Compositions and methods for intrauterine artificial insemination (IUI)

Abstract

Described herein are methods, uses, and compositions comprising FSH for use in the treatment of infertility by intrauterine artificial insemination.

Description

[0001] The present invention relates to methods, compositions and pharmaceutical products for treating infertility. Background Art

[0002] Assisted reproductive technologies (ART) such as in vitro fertilization (IVF) are well known. ART generally requires a controlled ovarian stimulation (COS) step in which a group of follicles are stimulated to full maturity. Standard COS protocols involve the administration of gonadotropins such as follicle stimulating hormone (FSH), alone or in combination with luteinizing hormone (LH) activity, to stimulate multiple follicles to develop. Typically, COS requires the administration of GnRH analogs (GnRH agonists) or GnRH antagonists prior to and / or during stimulation to prevent a premature LH surge that could induce ovulation prior to planned oocyte retrieval. The goal of COS is generally to stimulate the maturation of multiple follicles so that when ovulation is triggered, multiple oocytes can be retrieved for fertilization. Generally, the best oocytes are selected for implantation, while others may be cryopreserved for future use.

[0003] In cases where the ovarian response is too high, COS may be associated with a risk of ovarian hyperstimulation syndrome (OHSS), which may lead to the cancellation of the COS cycle and, in severe cases, may be life-threatening. The ability to predict a woman's ovarian response potential to COS may allow the development of a personalized or individualized COS regimen. For example, such an individualized regimen may reduce the risk of OHSS in women predicted to have an excessive ovarian response to COS and prevent the cancellation of a COS cycle. The level of anti-Mullerian hormone (AMH) is directly related to the response of the ovaries to gonadotropins during COS. Therefore, high levels of AMH are a good predictor of excessive ovarian response and an indicator of OHSS risk, while low levels of AMH predict a poor ovarian response to COS.

[0004] Clinical research over the past few years has focused on the development of personalized dosing regimens for COS, initially without the use of AMH but based on other predictors of ovarian response. These predictors include age, body mass index (BMI), FSH, and antral follicle count (AFC).

[0005] As mentioned above, the standard COS protocol requires daily administration of FSH to induce the growth of multiple follicles to obtain enough oocytes for IVF. FSH is a natural hormone secreted by the anterior pituitary gland. In healthy women, FSH induces the growth of a single dominant follicle each month, which ovulates during each natural cycle. FSH purified from the urine of postmenopausal women has been used for many years in the treatment of infertility, both to promote ovulation in natural reproduction and to induce the growth of multiple follicles to obtain enough oocytes for ART.

[0006] So far, the only recombinant FSH (rFSH) products approved for ovarian stimulation are follicle-stimulating hormone alpha ( Merck Serono / EMD Serono) and follitropin beta ( Merck & Co. / Schering-Plough (MSD / Schering-Plough), are derived from the Chinese Hamster Ovary (CHO) cell line and have only 2,3-sialylation. The applicant has developed human cell line-derived rFSH, which is the subject of international patent application number PCT / GB 2009 / 000978 published as WO 2009 / 127826 A. On December 13, 2016, the European Commission (EC) approved (follitropin delta, also known as FE999049), a human cell line-derived recombinant follicle-stimulating hormone (human rFSH), for use in controlled ovarian stimulation of multiple follicle development in women undergoing assisted reproductive technology (ART), such as in vitro fertilization (IVF) cycles. It is the first rFSH derived from a human cell line. The (Follitropin Delta) product is produced by the method disclosed in International Patent Application No. PCT / GB 2009 / 000978.

[0007] In the context of IVF, The dosimetry was individualized for each patient and was designed to achieve an ovarian response associated with a favorable safety / efficacy profile, i.e., to achieve an adequate number of retrieved oocytes and to reduce the number of interventions required to prevent OHSS. Doses are given in microgram (μg) quantities. Individualized doses can be modeled based on AMH and body weight to obtain 8-14 oocytes in an ART cycle. To this end, for the first treatment cycle, an individual daily dose can be determined based on the woman's serum AMH concentration (also referred to herein as "serum AMH level") and her body weight (which depends on the serum AMH concentration). This dose can be based on the most recent (i.e., within the last 24 months or within the last 12 months) AMH was determined by AMH Plus immunoassay (Roche). The individual daily dose was maintained throughout the stimulation period. For women with AMH < 15 pmol / L, regardless of body weight, The daily dose can be 12 μg. For women with AMH ≥ 15 pmol / L, The daily dose may be lower and may range from 0.19 μg / kg to 0.10 μg / kg at AMH concentrations of 15 to ≥40 pmol / L, with a maximum dose of 12 μg in the first cycle. For subsequent treatment cycles, the dose may be maintained or modified based on the patient's ovarian response in the previous cycle. The same daily dose can be used if the patient had an adequate ovarian response in the previous cycle and did not develop OHSS. In case of a low ovarian response in the previous cycle, the daily dose can be increased by 25% or 50% in subsequent cycles, depending on the degree of response observed. In case of a high ovarian response in the previous cycle, the daily dose can be reduced by 20% or 33% in subsequent cycles, depending on the degree of response observed. In patients who developed OHSS or are at risk of OHSS in the previous cycle, the daily dose in subsequent cycles can be 33% lower than the dose in the cycle in which OHSS occurred or was at risk of OHSS. The maximum daily dose is usually 24 μg.

[0008] Intrauterine insemination (IUI) is a fertility treatment method that uses a small catheter to place sperm directly into the uterus. For example, it can be used in situations where vaginal intercourse is not possible (e.g. due to physical disabilities or psychosexual problems), or to treat couples who are infertile due to medical conditions (e.g., endometriosis or low sperm count or quality), or for couples with unexplained infertility. IUI is widely used because it is a minimally invasive, low-cost alternative to in vitro fertilization (IVF) and can be conveniently performed in a clinic. The goal of IUI is to improve the chances of fertilization by increasing the number of healthy sperm that reach the fallopian tubes when the woman is most fertile. IUI can be performed in patients who have undergone ovarian stimulation to increase the likelihood of a positive outcome. However, unlike COS used in IVF and ART, which aims to obtain 8-14 oocytes before triggering ovulation, IUI aims to obtain only two to three follicles ≥16 mm on the day before or on the day of triggering ovulation and to avoid multiple pregnancies.

[0009] Individualized stimulation regimens are needed to provide improved pregnancy outcomes for patients undergoing IUI. Summary of the invention

[0010] In the proof-of-concept study described below, the applicants demonstrated that The effectiveness of personalized dosage regimens based on AMH and weight. In the first cycle, the second cycle, and the third cycle, the percentages of 2 or 3 mature follicles (defined as follicles of ≥16mm detected on the day before triggering ovulation or on the day of triggering ovulation and / or for example in the last ultrasound scan before triggering) in the treated patients were 34%, 37%, and 47%, respectively. The percentages of patients with more than 3 follicles were 1.9%, 0%, and 1.5%, respectively. Therefore, the dosage regimen described herein achieves the expected goal. Among 40 clinical pregnancies, only 6 multiple pregnancies (15%) (twins only) were observed, indicating that the dosage regimen is a safe method. In 3 IUI cycles, the clinical pregnancy rates of each IUI cycle of intended treatment were 16%, 14.3%, and 16.2%, respectively. The cumulative clinical pregnancy rate of patients who completed the study within 3 cycles was 37.7%, which is higher than previous studies using conventional rFSH administration with only 2,3-sialylation, indicating that it is useful for clinical practice.

[0011] According to some aspects, a composition comprising follicle stimulating hormone (FSH) is provided, the composition is used for use in the infertility of the patient whose serum AMH level is <15pmol / L by intrauterine artificial insemination (for example, intrauterine artificial insemination is performed by controlled ovarian stimulation to treat infertility) [for example, to improve pregnancy rate and / or live birth rate, for example, to improve pregnancy rate and / or live birth rate compared with the treatment performed by utilizing only 2,3-sialylated rFSH, for example, to improve pregnancy rate and / or live birth rate compared with the fixed dose treatment performed by utilizing only 2,3-sialylated rFSH], wherein the composition will be administered with 0.048 μg to 0.052 μg, for example, 0.05 μg recombinant FSH / kg patient weight / day or a dosage equivalent thereto. The use may include the step of determining the serum AMH level of the patient, and the step of administering the dosage to the patient whose serum AMH level is <15pmol / L. In some aspects, the composition will be administered with a dosage of 0.05 μg recombinant FSH / kg patient weight / day. In some aspects, FSH is recombinant FSH, such as recombinant FSH including α2,3-sialylation and α2,6-sialylation, such as recombinant FSH including α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation and wherein 80% to 95% of the total sialylation is α2,3-sialylation. In some aspects, FSH is recombinant FSH produced or expressed in a human cell line. The use may include another step of triggering ovulation (e.g., by administering a dose of 4,000 to 11,000 IU hCG or a dose equivalent thereto). The use may include another step of intrauterine artificial insemination. Treatment of infertility by intrauterine artificial insemination may be intrauterine artificial insemination by controlled ovarian stimulation [e.g., by controlled ovarian stimulation to prepare the patient for (subsequent step) intrauterine artificial insemination]. Treatment of infertility by intrauterine insemination may include controlled ovarian stimulation (e.g. using rFSH with α2,3-sialylation and α2,6-sialylation) with the aim of obtaining 2 or 3 mature follicles (defined as follicles ≥ 16 mm detected on the day before or on the day of triggered ovulation and / or e.g. on the last ultrasound scan before triggering) for a subsequent intrauterine insemination step.

[0012] According to some aspects, a composition comprising follicle stimulating hormone (FSH) is provided, the composition is used for treating the infertility of the patient with serum AMH level ≥15pmol / L (for example, serum AMH ≥23pmol / L) by intrauterine artificial insemination (for example, treating infertility by intrauterine artificial insemination with controlled ovarian stimulation) [for example, to improve pregnancy rate and / or live birth rate, for example, to improve pregnancy rate and / or live birth rate compared with the treatment performed by utilizing only 2,3-sialylated rFSH, for example, to improve pregnancy rate and / or live birth rate compared with the fixed dose treatment performed by utilizing only 2,3-sialylated rFSH], wherein the composition will be used with 0.025 to 0.0475 μg recombinant FSH / kg patient weight / day or a dosage suitable therefor. In some aspects, the patient can be a patient with polycystic ovary syndrome (PCOS). In some aspects, the patient can be a patient with PCOS of serum AMH ≥23pmol / L. According to some aspects, a composition comprising follicle stimulating hormone (FSH) is provided for use in treating infertility in patients with PCOS with serum AMH levels ≥ 15 pmol / L by intrauterine insemination (e.g., treating infertility by intrauterine insemination with controlled ovarian stimulation) [e.g., to improve pregnancy rate and / or live birth rate, e.g., to improve pregnancy rate and / or live birth rate compared to treatment with rFSH comprising only 2,3-sialylation, e.g., to improve pregnancy rate and / or live birth rate compared to fixed-dose treatment with rFSH comprising only 2,3-sialylation], wherein the composition will be administered at a dose of 0.025 to 0.0475 μg recombinant FSH / kg patient weight / day or equivalent thereto. In some aspects, the composition will be administered at a dose of 0.025 to 0.0475 μg recombinant FSH / kg patient weight / day. In some aspects, FSH is recombinant FSH, for example, including α2,3-sialylated and α2,6-sialylated recombinant FSH, for example, including α2,3-sialylated and α2,6-sialylated recombinant FSH, wherein 5% to 20% of total sialylation is α2,6-sialylated and wherein 80% to 95% of total sialylation is α2,3-sialylated. In some aspects, FSH is recombinant FSH produced or expressed in human cell line. The use may include the step of determining the serum AMH level of the patient, and the step of applying the dosage to the patient of serum AMH level ≥15pmol / L. The use may include another step of triggering ovulation (for example, by applying 4,000 to 11,000IU hCG dosage or dosage comparable thereto). The use may include another step of intrauterine artificial insemination. Treatment of infertility by intrauterine insemination may be intrauterine insemination with controlled ovarian stimulation [eg, controlled ovarian stimulation to prepare the patient for (a subsequent step of) intrauterine insemination].Treatment of infertility by intrauterine insemination may include controlled ovarian stimulation (e.g. using rFSH with α2,3-sialylation and α2,6-sialylation) with the aim of obtaining 2 or 3 mature follicles (defined as follicles ≥ 16 mm detected on the day before or on the day of triggered ovulation and / or e.g. on the last ultrasound scan before triggering) for a subsequent intrauterine insemination step.

[0013] The composition can be used to administer rFSH at a prescribed dose (e.g., a starting dose of rFSH) from day 1 to day 6 of treatment, i.e., from day 1 to day 6 of stimulation. Starting from day 7 of treatment (day 7 of stimulation), the dose of rFSH can be: increased (e.g., increased to a dose of up to 150% of the starting dose, e.g., increased to a dose of 120% to 150% of the starting dose); reduced (e.g., reduced to a dose of 50% of the starting dose, e.g., reduced to a dose of 50% to 80% of the initial dose); or maintained at the starting dose. The dose can be increased, reduced, or maintained based on the patient's ovarian response (e.g., measured by ultrasonography).

[0014] The (e.g., starting) dose disclosed herein may be a dose for the first cycle of IUI. For the second and subsequent cycles of IUI, the "starting dose" may be: increased (e.g., increased to a dose of up to 150% of the starting dose of the first cycle, e.g., increased to a dose of 120% to 150% of the starting dose of the first cycle); reduced (e.g., reduced to a dose of 50% of the starting dose of the first cycle, e.g., reduced to a dose of 50% to 80% of the starting dose of the first cycle); or maintained at the starting dose of the first cycle. The dose may be increased, decreased, or maintained based on the patient's response to the first cycle of IUI (e.g., measured by the number of mature follicles ≥16 mm obtained in the first cycle on the day before or on the day of triggering and / or detected, for example, in the last ultrasound scan before triggering).

[0015] According to some aspects, a method for treating infertility in patients with serum AMH levels <15pmol / L by intrauterine artificial insemination is provided (e.g., a method for treating infertility by intrauterine artificial insemination with controlled ovarian stimulation), the method comprising administering to the patient 0.048μg to 0.052μg recombinant FSH (rFSH) / kg patient weight / day, for example 0.05μg rFSH / kg patient weight / day or a dose equivalent thereto, optionally wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation. The method may be a method for improving one or both of pregnancy rate and live birth rate, for example, a method for improving one or both of pregnancy rate and / or live birth rate compared to treatment with rFSH comprising only 2,3-sialylation, for example, a method for improving one or both of pregnancy rate and / or live birth rate compared to fixed-dose treatment with rFSH comprising only 2,3-sialylation. The method may be included in determining the serum AMH level of the patient before administration, and administering rFSH dosage to the patient of serum AMH level <15pmol / L. In some aspects, rFSH is administered with a dosage of 0.05 μg rFSH / kg patient weight / day. In some aspects, rFSH includes α2,3-sialylation and α2,6-sialylation, for example, includes α2,3-sialylation and α2,6-sialylated rFSH, wherein 5% to 20% in total sialylation is α2,6-sialylation and wherein 80% to 95% in total sialylation is α2,3-sialylation. In some aspects, rFSH has been used in human cell lines (e.g. cell line). The method may further include triggering ovulation (e.g., by administering hCG at a dose of 4,000 to 11,000 IU hCG). The method may further include the step of intrauterine insemination. Treatment of infertility by intrauterine insemination may be intrauterine insemination by controlled ovarian stimulation, for example, by controlled ovarian stimulation to prepare the patient for (subsequent step) intrauterine insemination. Treatment of infertility by intrauterine insemination may include controlled ovarian stimulation (e.g., using rFSH with α2,3-sialylation and α2,6-sialylation), with the aim of obtaining 2 or 3 mature follicles (wherein "mature follicles" are defined as follicles ≥16 mm detected on the day before or on the day of triggering ovulation and / or, for example, in the last ultrasound scan before triggering) for a subsequent intrauterine insemination step.

[0016] According to some aspects, a method for treating infertility of a patient with serum AMH level ≥15pmol / L (e.g., serum AMH ≥23pmol / L) by intrauterine artificial insemination is provided (e.g., a method for treating infertility by intrauterine artificial insemination with controlled ovarian stimulation), the method comprising administering 0.025 to 0.0475 μg recombinant FSH (rFSH) / kg patient weight / day or a dose equivalent thereto to the patient, optionally wherein rFSH includes α2,3-sialylation and α2,6-sialylation. In some aspects, the patient may be a patient with polycystic ovary syndrome (PCOS). The method may be a method for improving one or both of pregnancy rate and live birth rate, such as one or both of pregnancy rate and / or live birth rate compared to treatment using only 2,3-sialylated rFSH, such as one or both of pregnancy rate and / or live birth rate compared to fixed dose treatment using only 2,3-sialylated rFSH. In some aspects, rFSH is administered at a dose of 0.025 to 0.0475 μg rFSH / kg patient body weight / day based on the patient's serum AMH level, as follows:

[0017]

[0018]

[0019] In some aspects, rFSH includes α2,3-sialylation and α2,6-sialylation, for example, rFSH includes α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation and wherein 80% to 95% of the total sialylation is α2,3-sialylation. In some aspects, rFSH has been expressed in human cell lines (e.g. Cell line). The method may be included in determining the serum AMH level of the patient before administration, and applying rFSH dosage to the patient with serum AMH level ≥15pmol / L. The method may further include triggering ovulation (e.g., by administering hCG with a dose of 4,000 to 11,000IU hCG). The method may further include the step of intrauterine artificial insemination. Treatment of infertility by intrauterine artificial insemination may be intrauterine artificial insemination by controlled ovarian stimulation, for example, by controlled ovarian stimulation to prepare the patient for (subsequent step) intrauterine artificial insemination. Treatment of infertility by intrauterine artificial insemination may include controlled ovarian stimulation (e.g., using rFSH with α2,3-sialylation and α2,6-sialylation), with the aim of obtaining 2 or 3 mature follicles (wherein "mature follicles" are defined as ≥16mm follicles detected the day before triggering ovulation or the day of triggering ovulation and / or for example in the last ultrasound scan before triggering) for subsequent intrauterine artificial insemination steps. DETAILED DESCRIPTION

[0020] The applicant has demonstrated the effectiveness of an AMH and weight-based personalized dosage regimen of rFSH including α2,3-sialylation and α2,6-sialylation (e.g., 5% to 20% of total sialylation is α2,6-aluminate, and 80% to 95% of total sialylation is α2,3-sialylation) in IUI (e.g., intrauterine insemination by controlled ovarian stimulation to treat infertility). In the first, second, and third cycles of IUI, the percentages of 2 or 3 mature follicles (“mature follicles” are defined as follicles of ≥16 mm detected on the day before or on the day of triggering ovulation and / or, for example, in the last ultrasound scan before triggering) in the treated patients were 34%, 37%, and 47%, respectively. The percentages of patients reaching more than 3 follicles were 1.9%, 0%, and 1.5%, respectively. Therefore, the dosing regimen described herein achieves the desired goal. Among the 40 clinical pregnancies, only 6 multiple pregnancies (15%) were observed, indicating that this dosing regimen is a safe method. In the 3 IUI cycles, the clinical pregnancy rates of each IUI cycle for the intended treatment were 16%, 14.3%, and 16.2%, respectively. The cumulative clinical pregnancy rate of patients who completed the study within 3 cycles was 37.7%, indicating that it is useful for clinical practice.

[0021] Thus, provided herein are treatment and dosing regimens constructed for treating infertility in patients via IUI.

[0022] definition

[0023] Unless otherwise defined, the technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art of assisted reproductive technology to which the present invention belongs. Reference is made herein to various methods known to those of ordinary skill in the art. Any suitable materials and / or methods known to those of ordinary skill in the art may be used to implement the present invention, according to the guidance provided herein. However, specific materials and methods are described. Unless otherwise stated, the materials, reagents, etc. referenced in the following description and examples may be obtained from commercial sources.

[0024] It should be understood that any definitions and terms defined herein are intended to have the same meaning and intent in any aspects and embodiments of the present invention unless expressly stated otherwise.

[0025] As used herein, the singular forms "a," "an," and "the" refer to both the singular and the plural, unless explicitly stated to refer to the singular only.

[0026] As used herein, the term "about" means that as will be understood by one of ordinary skill in the art, depending on the context in which a number or range is used, the number or range is not limited to the exact number or range set forth, but encompasses a range around the number or range recited. Unless otherwise apparent from the context or custom in the art, "about" means plus or minus 10% of the particular term.

[0027] The terms "patient" and "subject," and "female" and "woman" are used interchangeably herein.

[0028] In this article, the term "treatment of infertility" includes treating infertility by controlled ovarian stimulation (COS) or a method including a controlled ovarian stimulation (COS) step or stage. The term "treatment of infertility" includes treating infertility in subjects with tubal or unexplained infertility (including treating infertility in subjects with endometriosis (e.g., stage I or stage II endometriosis)), and / or infertility in subjects whose partners suffer from male factor infertility. The compositions and methods described herein can be used for the treatment of infertility (and / or for controlled ovarian stimulation) in subjects with endometriosis (e.g., in subjects with stage I or stage II endometriosis) (for use), as defined by the American Society for Reproductive Medicine (ASRM) classification system for the various stages of endometriosis, (stage IV is the most severe; stage I is the least severe). See American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine Classification of Endometriosis: 1996. Fertil. Steril. 1997; 67, 817-821.

[0029] As used herein, the term "treatment of infertility by intrauterine insemination" includes intrauterine insemination by controlled ovarian stimulation. In other words, treatment of infertility by intrauterine insemination includes controlled ovarian stimulation (using, for example, rFSH with α2,3-sialylation and α2,6-sialylation) with the goal of obtaining 2 or 3 mature follicles (wherein "mature follicles" are defined as follicles ≥ 16 mm detected on the day before or on the day of triggered ovulation and / or, for example, in the last ultrasound scan before triggering) for a subsequent intrauterine insemination step.

[0030] As used herein, the term "positive pregnancy test" is defined as a positive urine pregnancy test. As used herein, the term "clinical pregnancy" is defined as a viable intrauterine pregnancy of 6-8 weeks confirmed by ultrasound scanning. As used herein, the term "ongoing pregnancy" is defined as a viable intrauterine pregnancy of at least 12 weeks confirmed by ultrasound scanning. As used herein, the term "pregnancy loss" is defined as the spontaneous death of a pregnancy before 24 weeks of gestational age. As used herein, the term "multiple pregnancy rate" is defined as the number of embryos with a fetal heartbeat observed under viability ultrasound between 6 and 8 weeks of gestation per total number of clinical pregnancies.

[0031] As used herein, the term "oligoovulation" refers to infrequent or irregular ovulation for a total of eight (8) or fewer menstrual cycles (menstrual periods) per year, and may include women with cycles ≥ 31 days. As used herein, the phrases "identified as having oligoovulation" or "diagnosed as having oligoovulation" and "suffering from oligoovulation" are used interchangeably and refer to patients with 8 or fewer menstrual cycles (menstrual periods) in a year, and do not include patients with anovulation. Oligoovulation is one of the most common causes of female infertility.

[0032] As used herein, the term "anovulatory" or "anovulation" refers to a patient whose ovaries do not release an oocyte during the menstrual cycle. Therefore, ovulation does not occur. Chronic anovulation is a common cause of infertility.

[0033] Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of childbearing age. Clinical features may include hyperandrogenism (clinically manifested as oligomenorrhea, hirsutism, and acne), ovulatory disorders (e.g. infrequent, irregular, and / or prolonged menstrual cycles), and polycystic ovarian morphology. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) website states that in adults, PCOS should be diagnosed if two of the following three criteria are present, provided that other causes of menstrual disorders and hyperandrogenism have been ruled out: clinical and / or biochemical signs of hyperandrogenism; oligoovulation or anovulation; and polycystic ovaries, which are defined as the presence of 12 or more follicles (measuring 2 to 9 mm in diameter) and / or an enlarged ovarian size (greater than 10 cm 3 ).

[0034] As used herein, "patients with polycystic ovary syndrome" or "patients with PCOS" refer to patients (women) with PCOS, including patients who have been diagnosed with PCOS. Patients with PCOS may meet two or more of the following criteria (usually used to diagnose PCOS, other causes of menstrual disorders and hyperandrogenism have been excluded): clinical and / or biochemical signs of hyperandrogenism; oligoovulation or anovulation; and polycystic ovaries, which are defined as the presence of 12 or more follicles (measuring 2 to 9 mm in diameter) and / or increased ovarian size (greater than 10 cm 3). To date (June 2023), PCOS guidelines indicate that serum AMH levels should not be used as a surrogate for detecting polycystic ovarian morphology (PCOM) or as a stand-alone test for diagnosing PCOS. However, there is emerging evidence that AMH assays will be more accurate in detecting PCOM and as a stand-alone test for diagnosing PCOS with improved assay standardization and cutoff levels or thresholds established based on large-scale validation in different age and ethnic populations. As used herein, the terms "patients with polycystic ovary syndrome" or "patients with PCOS" may additionally refer to patients (women) with PCOS, including patients who have been diagnosed with PCOS with a serum AMH of 23 pmol / L or greater (based on the new ESHRE guidelines).

[0035] The term "follicle" herein means an ovarian follicle, which is a fluid-filled sac that contains an immature egg or oocyte.

[0036] Blastocysts are formed in the early development of humans (or other mammals). In humans, blastocyst formation begins about 5 days after fertilization. Blastocysts used in IVF typically involve extracting (harvesting) multiple oocytes from a controlled ovarian stimulation cycle from a woman; fertilizing one or more oocytes (artificial insemination) and culturing the fertilized eggs (oocytes) for five days to form blastocysts (i.e., allowing the fertilized oocytes to develop to the blastocyst stage); and implanting the blastocysts into the uterus.

[0037] Embryos are formed in the early development of humans (or other mammals). The embryos used in IVF generally involve extracting (harvesting) multiple oocytes from a controlled ovarian stimulation cycle from a woman; fertilizing one or more oocytes (artificial insemination) and culturing the fertilized eggs (oocytes) for, for example, 3 days to form embryos (i.e., allowing the fertilized oocytes to develop to the embryonic stage); and implanting the embryos into the uterus.

[0038] Although the treatment described herein is primarily directed toward IUI, in the event of an over-response (e.g., more oocytes are produced than are needed for IUI), oocytes may be harvested and used for IVF, including harvesting and freezing for subsequent use in IVF (e.g., a "freeze-thaw" cycle for an IVF regimen).

[0039] Dosage regimen

[0040] The serum concentration of anti-mullerian hormone (AMH) is now established as a reliable marker of ovarian reserve. AMH levels are reduced during COS and are associated with reduced ovarian response to gonadotropins. In addition, high levels of AMH are good predictors of excessive ovarian response and are indicators of OHSS risk. In the dosing regimen described herein, for the first (and in some cases, subsequent) IUI treatment cycle, the individual daily dose is based on the woman's serum AMH concentration (also referred to herein as "serum AMH level") and her weight (depending on her serum AMH concentration) Determine. The dose is based on the most recent (i.e., within the last 24 months, including within the last 12 months) determined, for example, by Its serum AMH determined by measuring AMH Plus immunoassay (Roche) or similar assay (such as ACCESS AMHAdvanced from Beckman Coulter or UMIPULSE G AMH from Fujirebio) is measured. Additionally or alternatively, the serum concentration of anti-mullerian hormone (AMH) in the patient can be determined using the Beckmann-CoulterGen 2 assay described in Arce et al., Fertility and Sterility [fertility and infertility] 99: 1644-53 (2013), or can be an equivalent method.

[0041] The subject may have a normal serum FSH level, such as a serum FSH level of 1 to 16 IU / L (e.g., 1 to 15 IU / L, such as 1 to 12 IU / L, such as 2 to 10 IU / L), all of which are measured in the early follicular phase. Therefore, compositions as described herein or medicament or methods may be used for the treatment of infertility (and / or for controlled ovarian stimulation) in a subject with (or accredited as having) a normal serum FSH level of 1 to 16 IU / L (e.g., 1 to 15 IU / L, such as 1 to 12 IU / L, such as 2 to 10 IU / L), all of which are measured in the early follicular phase. Serum FSH may be measured by methods well known in the art, and optionally, the serum FSH may be used to identify a patient for treatment.

[0042] Subjects may have a BMI > 15 and a BMI < 40 kg / m 2 , such as BMI>17.5 and BMI<38kg / m 2 , such as BMI>18 and BMI<25kg / m 2 , for example, BMI>20 and BMI<25kg / m 2 Therefore, the composition, medicament or method described herein can be used to treat BMI>1 and BMI<40kg / m2 Patients with BMI>17.5 and BMI<38 kg / m 2 Subjects with BMI>18 and BMI<25kg / m 2 Subjects with BMI>20 and BMI<25kg / m 2 Therefore, the composition, medicament or method described herein can be used to treat infertility in subjects with BMI>17.5 and BMI<32 kg / m 2 The patient's (subject's) BMI may be 30 kg / m 2 or higher, such as a BMI of 30 to 40 kg / m 2 BMI can be measured by methods well known in the art, and optionally can be used to identify patients for treatment.

[0043] According to all aspects described herein, it is preferred that the treatment of infertility described herein is or comprises a step of COS. In other words, the treatment of infertility is intrauterine insemination with controlled ovarian stimulation (as described herein). The cause of infertility may be that the woman's partner suffers from male infertility, but it is understood that according to the present invention, it is the woman (female) who is treated by COS.

[0044] As used herein, "the first day of treatment", also referred to as "the first day of stimulation", refers to the first day of the dosage of rFSH administered to the patient. The first day of treatment (stimulation) can occur on the 1st day, 2nd day or 3rd day of the patient's menstrual cycle, such as the 2nd day or the 3rd day. In other words, the first day of treatment (stimulation) can be one day, two days or three days after the patient starts menstrual bleeding, such as two days or three days, which is consistent with the usage of the term in the clinical practice of GnRH antagonists or GnRH agonist regimens. The term "treatment period" means one or several days during which rFSH is administered to the patient.

[0045] In treatment as herein described, medicament, method and purposes, the use of recombinant FSH (rFSH) starts at the first day for the treatment of and can continue two to twenty days, for example, sustainable 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 days.The dosage used on the 1st day is referred to as " starting dose " in this article.The use of rFSH starts from the first day for the treatment of and can continue four to twenty days, for example seven to 13 days, for example nine to 13 days, for example 10 to 13 days, for example 10 to 11 days.Dosage can be the same every day.However, it is possible and indeed more likely that dosage is dependent on the change of the patient's ovarian response (for example, as measured by ultrasonography).

[0046] Therefore, the compositions or medicaments described herein can be used for the following administration and the methods or uses described herein can include the following administration: rFSH is administered at a prescribed dose (e.g., a starting dose of rFSH) from the 1st day of treatment to the 6th day, i.e., from the 1st day of stimulation to the 6th day. Starting from the 7th day of treatment (the 7th day of stimulation), the dose of rFSH can be: increased (e.g., increased to a dose of up to 150% of the starting dose, e.g., increased to a dose of 120% to 150% of the starting dose); reduced (e.g., reduced to a dose of 50% of the starting dose, e.g., reduced to a dose of 50% to 80% of the initial dose); or maintained at the starting dose. The dose can be increased, reduced, or maintained based on the patient's ovarian response (e.g., measured by ultrasonography).

[0047] The dosage (e.g., starting dosage) disclosed herein can be the dosage for the first cycle of IUI. For the second and subsequent cycles of IUI, the "starting dosage" can be: increased (e.g., increased to a dosage of up to 150% of the starting dosage of the first cycle, for example, increased to a dosage of 120% to 150% of the starting dosage of the first cycle); reduced (e.g., reduced to a dosage of 50% of the starting dosage of the first cycle, for example, reduced to a dosage of 50% to 80% of the starting dosage of the first cycle); or maintained at the starting dosage of the first cycle. The dosage can be increased, decreased, or maintained based on the patient's response to the first cycle (e.g., measured by the number of mature follicles ≥16 mm obtained in the first cycle on the day before or on the day of triggering and / or detected, for example, in the last ultrasound scan before triggering).

[0048] As used herein, "equivalent to" in relation to administration means a dose having the same pharmaceutical effect as the dose described in the claims or herein. For example, a dose of or equivalent to 0.05 μg per day may be a dose of 0.05 μg per day, or may be a pharmaceutically equivalent dose, such as a dose of 0.15 μg every 3 days. It should be understood that this applies to any dose described herein.

[0049] According to all aspects described herein, the recombinant FSH may be a recombinant FSH derived from a human cell line as described in more detail below. In all aspects, the recombinant FSH may be obtained under the trademark (Follitropin delta) (sold by Ferring BV). In all aspects, the recombinant FSH may be administered by injection, for example subcutaneously.

[0050] Typically, according to all aspects described herein, a recombinant FSH composition (e.g., a pharmaceutical composition) or an agent is administered or administered prior to administration of a high (ovulation) dose of human chorionic gonadotropin (hCG) (e.g., 4,000 to 11,000 IU hCG, e.g., 5,000 IU hCG, 10,000 IU hCG, etc.; or 150 to 500 μg recombinant hCG, e.g., 250 μg recombinant hCG) to induce final follicular maturation (e.g., trigger ovulation). Thus, in some embodiments, the methods described herein further comprise administering a high (ovulation) dose of human chorionic gonadotropin (hCG).

[0051] The compositions, uses and methods described herein are useful and can be effectively used for intrauterine insemination in patients suffering from infertility.

[0052] The recombinant FSH dosages listed herein can be used to treat infertility in the first stimulation regimen (first stimulation "cycle") of a patient (subject) by the methods and treatment regimens described herein. Thus, the one or more compositions can be used for use in the treatment of infertility in patients (subjects) who have not previously been treated for infertility by controlled ovarian stimulation; for use in the treatment of infertility in patients (subjects) who have not previously completed infertility treatment by controlled ovarian stimulation; or for use in the treatment of infertility in patients (subjects) who have not been treated for infertility by controlled ovarian stimulation in the past six months, more preferably in the treatment of infertility in patients (subjects) who have not been treated for infertility by controlled ovarian stimulation in the past twelve months. It should be understood that for further stimulation cycles (i.e., treatment of infertility by controlled ovarian stimulation) by the methods and treatment regimens described herein, the dosage can be adjusted by the methods and treatment regimens described herein according to the actual ovarian response in the first cycle, as described above.

[0053] treat

[0054] In the proof-of-concept study described below, the applicants demonstrated that The effectiveness of the personalized dosage regimen based on AMH and body weight. In the first cycle, the second cycle and the third cycle, the percentage of 2 or 3 mature follicles (defined as the day before triggering ovulation or the day of triggering ovulation and / or the follicles of ≥16mm detected in the last ultrasound scan before triggering) obtained in the treated patients was 34%, 37% and 47% respectively. The percentage of patients reaching more than 3 follicles was 1.9%, 0% and 1.5% respectively. Therefore, the dosage regimen described herein achieves the desired goal. In 40 clinical pregnancies, only 6 multiple pregnancies (15%) were observed, indicating that this is a safe method. In 3 IUI cycles, the clinical pregnancy rates of each IUI cycle of intended treatment were 16%, 14.3% and 16.2% respectively. The cumulative clinical pregnancy rate of the patients who completed the study in 3 cycles was 37.7%, indicating that it is useful for clinical practice.

[0055] In a first aspect, a composition (e.g., a pharmaceutical composition) comprising recombinant follicle stimulating hormone (rFSH) (optionally, including α2,3-sialylated and α2,6-sialylated rFSH) and a corresponding treatment method are provided, the composition being used for use in treating infertility in patients with serum AMH levels <15 pmol / L by intrauterine artificial insemination (e.g., to improve pregnancy rate and / or live birth rate, e.g., to improve pregnancy rate and / or live birth rate compared to treatment with rFSH comprising only 2,3-sialylated, e.g., to improve pregnancy rate and / or live birth rate compared to fixed-dose treatment with rFSH comprising only 2,3-sialylated), wherein the composition is administered at a dose of 0.048 μg to 0.052 μg, e.g., 0.05 μg rFSH / kg patient weight / day or equivalent thereto. In an example, the composition is administered at a dose of 0.05 μg rFSH / kg patient weight / day. The use or method may include the step of determining the patient's serum AMH level (e.g. using an automated AMH assay from Roche Diagnostics). AMH determination or similar method), and the step of applying the dosage to a patient with a serum AMH level of <15pmol / L. The age of the patient may be <35 years old, 35 to 40 years old or>40 years old. The use or method may include the step of determining the age of the patient, and the step of applying rFSH to a patient <35 years old. The use may include the step of determining the age of the patient, and the step of applying rFSH to a patient aged 35 to 40 years old. The use may include the step of determining the age of the patient, and the step of applying rFSH to a patient aged>40 years old. The rFSH may be rFSH comprising α2,3-sialylation and α2,6-sialylation, for example, recombinant FSH comprising α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation and wherein 80% to 95% of the total sialylation is α2,3-sialylation. The rFSH may be rFSH produced or expressed in a human cell line. The use or method may include a further step of triggering ovulation (e.g., by administering a dose of 4,000 to 11,000 IU hCG). The use or method may include a further step of intrauterine insemination. Treatment of infertility by intrauterine insemination may be intrauterine insemination by controlled ovarian stimulation (e.g., by controlled ovarian stimulation to prepare the patient for (a subsequent step) intrauterine insemination). Treatment of infertility by intrauterine insemination may include controlled ovarian stimulation (e.g., using rFSH with α2,3-sialylation and α2,6-sialylation), with the aim of obtaining 2 or 3 mature follicles (defined as follicles ≥16 mm detected the day before or on the day of triggering ovulation and / or, for example, in the last ultrasound scan before triggering) for a subsequent intrauterine insemination step.

[0056] On the other hand, a composition (e.g., pharmaceutical composition) comprising recombinant follicle stimulating hormone (rFSH) (optionally, including α2,3-sialylated and α2,6-sialylated rFSH) and a corresponding method of treatment are provided, the composition is used for use in infertility of patients with serum AMH levels ≥15pmol / L treated by intrauterine artificial insemination (e.g., to improve pregnancy rate and / or live birth rate, e.g., to improve pregnancy rate and / or live birth rate compared with treatment using only 2,3-sialylated rFSH, e.g., to improve pregnancy rate and / or live birth rate compared with fixed-dose treatment using only 2,3-sialylated rFSH), wherein the composition will be administered at 0.025 to 0.0475 μg rFSH / kg patient weight / day or a dosage equivalent thereto. The patient may be a patient suffering from polycystic ovary syndrome (PCOS). In another aspect, a composition (e.g., a pharmaceutical composition) comprising recombinant follicle stimulating hormone (rFSH) (optionally, comprising α2,3-sialylated and α2,6-sialylated rFSH) and a corresponding treatment method are provided, wherein the composition is used for use in treating infertility in patients with PCOS with serum AMH levels ≥15 pmol / L (preferably serum AMH ≥23 pmol / L) by intrauterine insemination (e.g., to improve pregnancy rate and / or live birth rate, e.g., to improve pregnancy rate and / or live birth rate compared to treatment with rFSH comprising only 2,3-sialylated, e.g., to improve pregnancy rate and / or live birth rate compared to fixed-dose treatment with rFSH comprising only 2,3-sialylated), wherein the composition is administered at a dose of 0.025 to 0.0475 μg rFSH / kg patient body weight / day or equivalent thereto. In another aspect, a composition (e.g., a pharmaceutical composition) comprising recombinant follicle stimulating hormone (rFSH) (optionally, comprising α2,3-sialylated and α2,6-sialylated rFSH) and a corresponding treatment method are provided, wherein the composition is used for use in treating infertility in patients with PCOS [e.g., patients with serum AMH levels ≥15 pmol / L (preferably, serum AMH ≥23 pmol / L)] by intrauterine insemination (e.g., to improve pregnancy rate and / or live birth rate, e.g., to improve pregnancy rate and / or live birth rate compared to treatment with only 2,3-sialylated rFSH, e.g., to improve pregnancy rate and / or live birth rate compared to fixed-dose treatment with only 2,3-sialylated rFSH), wherein the composition is administered at a dose of 0.025 to 0.0475 μg rFSH / kg patient body weight / day or equivalent thereto. In one example, the composition will be administered at a dosage of 0.025 to 0.0475 μg rFSH / kg patient body weight / day.The use or method may include the step of determining the patient's serum AMH level (e.g. using automation from Roche Diagnostics. AMH determination or similar method), and the step of applying the dose to a patient with a serum AMH level of ≥15pmol / L. The age of the patient may be <35 years old, 35 to 40 years old, or >40 years old. The use or method may include the step of determining the age of the patient, and the step of administering recombinant FSH to a patient <35 years old. The use or method may include the step of determining the age of the patient, and the step of administering rFSH to a patient aged 35 to 40 years old. The use or method may include the step of determining the age of the patient, and the step of administering rFSH to a patient aged >40 years old. The rFSH may be rFSH comprising α2,3-sialylation and α2,6-sialylation, for example, rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation and wherein 80% to 95% of the total sialylation is α2,3-sialylation. The rFSH may be rFSH that has been produced or expressed in a human cell line. The use or method may include a further step of triggering ovulation (e.g., by administering a dose of 4,000 to 11,000 IU hCG). The use or method may include a further step of intrauterine insemination. Treatment of infertility by intrauterine insemination may be intrauterine insemination by controlled ovarian stimulation (e.g., by controlled ovarian stimulation to prepare the patient for (a subsequent step) intrauterine insemination). Treatment of infertility by intrauterine insemination may include controlled ovarian stimulation (e.g., using rFSH with α2,3-sialylation and α2,6-sialylation), with the aim of obtaining 2 or 3 mature follicles (defined as follicles ≥16 mm detected the day before or on the day of triggering ovulation and / or, for example, in the last ultrasound scan before triggering) for a subsequent intrauterine insemination step.

[0057] According to the present invention, on the other hand, a composition (e.g., a pharmaceutical composition) comprising follicle stimulating hormone (FSH) is provided for use in treating infertility in patients with PCOS by intrauterine insemination, wherein the follicle stimulating hormone (FSH) comprises α2,3-sialylation and α2,6-sialylation. Preferably, the FSH is a recombinant FSH comprising α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation and wherein 80% to 95% of the total sialylation is α2,3-sialylation. FSH may be a recombinant FSH that has been produced or expressed in a human cell line. Treatment of infertility by intrauterine insemination may be performed by controlled ovarian stimulation for intrauterine insemination. FSH may be administered at a daily dose of 3 μg to 7 μg, preferably 3 μg to 5 μg. The patient's BMI may be 30 40 kg / m 2 or higher.

[0058] Patients with PCOS may meet two or more of the following criteria (usually after other causes of menstrual irregularities and hyperandrogenism have been ruled out): clinical and / or biochemical signs of hyperandrogenism; oligo- or anovulation; and polycystic ovaries, which are defined as the presence of 12 or more follicles (measuring 2 to 9 mm in diameter) in one or both ovaries and / or increased ovarian size (greater than 10 cm 3 ). Alternatively or additionally, the serum AMH of a patient with PCOS may be ≥23pmol / L. The use or method may include the step of identifying (e.g., diagnosing) the patient as a patient with PCOS. The use or method may include the step of identifying (e.g., diagnosing) the patient as a patient with PCOS, and the step of administering the dose to a patient with PCOS. The patient may be identified as having PCOS (optionally by a medical practitioner) before treatment. The patient may be identified as having PCOS (optionally by a medical practitioner, e.g., before treatment) by assessing whether the patient meets two or more of the following criteria (and other causes of menstrual disorders and hyperandrogenemia are usually also excluded): clinical and / or biochemical signs of hyperandrogenemia; oligoovulation or anovulation; and polycystic ovaries, which are defined as the presence of 12 or more follicles (measuring 2 to 9 mm in diameter) and / or increased ovarian volume (more than 10 cm 3 Alternatively or additionally, a patient may be identified as having PCOS by assessing whether the patient's serum AMH is ≥23 pmol / L. Serum AMH may be determined, for example, by AMHPlus immunoassay (Roche) or similar assays (such as ACCESS AMH Advanced from Beckman Coulter or UMIPULSE G AMH from Fujirebio) are measured. Additionally or alternatively, the serum concentration of anti-mullerian hormone (AMH) in the patient can be determined using the Beckmann-CoulterGen 2 assay described in Arce et al., Fertility and Sterility [fertility and infertility] 99: 1644-53 (2013), or an equivalent method. AMH should be determined within 24 months before treatment (including within 12 months). Serum AMH≥23pmol / L indicates PCOS.

[0059] The composition can be used for the following administration and the method may include the following administration: rFSH is administered at a prescribed dose (e.g., a starting dose of rFSH) from day 1 to day 6 of treatment, i.e., from day 1 to day 6 of stimulation. Starting from day 7 of treatment (day 7 of stimulation), the dose of rFSH may be: reduced (e.g., reduced to a dose of 50% of the starting dose, e.g., reduced to a dose of 50% to 80% of the initial dose); or maintained at the starting dose. In other embodiments, starting from day 7 of treatment (day 7 of stimulation), the dose of FSH may be increased (e.g., increased to a dose of up to 150% of the starting dose, e.g., increased to a dose of 120% to 150% of the starting dose); the dose may be increased, decreased, or maintained based on the patient's ovarian response (e.g., measured by ultrasound examination).

[0060] The dosage (e.g., starting dose) disclosed herein can be the dosage for the first cycle of IUI. For the second and subsequent cycles of IUI, the "starting dose" can be: increased (e.g., increased to a dose of up to 150% of the starting dose of the first cycle, for example, increased to a dose of 120% to 150% of the starting dose of the first cycle, for example, increased to a dose of 125% or 150% of the dose of the starting cycle); reduced (e.g., reduced to a dose of 50% of the starting dose of the first cycle, for example, reduced to a dose of 50% to 80% (e.g., 67%) of the starting dose of the first cycle); or maintained at the starting dose of the first cycle. The dose can be increased, reduced, or maintained based on the patient's response to the first cycle (e.g., measured by the number of mature follicles ≥16 mm obtained in the first cycle, for example, on the day before or on the day of triggering, and / or detected, for example, in the last ultrasound scan before triggering).

[0061] In some examples, for the third and subsequent cycles of IUI, the "starting dose" may be: increased (e.g., increased to a dose of up to 150% of the starting dose of the second cycle, e.g., increased to a dose of 120% to 150% of the starting dose of the second cycle, e.g., increased to a dose of 125% or 150% of the dose of the second cycle); decreased (e.g., decreased to a dose of 50% of the starting dose of the second cycle, e.g., decreased to a dose of 50% to 80% (e.g., 67%, 80%) of the starting dose of the second cycle); or maintained at the starting dose of the second cycle. The dose may be increased, decreased, or maintained based on the patient's ovarian response to the second cycle (e.g., measured by the number of mature follicles ≥16 mm obtained in the second cycle, e.g., on the day before or on the day of triggering, and / or detected, e.g., in the last ultrasound scan before triggering).

[0062] As noted above, typically, a recombinant FSH composition (e.g., a pharmaceutical composition) or agent is administered or administered prior to administration of a high (ovulation) dose of human chorionic gonadotropin (hCG) (e.g., 4,000 to 11,000 IU hCG, e.g., 5,000 IU hCG, 10,000 IU hCG, etc.; or 150 to 500 μg recombinant hCG, e.g., 250 μg recombinant hCG) to induce final follicular maturation. Thus, in some embodiments, the methods described herein further comprise administering a high (ovulation) dose of human chorionic gonadotropin (hCG).

[0063] Additionally or alternatively, the treatment may further include monitoring and / or controlling an excessive response to the treatment (eg, OHSS).

[0064] Recombinant FSH and rFSH Combinations

[0065] As noted above, the methods and compositions described herein use recombinant FSH (rFSH). FSH comprises an alpha subunit of 92 amino acids (also a common subunit of other glycoprotein hormones LH and chorionic gonadotropin (CG)), and a beta subunit of 111 amino acids unique to FSH (which imparts the biological specificity of the hormone) (Pierce and Parsons, 1981). Each subunit is post-translationally modified by the addition of complex carbohydrate residues. Both subunits carry 2 N-linked glycan attachment sites, an alpha subunit at amino acids 52 and 78 and a beta subunit at amino acid residues 7 and 24. Thus, FSH is glycosylated to about 30% by mass.

[0066] The glycosylation of the rFSH product reflects the range of glycosyltransferases present in the host cell line. Commercially available rFSH products derived from engineered Chinese hamster ovary (CHO) cells have a more limited range of glycan modifications than those found in the natural product. Examples of reduced glycan heterogeneity found in CHO cell-derived rFSH include the lack of bisecting glucosamine and the reduction in the content of core fucosylation and acetyllactosamine extensions. In addition, CHO cells are only able to add sialic acid using α2,3 linkage; CHO cell-derived rFSH only includes α2,3-linked sialic acid and does not include α2,6-linked sialic acid. Therefore, CHO cell-derived rFSH is different from naturally produced FSH (e.g., human pituitary / serum / urinary FSH), which contains glycans with a mixture of α2,3 and α2,6-linked sialic acids (with the former predominating).

[0067] As mentioned above, the applicant has developed human cell line derived rFSH which is the subject of international patent application number PCT / GB 2009 / 000978 published as WO 2009 / 127826A and which was also approved by the EC as (Follitropin delta, also known as FE 999049). Recombinant FSH with a mixture of α2,3 and α2,6-linked sialic acids was prepared by engineering a human cell line to express rFSH and α2,3 sialyltransferase. The amino acid sequence of human cell line-derived recombinant FSH, which is the subject of International Patent Application No. PCT / GB 2009 / 000978 published as WO 2009 / 127826 A (e.g., FE 999049), is the natural human FSH sequence, but the product has a different glycosylation pattern. The expressed product is highly acidic and carries a mixture of α2,3- and α2,6-linked sialic acids; the latter is provided by endogenous sialyltransferase activity. It was found that the type of sialic acid bond, α2,3- or α2,6-, can have a significant effect on the biological clearance of FSH. Therefore, compared with CHO cell-derived recombinant products that have only α2,3-linked sialic acid and have reduced sialic acid content, (e.g., FE 999049) may be more biologically appropriate.

[0068] Thus, the recombinant FSH used in accordance with the methods and compositions described herein can be expressed in human cell lines (e.g. Recombinant FSH can be produced or expressed in Cell line (deposited under ECACC deposit number 96022940), Derived cell lines or modified Produced or expressed in cell lines. The recombinant FSH produced or expressed in the cell line will include some α2,6-linked sialic acids (α2,6 sialylation) provided by the endogenous sialyltransferase activity (of the cell line), and will include some α2,3-linked sialic acids (α2,3 sialylation) provided by the endogenous sialyltransferase activity. The cell line can be modified using α2,3-sialyltransferase. The cell line can be modified using α2,6-sialyltransferase. Alternatively or in addition, the recombinant FSH can include α2,6-linked sialic acids (α2,6 sialylation) provided by the endogenous sialyltransferase activity (of the cell line).

[0069] The recombinant FSH used in the methods and compositions described herein may include α2,3-sialylation and α2,6-sialylation. The recombinant FSH used for use according to the present invention may have 1% to 99% of the total sialylation as α2,3-sialylation. The recombinant FSH used for use according to the present invention may have 1% to 99% of the total sialylation as α2,6-sialylation. The recombinant FSH may have 1% to 50% of the total sialylation as α2,6-sialylation, and 50% to 99% of the total sialylation as α2,3-sialylation. For example, 80% to 95% (e.g., 80% to 90%, such as 82% to 89%, such as 85% to 89%) of the total sialylation may be α2,3-sialylation. For example, 5% to 20% (e.g., 10% to 20%, such as 11% to 18%, such as 11% to 15%) of the total sialylation may be α2,6-sialylation. In an example, the recombinant FSH has 5% to 20% of the total sialylation as α2,6-sialylation, and 80% to 95% of the total sialylation as α2,3-sialylation. In another example, the recombinant FSH has 50% to 80% of the total sialylation as α2,6-sialylation, and 20% to 50% of the total sialylation as α2,3-sialylation.

[0070] In this article, "sialylation", it means the amount of sialic acid residues present on the recombinant FSH carbohydrate structure. Consistent with the usage in the art, α2,3-sialylation means sialylation at 2,3 positions and α2,6 sialylation means sialylation at 2,6 positions. Therefore, "% in total sialylation can be α2,3 sialylation" refers to the total number of sialic acid residues present in FSH (or hCG) sialylated at 2,3 positions. The term "% in total sialylation is α2,6-sialylation" refers to the total number of sialic acid residues present in FSH (or hCG) sialylated at 2,6 positions.

[0071] In all aspects, rFSH may be present as a single isoform or as a mixture of isoforms.

[0072] The composition can be a pharmaceutical composition. The pharmaceutical composition is used for the treatment of infertility. The treatment of infertility can include COS before IUI. According to the methods and treatment regimens disclosed herein, the pharmaceutical composition can be used, for example, in the medical indications of known FSH preparations in IUI.

[0073] Recombinant FSH, the composition or the pharmaceutical composition can be formulated into well-known compositions for subcutaneous administration (for example, for subcutaneous injection). Typical compositions contain pharmaceutically acceptable carriers, such as aqueous solutions, non-toxic excipients (including salts and preservatives, buffers, etc.), as described in Remington’s Pharmaceutical Sciences, 15th Edition (Matt Publishing Company, 1975), pages 1405 to 1412 and 1461 to 1487, and national formulary XIV, 14th Edition (American Pharmaceutical Association, 1975), etc. For example, recombinant FSH, the composition or the pharmaceutical composition can be formulated for injection, such as for subcutaneous injection.

[0074] Examples of suitable aqueous and non-aqueous pharmaceutical carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and its suitable mixtures, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate).

[0075] The composition of the present invention can also contain additives, such as but not limited to preservatives, wetting agents, emulsifying agents, surfactants and dispersants. Antibacterial and antifungal agents can be included to prevent the growth of microorganisms, and include, for example, m-cresol, benzyl alcohol, parabens, chlorobutanol, phenol, sorbic acid, etc. If a preservative is included, benzyl alcohol, phenol and / or m-cresol are preferred; however, the preservatives are by no means limited to these examples. In addition, it may be desirable to include isotonic agents, such as sugars, sodium chloride, amino acids, etc.

[0076] For example, the composition or the medicament can contain one or more of recombinant FSH and polysorbate 20, L-methionine, phenol and arginine hydrochloride. Such a composition can be formulated for injection, such as for subcutaneous injection. For example, the composition or the medicament can be a formulation (rFSH with excipients phenol, polysorbate 20, L-methionine, sodium sulfate decahydrate, disodium hydrogen phosphate dodecahydrate, phosphoric acid [concentrated, for pH adjustment], sodium hydroxide [for pH adjustment] and water for injection).

[0077] Injectable formulations can be sterilized, for example, by filtration through a bacterial barrier filter, or by incorporating sterilizing agents in the form of sterile solid compositions (which can be dissolved or dispersed in sterile water or other sterile injectable media prior to use). Injectable formulations can be provided in any suitable container (e.g., vials, prefilled syringes, injection boxes, etc.).

[0078] Recombinant FSH, compositions or medicaments can be formulated for single use or for multiple use (multiple doses). If recombinant FSH, compositions or medicaments are formulated for multiple use, one or more preservatives are typically included. If preservatives are included, benzyl alcohol, phenol or meta-cresol are preferred; however, preservatives are by no means limited to these examples. The single use or multiple use compositions or medicaments prepared can further include amino acids or amino acid combinations. Typically, the amino acid is arginine, for example, added as arginine or more typically arginine hydrochloride.

[0079] The recombinant FSH, composition or medicament may be included in a container, such as a vial, a prefilled cartridge (eg, for single administration or multiple uses), or an injection device (such as a "pen", for example, for multiple dose administration).

[0080] The recombinant FSH, composition or pharmaceutical composition may be a formulation (eg, an injectable formulation) comprising rFSH.

[0081] Recombinant FSH, compositions or medicaments can be provided with any suitable packaging. For example, compositions or medicaments can include multiple containers (for example, pre-filled syringes or vials) containing FSH. Syringes or vials can be packaged in blister packs or keep sterile by other means. Any compositions or medicaments can optionally include instructions for use of FSH preparations.

[0082] The pH and the exact concentration of the various components of the pharmaceutical composition can be adjusted according to conventional practice in the art. Referring to GOODMAN and GILMAN's THE PHARMACOLOGICAL BASIS FOR THERAPEUTICES, the 7th edition. In a typical embodiment, recombinant FSH, compositions or medicaments are provided as compositions for parenteral administration. The general method for preparing parenteral formulations is known in the art and is described in REMINGTON; THE SCIENCE AND PRACTICE OF PHARMACY, ibid., pages 780 to 820. The parenteral composition can be provided in the form of a liquid formulation or as a solid, which will be mixed with a sterile injectable medium just before administration. Parenteral compositions can be provided in dosage unit form to be easy to use and to achieve dosage uniformity.

[0083] In a further aspect there is provided the use of recombinant follicle stimulating hormone (FSH) in the manufacture of a medicament for use as described and claimed herein.

[0084] Further aspects are demonstrated in the following examples, which are not limiting in any respect.

[0085] Examples

[0086] The following example uses Follicle-stimulating hormone delta, which is Recombinant FSH expressed in a cell line engineered by the methods disclosed in WO 2013 / 020996 and WO 2009 / 127826 A.

[0087] The marketing authorisation holder for is Ferring Pharmaceuticals A / S, KayFiskers Plads 11, 2300 Copenhagen, Denmark and in the UK it is available from Ferring Pharmaceuticals, Drayton Hall, Church Road, West Drayton, UB7 7PS, UK

[0088] The active substance in is follitropin delta (FE 999049). Highly sialylated and includes α2,3-sialylation and α2,6-sialylation, wherein about 85% to 90% of the total sialylation is α2,3-sialylation and about 10% to 15% of the total sialylation is α2,6-sialylation.

[0089] It is a transparent, colorless solution for injection (injection). 1 mL of solution contains 33.3 micrograms of follitropin delta in each mL of solution. The other ingredients are phenol, polysorbate 20, L-methionine, sodium sulfate decahydrate, disodium hydrogen phosphate dodecahydrate, concentrated phosphoric acid, sodium hydroxide, and water for injection.

[0090] Example 1: Personalized IUI Treatment Study (PITS): A proof-of-concept study evaluating the effect of personalized doses of follitropin delta in intrauterine insemination

[0091] Clinical trial registration number: NCT03830723

[0092] introduce

[0093] The PITS study was designed to evaluate the effect of follitropin delta on ovarian response during IUI with controlled ovarian stimulation using an individualized dosing regimen. Secondary objectives were the incidence of cycle cancellation, multiple pregnancy, and cumulative clinical pregnancy rate after 3 consecutive cycles.

[0094] method

[0095] design

[0096] This was a single-center, open-label, single-cohort prospective study to evaluate the efficacy and safety of personalized doses of follitropin delta for intrauterine insemination. Patients were recruited at a single center in Canada and underwent up to three cycles of IUI. The study protocol was approved by local regulatory authorities and an independent ethics committee. The study was conducted in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonization Guidelines for Good Clinical Practice, and local regulatory requirements. All participants provided written informed consent before undergoing any study-related procedures.

[0097] Participants

[0098] Women enrolled in this study were aged between 18 and 42 years, had at least one patent fallopian tube as confirmed by laparoscopy, hysterosalpingography (HSG), or hysterosalpingography sonosonography (HSSG), or had a pregnancy within the past 3 years and were followed at a fertility center. Other inclusion criteria were regular menstrual cycles of 26 to 39 days, presence of bilateral ovaries, use of partner or donor ejaculated sperm (fresh or frozen), and semen analysis deemed adequate for IUI according to the center's standard practice. Major exclusion criteria were high risk of OHSS (AMH ≥ 35 pmol / L (4.9 ng / mL)), body weight > 100 kg, history of severe malformation (unicornuate or bicornuate uterus) or uterine anomaly (including fibroids ≥ 5 cm), uncontrolled thyroid or adrenal dysfunction, pituitary tumors or persistent ovarian cysts or enlargement > 3 cm not caused by PCOS. Other exclusion criteria were: use of hormonal therapy within the last 3 months before the start of stimulation, diagnosis of hydrosalpinx, malignancy, breast pathology incompatible with gonadotropin stimulation, hypersensitivity to follitropin delta or any component of the preparation, and addition of other infertility drugs that could affect follicle stimulation and maturation, such as growth hormone (GH).

[0099] program

[0100] All study participants received a personalized daily subcutaneous dose of follitropin delta ( Treatment was performed by Ferring Pharmaceuticals, Inc., with the dose determined based on body weight and serum AMH levels measured within the last 24 months before the start of ovarian stimulation (Table 1).

[0101] Table 1: Follitropin delta administration for IUI

[0102]

[0103]

[0104] These doses are designed to obtain 2-3 mature follicles for IUI.

[0105] For cycles 2 and 3, the follitropin delta dose was adjusted (see Table 5) taking into account the number of mature follicles seen on the last ultrasound examination before insemination (by transvaginal ultrasonography (TVU)) and the age of the participant (Tables 2 and 3), even if adjustments were made during the first cycle. In addition, if more than 4 follicles were 13.0-15.9 mm in diameter, the follitropin delta dose was reduced by 33% from the prescribed initial dose to reduce the risk of a hyperresponse in the next cycle.

[0106] Table 2

[0107]

[0108] *The previous cycle will be cancelled according to the cancellation criteria

[0109] Table 3

[0110]

[0111] *The previous cycle will be cancelled according to the cancellation criteria

[0112] Follicle-stimulating hormone delta therapy was started on day 3 of the menstrual cycle, and the dose remained the same during the first 5 days of stimulation. Starting from day 8 (day 6 of stimulation), the response to stimulation was monitored by transvaginal ultrasound (TVU). After day 6 of stimulation, participants underwent transvaginal ultrasound every 2-3 days (based on the expected growth rate of 2 mm / day for follicles ≥ 12 mm). Follicle-stimulating hormone delta dose adjustments were made during the cycle according to the predefined criteria described in Table 4. The size of the follicle was calculated by measuring the two largest diameters of the follicle (two-dimensional size).

[0113] Table 4

[0114]

[0115] Targeted ovarian response was defined as 2 to 3 follicles ≥ 16 mm detected on the day of triggering or the day before triggering and / or e.g. the last ultrasound scan before triggering. If only 1 mature follicle developed, the physician continued with IUI as per the clinic’s standard of care. If more than 3 mature follicles developed, cancellation or conversion to IVF was considered.

[0116] The triggering drug is human chorionic gonadotropin alfa ( EMD Serono) and was administered when clinically indicated. All women in the study were administered 100 mg progesterone vaginal tablets twice daily starting on the day of IUI ( Ferring Pharmaceuticals) for luteal phase support until a urine pregnancy test on day 14.

[0117] definition

[0118] A positive pregnancy test was defined as a positive urine pregnancy test. A clinical pregnancy was defined as a viable intrauterine pregnancy of 6–8 weeks confirmed by ultrasound scan. An ongoing pregnancy was defined as a viable intrauterine pregnancy of at least 12 weeks duration confirmed by ultrasound scan. Pregnancy loss was defined as spontaneous death of pregnancy before 24 weeks of gestational age. The multiple pregnancy rate was defined as two or more embryos with fetal heartbeats observed on viable ultrasound between 6 and 8 weeks of gestation per total number of clinical pregnancies.

[0119] ending

[0120] The co-primary endpoints of this study included ovarian response (specifically the proportion of cycles achieving 2 or 3 mature follicles) and clinical pregnancy rate. As secondary endpoints, the cumulative clinical pregnancy rate up to three IUI cycles and the proportion of subjects with multiple pregnancies were also studied.

[0121] Other secondary endpoints included duration of stimulation, total drug dose, drug dose adjustments, and endometrial thickness.

[0122] Safety endpoints included the proportion of patients who cancelled their cycles and the reasons for cycle cancellation, the incidence of early OHSS (including moderate / severe OHSS), and the rate of conversion to IVF.

[0123] Statistical methods

[0124] This study used a single-cohort, prospective, open-label design. Continuous variables were assessed for normal distribution and reported as means and standard deviations. Differences between continuous variables were assessed by T-test or analysis of variance (ANOVA) and multiple regression analysis for normally distributed variables, or by Wilcoxon signed-rank test for non-normally distributed variables. Correlations between continuous variables were assessed by Pearson's correlation test. Effect sizes were assessed by Cohen's d test. Categorical variables were expressed as percentages and compared by Chi-square test or multiple regression analysis. Results for pregnancy outcomes were assessed by intention-to-treat.

[0125] The effect of age on treatment efficacy was assessed by differences in pregnancy outcomes between patients categorized into the following age groups: <35 years, 35–40 years, and >40 years. For continuous variables, ANOVA was used to assess differences between age groups, whereas for categorical variables, multivariate logistic regression was used. Statistical tests were performed using SPSS version 26 and R for Cohen’s d test.

[0126] result

[0127] The mean age of all subjects was 34.46 years (±4.5 years), stratified as follows: <35 years (47.7%), 35-40 years (38.5%), and >40 years (13.8%). The mean body weight was 69.2 kg (±11.24), the mean serum AMH level was 3.84 ng / ml (±13), the mean serum FSH level was 6.3 IU (±2.61), and the mean antral follicle count was 15 (±8.6). 54.5% of the participants had primary infertility, and the average infertility period was 2.48 (±3.57) years. Among the recruited participants, 41.8% of the infertility was unexplained, 19.1% was female factors, 26.3% was male factors, and 12.8% was other factors.

[0128] The clinical pregnancy rates for each IUI cycle with intention to treat (ITT) were 16%, 14.3%, and 16.2%, respectively (Table 5). The cumulative clinical pregnancy rate for patients who received up to 3 IUI cycles was 37.7% (Table 6). The cumulative live birth rate for ITT was 33% (Table 7) (temporary calculation because it was not part of the study protocol). Among the 40 pregnancies, only 6 multiple pregnancies (15%) were observed. These were all twin pregnancies. The multiple pregnancy rates for each IUI cycle were 12.5%, 8.3%, and 27.3%, respectively (Table 7).

[0129] Table 5: Pregnancy outcomes

[0130]

[0131]

[0132] Table 6: Cumulative pregnancy outcomes up to 3 cycles.

[0133] Accumulation rate up to 3 periods Positive pregnancy test 44.34％ Clinical pregnancy 37.73％ Ongoing pregnancy 33.96％ Live birth 33.02％

[0134] Table 7: Safety endpoints

[0135]

[0136] The percentages of patients who obtained 2 or 3 follicles in the first cycle, the second cycle, and the third cycle were 34%, 37%, and 47%, respectively, and the average number of mature follicles was 1.4, 1.4, and 1.6, respectively. The percentages of patients who achieved more than 3 follicles in the first cycle, the second cycle, and the third cycle were 1.9%, 0%, and 1.5%, respectively, demonstrating the safety of the follitropin delta dosing regimen. The proportions of patients with cycle cancellations in the first cycle, the second cycle, and the third cycle were 8.5%, 2.4%, and 8.8%, respectively (Table 7).

[0137] The reasons for the 17 cancellations during the 3 IUI cycles were: 7-no response, 4-excessive response, 2-premature ovulation, 2-ovarian cysts, and 2-patient withdrawal from the study. Throughout the 3 IUI cycles, no OHSS was reported and there were no conversions to IVF.

[0138] A statistically significant difference in the initial dose of follitropin delta was observed between the first (3.25 μg ± 0.74) and third (5.20 μg ± 1.89) IUI cycles. The mean total amount of follitropin delta used for each cycle was 27.7 μg (± 12.7), 31.4 μg (± 12.7), and 40.1 μg (± 19.1), respectively. There were significant differences between the first and second IUI cycles and between the second and third IUI cycles (P < 0.05). Between cycles, the follitropin delta dose adjustment averaged as follows: from the first IUI cycle to the second IUI cycle: +25% (44%) of the initial dose and +50% (6%) of the initial dose, and from the second IUI cycle to the third IUI cycle: +25% (20%) and +50% (24%) (Table 8). The mean number of days of follitropin delta stimulation per IUI cycle did not differ significantly: 8.5 (±3.0), 7.9 (±2.6), and 7.8 (±2.5), respectively.

[0139] Table 8: Ovarian response outcomes

[0140]

[0141]

[0142] The endometrial thickness increased from the first IUI cycle to the second and third IUI cycles, with the mean values ​​of each cycle being 9.3 mm (±2.1), 9.5 mm (±2.0), and 10.1 mm (±2.7), respectively, and there was a significant difference between the first and third IUI cycles (P=0.04). (Table 8).

[0143] There was no statistically significant correlation between the total amount of follitropin delta administered per cycle, the number of mature follicles, and clinical pregnancy rate. However, as the amount of follitropin delta used in the third IUI cycle increased, the number of mature follicles, clinical pregnancy rate, and multiple pregnancy rate showed an increasing trend.

[0144] discuss

[0145] This is the first study to evaluate the use of follitropin delta for ovarian stimulation before intrauterine insemination. The initial dose of follitropin delta for IUI was determined as shown in Table 1.

[0146] The gonadotropin doses (e.g., FSH doses) used for IUI and IVF are not comparable, at least because the expected (required) number of mature follicles is different and because of the risk of multiple pregnancies in IUI. To obtain 2-3 mature follicles in this trial, the dose used was approximately one-quarter of the dose used for IVF. This was a relatively conservative (low) dose designed to be clinically effective for all patients (e.g., provide the required number of 2-3 mature follicles) for the first cycle, but the dose was considered unlikely to result in multiple pregnancies in the first cycle. This conservative and safer dose for the first insemination allowed for better personalization of the dose for the second and third IUI cycles.

[0147] For the second and third cycles, the follitropin delta dose was adjusted taking into account the number of mature follicles reached during the previous fertilization cycle and the age of the participants (see table above). This enhances the individualized dosing approach. For example, oocyte quality generally decreases with age, and the dosing regimen described herein can compensate for quality with quantity.

[0148] The treatment approach described herein compares favorably with previously reported studies using FSH in IUI.

[0149] Gregoriou O et al., Fertil. Steril. [Fertility and Sterility] 2008; 90: 678-683, randomized 50 couples (mean age 32 years) who had previously failed three cycles of clomiphene / IUI to receive either FSH / IUI (Gonal F or Puregon, CHO cell line-derived recombinant FSH at a dose of 150 IU every two days) or letrozole / IUI for up to three cycles. The cumulative live birth rate was 28% in the FSH / IUI group and 20% in the letrozole / IUI group. In contrast, in the PITS study reported here, a higher live birth rate was observed (33% vs. 28%).

[0150] Three other randomized clinical trials compared clomiphene citrate (CC) / IUI with gonadotropin (recombinant FSH derived from a CHO cell line) / IUI. Berker B et al., Arch. Gynecol. Obstet. 2011; 284: 1561-1566, randomized 93 couples. The ongoing pregnancy rate per cycle of CC / IUI was 9.6%, while the ongoing pregnancy rate per cycle of gonadotropin / IUI was 15.6%, and the multiple pregnancy rate in the gonadotropin / IUI group was 13.3%. Dankert T et al., Hum. Reprod. 2007;22:792-797, randomized 68 couples and after four cycles of IUI, the cumulative live birth rate was 28.2% in the CC / IUI group and 26.9% in the gonadotropin (Gonal F) / IUI group, but the gonadotropin / IUI group had a higher cancellation rate (mainly due to overreaction) (8.7%). The AMIGOS trial reported by Diamond MP et al. in Fertil. Steril. 2015;103(4):962-973 compared the effects of gonadotropin (follicle-stimulating hormone alfa), estrogen antagonists, and aromatase inhibitors for up to four IUI cycles. The cumulative clinical pregnancy rates for these 3 classes of agents were 35.5%, 28.3%, and 22.4%, respectively, and the cumulative live birth rates were 32.2%, 23.3%, and 18.7%, respectively. The multiple pregnancy rates in the AMIGOS trial were 31.8%, 9.4%, and 13.4%, respectively, including 24 sets of twins and 10 sets of triplets in the gonadotropin / IUI group.

[0151] In the PITS study reported in this article, a higher cumulative clinical pregnancy rate (37.7%) and cumulative live birth rate (33%) were achieved compared with these three randomized clinical trials, and the improvement was achieved with only three cycles of IUI instead of four cycles. In addition, the multiple pregnancy rate in the PITS study (15%, no triplets) was half of that observed in the AMIGOS trial (31.8%), and the cancellation rate was lower than that observed in the Dankert trial. These results support the safety of the dosing regimen disclosed in this article. Although not wanting to be bound by theory, the use of a new type of human recombinant FSH (follicle-stimulating hormone delta) that has been shown to produce milder ovarian stimulation in patients with polycystic ovaries (PCO) may be part of the reason for the reduction in multiple pregnancy rates.

[0152] The PITS study demonstrated that a personalized approach using individualized dosing of follitropin delta resulted in higher clinical pregnancy rates (e.g., compared to using, for example, a fixed dose of only 2,3-sialylated rFSH), with multiple pregnancy rates comparable to those observed with oral agents and approximately half of the multiple pregnancy rates reported with other gonadotropins (including other forms of FSH), supporting the use of the dosing regimens disclosed herein in clinical practice.

[0153] in conclusion

[0154] The PITS study reported here is the first study to use follitropin delta stimulation in an intrauterine insemination protocol and confirms the efficacy and benefit of the personalized dosing regimen of follitropin delta described here.

[0155] Appendix of Examples

[0156] The results of the PITS study updated to June 2023 are consistent with those reported and discussed above.

[0157] Table 9 below shows the updated cumulative pregnancy outcomes for up to 3 cycles (106 patients):

[0158]

[0159] Therefore, the updated results of the PITS study also showed that a higher cumulative clinical pregnancy rate (40.6% compared to 37.7% before the update) and cumulative live birth rate (33% compared to 33% before the update) were achieved compared to the results of the above three prior art randomized clinical trials, and the improvement was achieved with only three cycles of IUI instead of four cycles. In addition, the multiple pregnancy rate in the PITS study [14% (6 / 43), no triplets] was less than half of that observed in the AMIGOS trial (31.8%), and the cancellation rate was lower than that observed in the Dankert trial. These results support the safety of the dosing regimen disclosed in this article. Although not wanting to be bound by theory, the use of a new type of human recombinant FSH (follicle-stimulating hormone delta) that has been shown to produce milder ovarian stimulation in patients with polycystic ovaries (PCO) may be part of the reason for the reduction in multiple pregnancy rates.

[0160] The PITS study demonstrated that a personalized approach using individualized dosing of follitropin delta resulted in higher clinical pregnancy rates (e.g., compared to using, for example, a fixed dose of only 2,3-sialylated rFSH), with multiple pregnancy rates comparable to those observed with oral agents and approximately half of the multiple pregnancy rates reported with other gonadotropins (including other forms of FSH), supporting the use of the dosing regimens disclosed herein in clinical practice.

[0161] Additional data breakdown

[0162] The data in Table 6 have been broken down by patient AMH group as follows:

[0163]

[0164] This subdivision demonstrated an improvement in the cumulative clinical pregnancy rate (above the AMIGOS state-of-the-art values ​​of 35.5%, 28.3% and 22.4%) in patients with AMH < 15 pmol / L (45%) and in patients with AMH ≥ 15 pmol / L (using data for patients with AMH 15.0 to 22.9 and patients with AMH ≥ 23 pmol / L). In addition, this subdivision demonstrated an improvement in the cumulative clinical pregnancy rate (above the AMIGOS state-of-the-art values ​​of 35.5%, 28.3% and 22.4%) in patients with PCOS (AMH ≥ 23.0 pmol / L) (36.4%).

[0165] Furthermore, the subdivision demonstrated an improvement in the cumulative live birth rate in patients with AMH < 15 pmol / L (35%) and in patients with AMH ≥ 15 pmol / L (using data from patients with AMH 15.0 to 22.9 and patients with AMH ≥ 23 pmol / L) (above the AMIGOS state of the art values ​​of 32,2%, 23,3% and 18.7%). Finally, the subdivision demonstrated an improvement in the cumulative live birth rate in patients with PCOS (AMH ≥ 23.0 pmol / L) (31.8%). There are some similarities with the 32.2% result in patients with high AMH and PCOS, but the improvement is clear when considering the multiple pregnancy rate of this trial (half that of the AMIGOS trial).

[0166] The method defined by the following numbered paragraphs has been disclosed above:

[0167] 1. A method for treating infertility in a patient with a serum AMH level <15 pmol / L by intrauterine artificial insemination, the method comprising administering to the patient a composition comprising rFSH at a dosage of 0.048 μg to 0.052 μg recombinant follicle stimulating hormone (rFSH) / kg patient body weight / day.

[0168] 2. The method according to paragraph 1, wherein the composition is administered at a dose of 0.05 μg rFSH / kg patient body weight / day.

[0169] 3. The method according to paragraph 1, wherein the rFSH comprises α2,6-sialylation and α2,3-sialylation.

[0170] 4. The method according to paragraph 3, wherein 5% to 20% of the total sialylation of the rFSH is α2,6-sialylation, and 80% to 95% of the total sialylation of the rFSH is α2,3-sialylation.

[0171] 5. The method according to paragraph 1, wherein the rFSH has been produced or expressed in a human cell line.

[0172] 6. The method according to paragraph 1 further comprises determining the patient's serum AMH level prior to administration.

[0173] 7. The method of paragraph 3, wherein the method is effective to increase one or both of pregnancy rate and live birth rate compared to a method using only α2,3-sialylated rFSH.

[0174] 8. The method according to paragraph 1, wherein the patient is <35 years old.

[0175] 9. The method according to paragraph 1, wherein the patient is 35 to 40 years old.

[0176] 10. The method according to paragraph 1, wherein the patient is >40 years old.

[0177] 11. The method according to paragraph 1, wherein the treatment of infertility by intrauterine insemination is intrauterine insemination by controlled ovarian stimulation.

[0178] 12. The method according to paragraph 1, further comprising triggering ovulation in the patient by administering hCG.

[0179] 13. The method according to paragraph 11, further comprising the step of intrauterine artificial insemination.

[0180] 14. A method for treating infertility in a patient with a serum AMH level ≥ 15 pmol / L by intrauterine artificial insemination, the method comprising administering to the patient a composition comprising recombinant follicle stimulating hormone (rFSH) at a dose of 0.025 μg to 0.0475 μg rFSH / kg patient body weight / day.

[0181] 15. The method according to paragraph 14, wherein the patient suffers from polycystic ovary syndrome (PCOS).

[0182] 16. The method according to paragraph 14, further comprising determining the patient's serum AMH level before administration.

[0183] 17. The method according to paragraph 14, wherein the rFSH comprises α2,6-sialylation and α2,3-sialylation.

[0184] 18. The method of paragraph 17, wherein 5% to 20% of the total sialylation of the rFSH is α2,6-sialylation, and 80% to 95% of the total sialylation of the rFSH is α2,3-sialylation.

[0185] 19. The method according to paragraph 14, wherein the rFSH has been produced or expressed in a human cell line.

[0186] 20. The method of paragraph 16, wherein the method is effective to increase one or both of pregnancy rate and live birth rate compared to a method using rFSH comprising only α2,3-sialylated rFSH.

[0187] 21. The method according to paragraph 14, wherein the patient is <35 years old.

[0188] 22. The method according to paragraph 14, wherein the patient is 35 to 40 years old.

[0189] 23. The method according to paragraph 14, wherein the patient is >40 years old.

[0190] 24. The method according to paragraph 14, wherein the treatment of infertility by intrauterine insemination is intrauterine insemination by controlled ovarian stimulation.

[0191] 25. The method of paragraph 14, further comprising triggering ovulation in the patient by administering hCG.

[0192] 26. The method according to paragraph 25, further comprising the step of intrauterine artificial insemination.

Claims

1. A composition comprising follicle stimulating hormone (FSH) for use in treating infertility in patients with serum AMH levels <15 pmol / L by intrauterine artificial insemination (e.g. to improve pregnancy rate and / or live birth rate), wherein the composition is administered at 0.048 μg to 0.052 μg, e.g. 0.05 μg recombinant FSH / kg patient body weight / day or a dosage equivalent thereto.

2. The composition for use according to claim 1, wherein the composition is to be administered at a dose of 0.05 μg recombinant FSH / kg patient body weight / day.

3. according to the described compositions for use of claim 1 or 2, wherein this use comprises the step of determining this patient's this serum AMH level, and the step of using this dosage to the patient of serum AMH level<15pmol / L.

4. A composition comprising follicle stimulating hormone (FSH) for use in treating infertility in patients with serum AMH levels ≥ 15 pmol / L by intrauterine artificial insemination (e.g. to improve pregnancy rate and / or live birth rate), wherein the composition is administered at a dose of 0.025 to 0.0475 μg recombinant FSH / kg patient body weight / day or equivalent.

5. The composition for use according to claim 4, wherein the patient suffers from polycystic ovary syndrome (PCOS).

6. A composition comprising follicle stimulating hormone (FSH) for use in the treatment of infertility in patients with PCOS with serum AMH levels ≥ 15 pmol / L (preferably serum AMH ≥ 23 pmol / L) by intrauterine artificial insemination (e.g. to improve pregnancy rate and / or live birth rate), wherein the composition is administered at 0.025 to 0.0475 μg recombinant FSH / kg patient body weight / day or a dosage equivalent thereto.

7. A composition for use according to any one of claims 4 to 6, wherein the composition is to be administered at a dose of 0.025 to 0.0475 μg recombinant FSH / kg patient body weight / day.

8. according to the compositions for use described in any one of claims 4 to 7, wherein the use comprises the step of determining the serum AMH level of the patient, and the step of applying the dosage to the patient of serum AMH level 〉=15pmol / L.

9. A composition for use according to any preceding claim, wherein the patient is < 35 years old.

10. The composition for use according to any one of claims 1 to 8, wherein the patient is between 35 and 40 years old.

11. The composition for use according to any one of claims 1 to 8, wherein the patient is > 40 years old.

12. A composition for use according to any preceding claim, wherein the FSH is recombinant FSH.

13. A composition for use according to any preceding claim, wherein the FSH is recombinant FSH comprising α2,3-sialylation and α2,6-sialylation.

14. A composition for use according to any preceding claim, wherein the FSH is recombinant FSH comprising α2,3-sialylation and α2,6-sialylation, wherein 5% to 20% of the total sialylation is α2,6-sialylation and wherein 80% to 95% of the total sialylation is α2,3-sialylation.

15. A composition for use according to any preceding claim, wherein the FSH is recombinant FSH which has been produced or expressed in a human cell line.

16. Composition for use according to any preceding claim, wherein the treatment of infertility by intrauterine insemination is intrauterine insemination by controlled ovarian stimulation.

17. Composition for use according to any preceding claim, wherein the treatment of infertility by intrauterine insemination comprises a further step of triggering ovulation (for example by administering a dose of 4,000 to 11,000 IU hCG or a dose equivalent thereto) and optionally a further step of intrauterine insemination.

18. A method for treating infertility in a patient with a serum AMH level <15 pmol / L by intrauterine artificial insemination, the method comprising administering to the patient a composition comprising recombinant follicle stimulating hormone (rFSH) at a dose of 0.048 μg to 0.052 μg rFSH / kg patient body weight / day.

19. A method for treating infertility in a patient with a serum AMH level ≥ 15 pmol / L by intrauterine artificial insemination, the method comprising administering to the patient a composition comprising recombinant follicle stimulating hormone (rFSH) at a dose of 0.025 μg to 0.0475 μg rFSH / kg patient body weight / day.

20. A composition comprising follicle stimulating hormone (FSH) for use in treating infertility in a patient with PCOS by intrauterine insemination, wherein the follicle stimulating hormone (FSH) comprises α2,3-sialylation and α2,6-sialylation.

21. The composition according to claim 20, wherein the FSH is for administration in a daily dose of 3 to 7 μg, preferably 3 to 5 μg.

22. The composition according to claim 20 or 21, wherein the patient has a BMI of 30 kg / m 2 or higher.

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