baseline to week 16 in the pain domain score of the Endometriosis Health Profile-30. • Change from baseline to week 16 in endometriosis-related quality of life, as measured by non-rehabilitation domains. Petition 870250084815, dated 09 / 19 / 2025, pp. 98 / 146 93 / 117 related to the pain of EHP-30. • Changes in baseline for weeks 4, 8, 12, and 16 in mean NRS scores for dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia. • Change in baseline for weeks 4, 8, 12, and 16 in the mean EAPP score in the NRS. • Patient Global Assessment (PGA) at week 16 for dysmenorrhea, post-menstrual dysmenorrhea (PMND), and function over the past 4 weeks, as well as current pain. • Patient Global Impression of Change (PGIC) for dysmenorrhea, postmenopausal meningitis, and dyspareunia at week 16 since the start of treatment. • Changes in rescue medication use (per 24 hours) at weeks 4 and 16 compared to baseline. Dosage and route of administration: Test product

[00292] Levonorgestrel Vaginal Delivery System (LVDS) 75 mcg / day.

[00293] Levonorgestrel Vaginal Delivery System (LVDS) 125 mcg / day.

[00294] Reference product

[00295] The placebo vaginal ring will be manufactured to match the shape, size, and color of the LVDS.

[00296] Each LVDS contains approximately 10 mg of LNG, which is designed to release 75 mcg / day and 125 mcg / day. Duration of treatment

[00297] Four treatment cycles of 28 days duration.

[00298] Participants will insert the vaginal ring on the day of Visit 1b and use it continuously for 28 days. After 28 days, participants will change the vaginal ring (remove the current one and insert the next vaginal ring). Petition 870250084815, dated 09 / 19 / 2025, pp. 99 / 146 94 / 117 (without a break).

[00299] The investigator will instruct the participant that the ring should not be removed for more than 3 hours in 24 hours. Statistical Methods

[00300] The primary outcome will be analyzed using an Analysis of Covariance (ANCOVA), all secondary outcomes will be analyzed using appropriate methods.

[00301] Efficacy analyses will be conducted using a modified Intention-to-Treat (mITT) population, defined as all randomized patients who received at least one dose of the randomized study drug, unless otherwise specified in the Statistical Analysis Plan. The randomization ratio will be 1:1:1 among the 3 treatment arms: LVDS 75 mcg / day. LVDS 125 mcg / day. Placebo

[00302] This study has a primary outcome defined as: • To demonstrate the efficacy of the two-dose levonorgestrel vaginal delivery system (LVDS), LVDS 75 mcg / day and LVDS 125 mcg / day, compared to placebo in the management of endometriosis-associated pelvic pain (EAPP) as assessed on a numerical rating scale (NRS).

[00303] EAPP includes dysmenorrhea, NMPP and, if applicable, dyspareunia. The mean baseline EAPP will be calculated using the EAPP scores documented in the e-diary during the last 28 days prior to Visit 1b.

[00304] This study has secondary outcomes defined as: • Proportion of patients meeting response criteria for dysmenorrhea after 12 weeks of treatment with 75 mcg / day and LVDS 125 mcg / day compared with placebo. Petition 870250084815, dated 09 / 19 / 2025, pp. 100 / 146 95 / 117 • Proportion of patients who met the response criteria for nonmenstrual pelvic pain (NMPP) after 12 weeks of treatment with 75 mcg / day and LVDS 125 mcg / day compared with placebo.

[00305] The assessment of pain at baseline will be based on the average of the values ​​observed during the baseline cycle up to the day before the date of the first dose of the randomized study medication.

[00306] A responder (defined for dysmenorrhea and NMPP separately) is defined as a patient who did not experience an increase in the use of rescue analgesic medication during the Week 12 / EOT pain assessment period (last 35 days before the last dose of study medication) compared to the Baseline pain assessment period and whose pain reduction exceeds the response threshold defined as follows: • For dysmenorrhea, achieving an average reduction in NRS scores of 50% compared to baseline. • For non-menstrual pelvic pain, achieving an average reduction in NRS scores of 50% compared to baseline.

[00307] Patients who complete <5 weeks of treatment will be considered non-responders for both dysmenorrhea and non-menstrual pelvic pain. For patients who complete at least 5 weeks of treatment, responder status for dysmenorrhea and non-menstrual pelvic pain will be defined as follows: • For dysmenorrhea, responder status will be defined using the following rules, taking into account analgesic use and requiring at least 2 days of NRS scores for dysmenorrhea in the electronic diary; the average will then be calculated and used in the assessment of responder status for dysmenorrhea. Petition 870250084815, dated 09 / 19 / 2025, pp. 101 / 146 96 / 117 a minimum of 2 days of NRS scores for dysmenorrhea is considered reasonable, since a typical menstrual cycle has bleeding days ranging from 3 to 7 days. • For non-menstrual pelvic pain, responder status was defined using the following rules, taking into account analgesic use and requiring at least 14 days of non-menstrual pelvic pain scores reported in the electronic diary. The average non-menstrual pelvic pain score will then be used to assess responder status for non-menstrual pelvic pain. Requiring a minimum of 14 days of non-menstrual pelvic pain scores is considered reasonable, as this corresponds to at least half of the non-menstrual days in a typical 28-day menstrual cycle.

[00308] The response rate for the placebo arm is assumed to be between 30 and 35%. Example 4

[00309] A single-center, phase 2, open-label clinical study to evaluate the ovulation inhibition of the levonorgestrel (LNG) vaginal delivery system (VDS), released over 28 days on a continuous regimen, in women with a BMI >30 was conducted as detailed below: 1. Study Design 1.1. Study Objectives:

[00310] Primary objective: • To evaluate the inhibition of ovulation measured by ovarian activity (determined using the Hoogland and Skouby score) of the levonorgestrel (LNG) vaginal delivery system (VDS) in treatment cycles (TCs) 1 and 2 in a group of women with BMI > 30 kg / m2.

[00311] Secondary objective: • To assess corpus luteum function after ovulation / luteinized unruptured follicle (LUF) syndrome using the Landgren et al. criteria. Petition 870250084815, dated 09 / 19 / 2025, pp. 102 / 146 97 / 117 • To evaluate the influence of LNG VDS on cervical mucus, endometrial thickness, and follicle-like structure (FLS) diameter. • To evaluate the impact of LNG VDS on blood levels of pituitary (FSH, LH) and ovarian (E2, P) hormones and sex hormone-binding globulin (SHBG). • Evaluate the safety and tolerability of VDS LNG.

[00312] Exploratory objective: • To evaluate the impact of body mass index (BMI) and SHBG levels on LNG pharmacokinetics (PK) and ovulation inhibition. 1.2. Methodology

[00313] Single-center, open-label, phase 2 clinical study to evaluate ovulation inhibition as measured by ovarian activity (determined using the Hoogland and Skouby score) of the levonorgestrel (LNG) vaginal delivery system (VDS) over 28 days on a continuous regimen in healthy female subjects aged 18–35 years with a BMI > 30 kg / m2. 1.3. Test product, dose and method of administration

[00314] LNG VDS was used for vaginal administration. Each LNG VDS contained approximately 10 mg of LNG, which was designed to release 75 pg / day of LNG. One LNG VDS was intended to last 28 continuous days. 1.4. Duration of treatment

[00315] The treatment was carried out in 2 treatment cycles of 28 days each, totaling 56 consecutive days. 2. Efficacy Results 2.1. Primary effectiveness objectives

[00316] The primary efficacy parameter ovulation inhibition was defined as HSS < 4, while no ovulation inhibition was defined as HSS > 5. Petition 870250084815, dated 09 / 19 / 2025, pp. 103 / 146 98 / 117

[00317] The analysis of this parameter was performed for the overall treatment period, as well as for each treatment cycle separately, with all 30 individuals included in the FAS. To detect potential BMI-dependent differences, the analysis of ovulation inhibition was additionally performed by BMI subgroup, with BMI subgroup 1 (30 < BMI < 35) comprising a total of 13 individuals and BMI subgroup 2 (BMI > 35) comprising 17 individuals. Petition 870250084815, dated 09 / 19 / 2025, pp. 104 / 146 Table 10: HSS-based inhibition Inhibition based on HSS - overall frequency analysis, including 95% CI by BMI subgroup (BMI subgroup 1: 30 < BMI > 35; BMI subgroup 2: BMI > 35) and by the total population (TOTAL) - PPS Inhibition Confidence Interval 95% BMI Subgroup Overall Treatment Period Yes No N Proportion Yes Type Lower Limit Upper Limit BMI Subgroup 1 Overall Treatment Period 12 0 12 1.0000 Clopper-Pearson (Exact) 0.7354 1.0000 BMI Subgroup 2 Overall Treatment Period 16 0 16 1.0000 Clopper-Pearson (Exact) 0.7941 1.0000 TOTAL Overall Treatment Period 28 0 28 1.0000 Clopper-Pearson (Exact) 0.8766 1.0000 99 / 117 BMI 2 subgroup: participant 1018 was excluded from the efficacy assessment due to aberrant LNG and SHBG values. Therefore, participant He was considered for this assessment. Petition 870250084815, dated 09 / 19 / 2025, pp. 105 / 146 100 / 117

[00318] Ovulation inhibition was achieved for all individuals throughout the treatment phase. Consequently, no difference was observed between the two BMI subgroups and between treatment cycle 1 and treatment cycle 2.

[00319] All sensitivity analyses performed, i.e., analyses per cycle and throughout the treatment phase for PPS, were in agreement with the result of the primary analysis.

[00320] As supporting analyses, the frequency of the HSS was determined for all individuals and separately by BMI subgroup: for most treatment cycles, the HSS was 4, with a trend towards a higher frequency of HSS 4 in the BMI 2 subgroup and slightly increasing frequencies throughout the treatment (BMI 1 subgroup: 61.54% in cycle 1 and 69.23% in cycle 2; BMI 2 subgroup: 82.35% in cycle 1 and 88.24% in cycle 2). Consequently, HSS values ​​of 3, 2, and 1 were present only in single cycles; due to the low numbers, no BMI dependence could be detected. Petition 870250084815, dated 09 / 19 / 2025, pp. 106 / 146 Table 11: Maximum HSS category. Maximum HSS category - frequency analysis by BMI subgroup (BMI subgroup 1: 30 < BMI > 35; BMI subgroup 2: BMI > 35) and by the total population (TOTAL) - FAS HSS Category Max none / minimum ovarian activity Residual ovarian activity High ovarian activity, including ovulation Not assessable Absent Total BMI Subgroup N % N % N % N % N % N % BMI Subgroup 1 2 15.38 11 84.62 0 0.00 0 0.00 0 0.00 13 100.00 BMI Subgroup 2 2 11.76 15 88.24 0 0.00 0 0.00 0 0.00 17 100.00 Total 4 13.33 26 86.67 0 0.00 0 0.00 0 0.00 30 100.00

[00321] Peak HSS during treatment cycles were assigned to categories such as no / minimal ovarian activity (score 1 / 2), residual ovarian activity (score 3 / 4), and high ovarian activity, including ovulation (score 5 / 6). Residual ovarian activity was observed in 84.62% and 88.24% of individuals in the BMI 1 subgroup and the BMI 2 subgroup, respectively. 101 / 117 Petition 870250084815, dated 09 / 19 / 2025, pp. 107 / 146 102 / 117

[00322] In summary, ovulation inhibition was successfully achieved in all individuals throughout the treatment phase, with no statistically significant differences between the two BMI subgroups. Most individuals still presented residual ovarian activity under treatment and had HSS values ​​of 4. A trend towards an increased frequency of HSS-4 values ​​was observed in cycle 2, with a slightly higher incidence in the BMI 2 subgroup. 2.2. Secondary efficacy objectives 2.2.1 Influence on cervical mucus

[00323] The influence of LVDS on cervical mucus was determined by evaluating the Insler score at each visit where a follicular diameter > 13 mm was observed. Maximum Insler scores were slightly lower during LNG treatment compared to the pre-treatment cycle, indicating a slightly reduced sperm permeability due to progestogen administration. The values ​​(±SD) obtained for the two BMI subgroups were comparable, with mean scores of 6.8 (±3.0) and 7.6 (±1.8) in BMI subgroup 1 and BMI subgroup 2, respectively. 2.2.2 Influence on the diameter of the dominant follicle-like structure

[00324] The influence of LVDS on the diameter of the dominant follicle-like structure was determined by TVUS at multiple study visits. In the pre-treatment cycle, the assessment was performed only until ovulation occurred.

[00325] In detail, in treatment cycle 1, the arithmetic means (± SD) of the DFM increased to 22.16 ± 9.43 mm in the BMI 1 subgroup and to 23.69 ± 9.08 mm in the BMI 2 subgroup. In treatment cycle 2, the arithmetic means (± SD) of the DFM increased to 20.94 ± 8.40 mm in the BMI 1 subgroup and to 25.46 ± 8.52 mm in the BMI 2 subgroup. The values ​​remained stable throughout the Petition 870250084815, dated 09 / 19 / 2025, pp. 108 / 146 103 / 117 treatment period and no ovulation was observed.

[00326] During the course of the study, endometrial proliferation was monitored through endometrial thickness (ET) measurements using TVUS.

[00327] During treatment, ETmax values ​​were reduced to a comparable extent in both BMI subgroups (BMI subgroup 1: 7.98 ± 1.15 mm; BMI subgroup 2: 8.66 ± 1.47 mm) from the summary assessment of both treatment cycles. Assessing the treatment cycles separately, the arithmetic mean of ETmax decreased even further in treatment cycle 2, which was comparable in both BMI subgroups.

[00328] In summary, endometrial proliferation was suppressed under LNG treatment and the extent of suppression did not differ between the two BMI subgroups. Suppression of endometrial proliferation is a known effect of continuous progestin treatment that can impair embryo implantation. 2.2.3 Pituitary and ovarian hormones

[00329] With respect to pituitary and ovarian hormones, the following main results were obtained: Table 12: Maximum FSH concentration [U / L] per cycle. Maximum FSH concentrations [U / L] per cycle - descriptive statistics by analyte, BMI subgroup (BMI 1 subgroup: 30 < BMI > 35; BMI 2 subgroup: BMI > 35) and by the total population (Total) - FAS Subgroup of BMI Treatment Cycle Parameter Subgroup of BMI 1 Subgroup of BMI 2 Total Treatment Cycle 1 N 13 17 30 Arithmetic Mean 6.130 6.726 6.468 Standard Deviation 0.946 1.143 1.087 Minimum 5.04 4.93 4.93 Median 5.780 6.670 6.320 Maximum 7.93 9.26 9.26 Petition 870250084815, dated 09 / 19 / 2025, pp. 109 / 146 104 / 117 Table 12: -continued- Subgroup of BMI Treatment Cycle Parameter Subgroup of BMI 1 Subgroup of BMI 2 Total Treatment Cycle 2 N 13 17 30 Arithmetic Mean 6.535 6.614 6.580 Standard Deviation 1.016 1.393 1.225 Minimum 5.10 4.24 4.24 Median 6.080 6.570 6.485 Maximum 8.14 10.26 10.26

[00330] Peak serum concentrations of follicle-stimulating hormone (FSH) per individual remained fairly stable during treatment, with only slight and comparable fluctuations in both BMI subgroups. Table 13: Maximum LH concentration [U / L] per cycle Maximum LH concentrations [U / L] per cycle - descriptive statistics by analyte, BMI subgroup (BMI 1 subgroup: 30 < BMI > 35; BMI 2 subgroup: BMI > 35) and by the total population (Total) FAS Subgroup of BMI Treatment Cycle Parameter Subgroup of BMI 1 Subgroup of BMI 2 Total Treatment Cycle 1 N 13 17 30 Arithmetic Mean 5.272 6.629 6.041 Standard Deviation 1.952 2.529 2.361 Minimum 2.62 3.28 2.62 Median 4.900 5.790 5.590 Maximum 9.55 11.78 11.78 Treatment Cycle 2 N 13 17 30 Arithmetic Mean 5.432 5.506 5.474 Standard Deviation 2.182 2.248 2.182 Minimum 1.97 1.49 1.49 Median 5.860 5.890 5.875 Maximum 9.59 9.52 9.59 Petition 870250084815, dated 09 / 19 / 2025, pp. 110 / 146 105 / 117

[00331] Peak serum luteinizing hormone (LH) concentrations per individual were influenced by ovulation inhibition, i.e., no LH surges occurred. Results were comparable in both BMI subgroups, with arithmetic means (± SD) of 5,272 ± 1,952 U / L in treatment cycle 1 and 5,432 ± 2,182 U / L in treatment cycle 2 in BMI subgroup 1, and 6,629 ± 2,529 U / L in treatment cycle 1 and 5,506 ± 2,248 U / L in treatment cycle 2 in BMI subgroup 2. All individual values ​​remained below 12 U / L.

[00332] In summary, LNG treatment resulted in the suppression of LH peaks and therefore LH values ​​in both BMI subgroups remained at levels significantly below 20 U / L. Table 14: Maximum E2 concentration [pg / mL] per cycle. Maximum E2 concentrations [pg / mL] per cycle - descriptive statistics by analyte, BMI subgroup (BMI subgroup 1: 30 < BMI < 35; BMI subgroup 2: BMI > 35) and by the total population (Total) - FAS Subgroup of BMI Treatment Cycle Parameter Subgroup of BMI 1 Subgroup of BMI 2 Total Treatment Cycle 1 N 13 17 30 Arithmetic Mean 170.538 208.353 191.967 Standard Deviation 130.587 150.904 141.363 Minimum 22.00 44.00 22.00 Median 163.000 153.000 158.000 Maximum 400.00 506.00 506.00 Treatment Cycle 2 N 13 17 30 Arithmetic Mean 87.538 141.235 117.967 Standard Deviation 77.954 116.740 103.759 Minimum 33.00 38.00 33.00 Median 57,000 103,000 87,000 Maximum 322.00 395.00 395.00 Petition 870250084815, dated 09 / 19 / 2025, pp. 111 / 146 106 / 117

[00333] Peak serum estradiol (E2) concentrations per individual decreased during treatment, from cycle 1 to cycle 2. They were slightly higher in the BMI 2 subgroup compared to the BMI 1 subgroup: in treatment cycle 1, the arithmetic mean (±SD) of the peak E2 concentration per individual was 170.538 ± 130.587 pg / ml in the BMI 1 subgroup and 208.353 ± 150.904 pg / ml in the BMI 2 subgroup, and in treatment cycle 2, the Max E2 was 87.538 ± 77.954 pg / ml and 141.235 ± 116.740 pg / ml, respectively. The Max E2 levels per individual showed great variation. The average Max E2 values ​​indicated that E2 concentrations were not consistently suppressed by LNG application, which is consistent with the observed follicular activity. Petition 870250084815, dated 09 / 19 / 2025, pp. 112 / 146 Table 15: Max E2 categories per cycle. Max E2 Categories per Cycle - Frequency Analysis by BMI Subgroups (BMI subgroup 1: 30 < BMI < 35; BMI subgroup 2: BMI > 35) and by the Total Population (TOTAL) - FAS Max Categories E2 Category 1 Category 2 Category 3 Category 4 Absent Total BMI Subgroup treatment cycle N % N % N % N % N % N % BMI Subgroup 1 treatment cycle 1 0 0.00 1 7.69 2 15.38 10 76.92 0 0.00 13 100.00 treatment cycle 2 0 0.00 0 0.00 5 38.46 8 61.54 0 0.00 13 100.00 BMI subgroup 2 treatment cycle 1 0 0.00 0 0.00 2 11.76 15 88.24 0 0.00 17 100.00 treatment cycle 2 0 0.00 0 0.00 4 23.53 13 76.47 0 0.00 17 100.00 107 / 117 Footnote: Category 1: Max E2 < 20 pg / ml, Category 2: 20 <= Max E2 < 30 pg / ml, Category 3: 30 <= Max E2 < 50 pg / ml, Category 4: >= 50 pg / ml.

[00334] Max E2 concentrations were assigned to categories. Most individuals' Max E2 concentrations fell into category 4 with concentrations > 50 pg / ml in both BMI subgroups and in both treatment cycles. For BMI subgroup 1, the frequency of category 4 was 76.92% in cycle 1 and 61.54% in cycle 2. For BMI subgroup 2, the frequency of category 4 was even higher in both cycles, at 88.24% and 76.47%, respectively. There were no cases of category 1 (< 20 pg / ml) and only one case of category 2 (< 30 pg / mL) in one treatment cycle in subgroup 1; the remaining 13 cycles fell into category 3 (> 30 and < 50 pg / ml). Petition 870250084815, dated 09 / 19 / 2025, pp. 113 / 146 Table 16: Average E2 concentrations [pg / ml] per cycle. Average E2 concentrations [pg / ml] per cycle - descriptive statistics by analyte, BMI subgroup (BMI subgroup 1: 30 < BMI > 35; BMI subgroup 2: BMI > 35) and by the total population (TOTAL) - FAS Subgroup of BMI Treatment Cycle Parameter Subgroup of BMI 1 Subgroup of BMI 2 Total Treatment Cycle 1 N 13 17 30 Arithmetic Mean 81.26999390 86.53501401 84.25350529 Standard Deviation 56.05868781 46.00338472 49.74975566 Minimum 18.8888889 30.0000000 18.8888889 Median 77.85714286 92.33333333 79.21527778 Maximum 201.5555556 193.5555556 201.5555556 Treatment Cycle 2 N 13 17 30 Arithmetic Mean 38.77579365 60.51307190 51.09358466 Standard Deviation 16.92309718 31.70753655 28.16417317 Minimum 19.0000000 25.4444444 19.0000000 Median 37.33333333 55.50000000 38.88888889 Maximum 81.2222222 118.3333333 118.3333333

[00335] The mean serum concentrations of estradiol (E2) per individual also showed a trend of di108 / 117 Petition 870250084815, dated 09 / 19 / 2025, p. 114 / 146: Decrease in values ​​throughout treatment, with higher values ​​in the BMI 2 subgroup: In cycle 1, an arithmetic mean of ~81.27 ± 56.06 pg / ml and ~86.54 ± 46.00 pg / ml was determined in BMI 1 and 2 subgroups, respectively. In cycle 2, an arithmetic mean of ~38.78 ± 16.92 pg / ml and ~60.51 ± 31.71 pg / ml was determined for BMI 1 and 2 subgroups, respectively. The mean E2 throughout the treatment period was ~60.52 ± 33.17 pg / ml in the BMI 1 subgroup and ~73.62 ± 35.16 pg / ml in the BMI 2 subgroup. In both BMI subgroups, the mean and median values ​​of the mean E2 concentrations were well above 30 pg / ml, which is the assumed lower limit to avoid accelerated bone loss. Table 17: Maximum P concentrations [nmol / L] per cycle. Max P concentrations [nmol / L] per cycle - descriptive statistics by analyte, BMI subgroup (BMI subgroup 1: 30 < BMI > 35; BMI subgroup 2: BMI > 35) and by the total population (TOTAL) - FAS Subgroup of BMI Treatment Cycle Parameter Subgroup of BMI 1 Subgroup of BMI 2 Total Treatment Cycle 1 N 13 17 30 Arithmetic Mean 0.959 0.849 0.897 Standard Deviation 0.452 0.333 0.386 Minimum 0.51 0.48 0.48 Median 0.860 0.700 0.830 Maximum 2.00 1.53 2.00 109 / 117 Petition 870250084815, dated 09 / 19 / 2025, pp. 115 / 146 Table 17: -continued Maximum P concentrations [nmol / L] per cycle - descriptive statistics by analyte, BMI subgroup (BMI subgroup 1: 30 < BMI > 35; BMI subgroup 2: BMI > 35) and by the total population (TOTAL) - FAS Subgroup of BMI Treatment Cycle Parameter Subgroup of BMI 1 Subgroup of BMI 2 Total treatment cycle 2 N 13 17 30 Arithmetic Mean 0.758 0.733 0.744 Standard Deviation 0.445 0.393 0.409 Minimum 0.00 0.00 0.00 Median 0.730 0.700 0.715 Maximum 1.60 1.60 1.60 110 / 117

[00336] Peak serum progesterone (P) concentrations per individual were comparable during both treatment cycles and for the overall treatment period; arithmetic mean values ​​(±SD) of both BMI subgroups were also comparable, with: 0.959 ± 0.452 nmol / l in treatment cycle 1 and 0.758 ± 0.445 nmol / l in treatment cycle 2 for BMI subgroup 1, and 0.849 ± 0.333 nmol / l and 0.733 ± 0.393 nmol / l for BMI subgroup 2, respectively. All individual values ​​were <2.0 nmol / l. In summary, serum P concentration remained low during treatment due to the absence of ovulation. Petition 870250084815, dated 09 / 19 / 2025, pp. 116 / 146 111 / 117

[00337] The impact of LVDS on blood levels of sex hormone-binding globulin (SHBG) was evaluated in comparison with baseline values ​​obtained during the pre-treatment cycle. Mean serum SHBG concentrations were similar in both BMI subgroups before the start of the study treatment (see Fig. 10).

[00338] SHBG levels clearly decreased under LNG therapy. After the start of treatment in cycle 1, the mean curves of both BMI subgroups show a comparable sharp decrease in SHBG levels for approximately the first half of the cycle. The decrease in SHBG concentrations continued into the second half of the first cycle, but was slower thereafter. During treatment cycle 2, the mean serum concentration vs. time curves show a relatively stable course throughout the cycle.

[00339] Assessment of the change from baseline confirms the impression derived from the serum concentration vs. time curves: SHBG levels clearly decreased under LNG treatment to a similar degree in both BMI subgroups: at visit D55, i.e., after 55 ± 1 days of LNG treatment, SHBG levels decreased to approximately 45% (23.54 of 52.24 nmol / l) of the baseline value in BMI subgroup 1 and to 48.74% (26.75 of 54.88 nmol / l) in BMI subgroup 2.

[00340] These results are well aligned with data from the literature that describe a 50% decrease in SHBG levels during LNG treatment. 2.2.4 Pharmacokinetic results

[00341] LNG pharmacokinetic assessment was performed during this clinical study to evaluate the impact of BMI on LNG pharmacokinetics as an exploratory objective of the study (see Fig. 11). Petition 870250084815, dated 09 / 19 / 2025, pp. 117 / 146 112 / 117

[00342] The mean plasma concentration vs. time curves obtained after multiple doses of LVDS in all individuals showed a relatively stable course throughout the treatment phase, with a slight continuous decrease from the start of treatment in cycle 1 (466 pg / mL) to the lowest concentration at the last visit during treatment in cycle 2 (382 pg / mL).

[00343] The mean curves separated by BMI subgroup generally confirm this course and are similar in shape. However, BMI 1 subgroup showed higher plasma concentrations for LNG throughout the course of treatment compared to BMI 2 subgroup. This observation is well aligned with literature data reporting lower plasma LNG concentrations in individuals with higher BMI.

[00344] The average pharmacokinetic parameters calculated for LNG corroborate the impression derived from the plasma concentration vs. time profiles.

[00345] For LNG, during the overall treatment period, the arithmetic mean minimum concentrations (± SD) were 452 pg / mL (± 86.5 pg / mL) in the BMI 1 subgroup and 374 pg / mL (± 101 pg / mL) in the BMI 2 subgroup, confirming the difference observed between both subgroups (i.e., approx. 17.26% difference between the BMI 1 subgroup and the BMI 2 subgroup).

[00346] The arithmetic mean values ​​per treatment cycle (TC) ranged from 428 pg / mL (TC2) to 476 pg / mL (TC1) in the BMI 1 subgroup and were 374 (TC1 and TC2) in the BMI 2 subgroup.

[00347] A similar trend was observed for the geometric mean of the Area Under the Curve calculated for the overall treatment period (AUC0-56,ss) totaling values ​​of 24900 day*pg / mL and 20900 day*pg / mL for the BMI 1 subgroup and the BMI 2 subgroup respectively (i.e., approx. 16.06% difference between the BMI 1 subgroup). Petition 870250084815, dated 09 / 19 / 2025, pp. 118 / 146 113 / 117 and the BMI 2 subgroup). The geometric mean values ​​per treatment cycle ranged from 11,800 day*pg / mL (TC2) to 13,100 day*pg / mL (TC1) in the BMI 1 subgroup and were 10,100 day*pg / mL (TC1 and TC2) in the BMI 2 subgroup.

[00348] The linear regression of AUC0-56,ss, as well as Cav,ss56, corroborates the impression derived from the analysis of variance: for both parameters, the regression lines show a decline with increasing BMI values. The assessments clearly indicate an influence of BMI on total exposure throughout the observed dosage range and a trend towards lower maximum exposure with increasing BMI. 3. CONCLUSIONS

[00349] Summarizing the results of this essay, the following conclusions are reached: • Treatment with 75 μg / day resulted in complete inhibition of ovulation in the study population of individuals with a BMI > 30 kg / m2. • Ovarian activity was not completely suppressed in most individuals; in both BMI subgroups, most individuals had HSS values ​​of 4. The profile referred to is generally intended for progestin-only treatment in order to avoid hypoestrogenic side effects. • Although ovarian activity was not completely suppressed, treatment with 75 μg / day of LNG adequately prevented the occurrence of LH surges and thus completely inhibited normal ovulations that could lead to pregnancy. • Mean plasma E2 levels were suppressed under treatment, but remained well above the commonly accepted threshold for clinically relevant bone mineral density loss, so no safety concerns should be inferred from this. Petition 870250084815, dated 09 / 19 / 2025, pp. 119 / 146 114 / 117 suppression of E2. • SHBG levels decreased clearly under LNG treatment to a similar degree in both BMI subgroups. • Pharmacokinetic evaluation clearly indicates the influence of BMI on total exposure over the observed dosing range and a trend toward lower peak exposure with increasing BMI (i.e., the arithmetic mean of Cav was approximately 17.26% lower and the geometric mean of AUC0-56.ss was approximately 16.06% lower when comparing the BMI 2 subgroup with the BMI 1 subgroup). • Comparison of pharmacodynamic parameters (HSS, E2 concentrations) in BMI subgroups showed a trend toward slightly less ovarian suppression in the higher BMI subgroup, but the variability was high and the difference in HSS was not statistically significant. • Treatment with LVDS was well tolerated. • The number of adverse events related to LNG VDS was comparable between the two BMI subgroups. REFERENCES (1) Merck Sharp & Dohme Limited. Cerazet® 75 pg (desogestrel). Data sheet (SmPC February 2019). Spanish Agency for Medicines and Health Products (AEMPS). Available at: https: / / cima.aemps.es / cima / dochtml / p / 62285 / P_62285.html (2) Rice C, Killick S, Hickling D, Coelingh Bennink H. Ovarian activity and vaginal bleeding patterns with a desogestrel-only preparation at three different doses. Hum Reprod 1996;11:737-40. (3) Rice CF, Killick SR, Dieben T, Coelingh Bennink H. A comparison of ovulation inhibition achieved by desogestrel 75 pg and levonorgestrel 30 pg daily. Hum Reprod 1999;14:982-5. (4) Duijkers IJM, Heger-Mahn D, Drouin D, Skouby S. A randomized Petition 870250084815, dated 09 / 19 / 2025, pp. 120 / 146 115 / 117 study comparing the effect on ovarian activity of a progestogen-only pill (POP) containing desogestrel and a new POP containing drospirenone in a 24 / 4 regimen. Eur J Contracept Reprod Health Care 2015;20:41927. (5) McCann MF, Potter LS. Progestin-only oral contraception: a comprehensive review. Contraception 1994;50(Suppl 1):S9-195. (6) Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill. A double-blind study comparing the contraceptive efficacy, acceptability and safety of two progestogen-only pills containing desogestrel 75 pg / day or levonorgestrel 30 pg / day. Eur J Contracept Reprod Health Care 1998;3:169-78. (7) Ingrid J.M. Duijkers , Christine Klipping , Tanja Rautenberg , Barbara S. Schug , Prithi S. Kochhar , Hermann Osterwald , Michael Oettel , Effect on ovarian activity and ovulation inhibition of different oral dosages of levonorgestrel, Contraception (2022), doi:https: / / doi.org / 10.1016 / j.contraception.2022. 01.018 (8) Sivin, I. 1984. Five-year clinical studies of Norplant implants. In: The Norplant Subdermal Contraceptive System. M.M. Shaaban (ed.). Assiut, Egypt: Assiut University, pp. 74-75. (9) Milsom I, Korver T. Ovulation incidence with oral contraceptives: a literature review. BMJ Sexual & Reproductive Health. 2008;34:237246. (10) V. Brache, F. Alvarez & A. Faundes (2001) Mechanism of action of levonorgestrel contraceptive implants, Gynecological Endocrinology, 15:sup2, 14-20, DOI: 10.1080 / gye.15.s2.14.20 (11) Meirik et al (2003) Implantable Contraceptive for women. Human Reproduction Update, 9(1): 49-59. (12) Glacier (2016) Anna Glasier, Chapter 134 - Contraception, Editor(s): J. Larry Jameson, Leslie J De Groot, David M. de Kretser, Linda C. Giudice, Ashley B. Grossman, Shlomo Melmed, John T. Potts, Gor Petição 870250084815, de 19 / 09 / 2025, pág. 121 / 146 116 / 117 don C. Weir, Endocrinology: Adult and Pediatric (Seventh Edition), W.B. Saunders, 2016, Pages 2297-2309.e2, (13) Barbieri (1992). „Hormone treatment of endometriosis: the estrogen threshold hypothesis”. Am J Obstet Gynecol. 1992 Feb;166(2): 740-5. doi: 10.1016 / 0002-9378(92)91706-g. (14) Schindler, AE (2011). Dienogest in long-term treatment of endometriosis. Int J Womens Health 3: 175-184. (15) Taylor, HS, Giudice, LC, Lessey, BA, Abrao, MS, Kotarski, J, Archer, DF, Diamond, MP, Surrey, E, Johnson, NP, Watts, NB, Gallagher, JC, Simon, JA, Carr, BR, Dmowski, WP, Leyland, N, Rowan, JP, Duan, WR, Ng, J, Schwefel, . B , Thomas , JW , Jain , RI and Chwalisz , K (2017). Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist. N Engl J Med 377(1): 28-40. (16) Vercellini, P, Viganò, P, Somigliana, E and Fedele, L (2014). Endometriosis: pathogenesis and treatment. Nature Reviews Endocrinology 10(5): 261-275. (17) Paolo Vercellini, MD, Laura Buggio, MD, Maria Pina Frattaruolo, MD, Alessandra Borghi, MD, Dhouha Dridi, MD, Edgardo Somigliana, MD. 51 , 68-9 (18) Casper, RF (2017). Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills. Fertil Steril 107(3): 533-536. (19) Caruso et al (2019). “Randomized study on the effectiveness of nomegestrol acetate plus 17β-estradiol oral contraceptive versus dienogest oral pill in women with suspected endometriosis-associated chronic pelvic pain”. BMC Womens Health. 2022 May 10;22(1):146. doi: 10.1186 / s12905-022-01737-7. (20) Vercellini, P, Bracco, B, Mosconi, P, Roberto, A, Alberico, D, Petição 870250084815, de 19 / 09 / 2025, pág. 122 / 146 117 / 117 Dhouha, D and Somigliana, E (2016). Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: a before and after study. Fertil Steril 105(3): 734-743.e733. (21) Bulun, Yang et al. (2002): “Estrogen production and Metabolism in Endometriosis” Annals New York Academy of Sciences 2002, pp 7585. (22) Brosens and Gellersen (2012): “The uterus under hormonal control- cycling for life” Molecular and Cellular Endocrinology, 358, (2012), 145,

Claims

1. Levonorgestrel for use in a method to provide contraception in a female individual, characterized in that it comprises the continuous administration of levonorgestrel to said individual, wherein the daily amount of levonorgestrel administered is from about 60 pg / day to about 100 pg / day, wherein the route of administration is vaginal administration.

2. Levonorgestrel for use in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea in a female individual, characterized in that it comprises the continuous administration of levonorgestrel to said individual, wherein the daily amount of levonorgestrel administered is from about 60 pg / day to about 160 pg / day, wherein the route of administration is vaginal administration.

3. Levonorgestrel for use in a method for treating endometriosis, endometriosis-associated pelvic pain (EAPP) and / or dysmenorrhea, according to claim 2, characterized in that said treatment also provides contraception.

4. Use of Levonorgestrel as a contraceptive, characterized by the fact that it comprises the continuous administration of Levonorgestrel in an amount of about 60 pg / day to about 200 pg / day to a female individual, wherein the route of administration is vaginal administration.

5. Levonorgestrel for use in a method according to any one of claims 1 to 3, or the use of Levonorgestrel as a contraceptive according to claim 4, characterized in that no additional contraceptive ingredient, preferably no estrogen, is administered to the female subject at the same time.

6. Levonorgestrel for use in accordance with any of claims 1 to 3, or use of Levonorgestrel in accordance with claims 4 or 5, characterized in that said administration of Levonorgestrel also induces amenorrhea.

7. Drug delivery device, characterized in that it comprises: (a) a core comprising a polymer, preferably polyurethane, (b) a sheath substantially or completely surrounding said core, said sheath comprising a polymer, preferably an ethylene vinyl acetate copolymer with a vinyl acetate content of about 10 to 40% w / w; and (c) Levonorgestrel dissolved or dispersed in said core and / or said sheath, wherein the total amount of Levonorgestrel present in said core and / or said sheath is between about 9 mg and about 11 mg.

8. Drug delivery device according to claim 7, characterized in that said device has a drug delivery profile particularized by the device releasing (i) no more than about 150 pg of levonorgestrel during an initial 24-hour release period, and (ii) about 60 pg to 90 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period; when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2 medium.

9. Drug delivery device according to claim 7, characterized in that said device has a drug delivery profile particularized by the device releasing (i) no more than 250 pg of levonorgestrel during an initial 24-hour release period, and (ii) about 90 pg to 150 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period; when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2 medium.

10. Drug delivery device according to claim 7, characterized in that said device has a drug delivery profile particularized by the device releasing (i) no more than about 300 pg of levonorgestrel during an initial 24-hour release period, and (ii) about 110 pg to 180 pg of levonorgestrel per day for at least 27 days after the initial 24-hour release period; when the device is subjected to an in vitro release test in a 0.2M sodium acetate buffer with 1.0% sodium lauryl sulfate (SLS) surfactant adjusted to pH 4.2 medium.

11. Drug delivery device, according to any one of claims 7 to 10, characterized in that said device provides a mean Cmax value for levonorgestrel of less than 1 ng / ml after a 28-day treatment cycle and less than 0.7 ng / ml after two 28-day treatment cycles, and a mean AUC (0.-t) value of less than 350 h*ng / ml after a 28-day treatment cycle and less than 370 h*ng / ml after two 28-day treatment cycles, in a female subject, after the delivery device has been placed intravaginally inside the subject's body.

12. Drug delivery device, according to Petition 870250084815, dated 09 / 19 / 2025, pp. 126 / 146 4 / 4 any of claims 7 to 10, characterized in that said device provides a mean Cmax value for levonorgestrel of less than 1.6 ng / ml after a 28-day treatment cycle and less than 1 ng / ml after two 28-day treatment cycles each, and a mean AUC (0-t) value of less than 580 h*ng / ml after a 28-day treatment cycle and less than 540 h*ng / ml after two 28-day treatment cycles each in a female subject, after the delivery device has been placed intravaginally inside the subject's body.

13. Drug delivery device, according to any one of claims 7 to 12, characterized in that the device does not comprise any additional contraceptive ingredient, preferably the device does not comprise any estrogen.

14. Drug delivery device, according to any one of claims 7 to 13, characterized in that (i) levonorgestrel is present in the core at a concentration of about 0.20 to about 1.00 % by weight based on the total weight of the core; and / or (ii) the sheath has a thickness between about 5 and about 500 µm, preferably from about 50 to about 200 µm.

15. Drug delivery device, according to any one of claims 7 to 14, characterized in that the drug delivery device has a shape selected from either a spiral shape or a ring shape, preferably in that the drug delivery device has a ring shape, preferably in that the device is a vaginal ring.

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