Compositions and methods for intrauterine insemination (IUI)

Abstract

Methods, uses and compositions comprising FSH for use in the treatment of infertility by intrauterine insemination are described.

Description

Technical Field

[0001] The present invention relates to methods, compositions, and pharmaceuticals for the treatment of infertility.

Background Art

[0002] Assisted reproductive technologies (ART) such as in vitro fertilization (IVF) are well known. ART generally requires a step of controlled ovarian stimulation (COS), in which a cohort of follicles is stimulated until complete maturation. Standard COS regimens include administration of a gonadotropin such as follicle-stimulating hormone (FSH) alone or in combination with luteinizing hormone (LH) activity that stimulates multiple follicular development. Usually, COS requires administration of a GnRH analogue (GnRH agonist) or GnRH antagonist before and / or during stimulation to prevent an early LH surge that may induce ovulation prior to the scheduled oocyte retrieval. The purpose of COS is generally to stimulate and mature a large number of follicles and retrieve a large number of oocytes for fertilization when ovulation is induced. Generally, the best oocytes are selected for transplantation, but other oocytes may be cryopreserved for future use.

[0003] When the ovarian response is too high, COS is considered to be associated with the risk of ovarian hyperstimulation syndrome (OHSS), which can lead to the cancellation of the COS cycle and, in severe cases, can be life-threatening. If it were possible to predict the likelihood of a woman's ovarian response to COS, it might be possible to develop personalized or individualized COS protocols. Such individualized protocols could, for example, reduce the risk of OHSS and prevent cancellation of the COS cycle in women predicted to have an excessive ovarian response to COS. Levels of anti-Müllerian hormone (AMH) are directly correlated with the ovarian response to gonadotropins during COS. Thus, high levels of AMH are a good predictor of excessive ovarian response and an indicator of the risk of OHSS, while low levels of AMH predict a poor ovarian response to COS.

[0004] In clinical research, the development of individualized dosing regimens for COS has been the focus in recent years. Initially, it was based on other predictors of ovarian response without using AMH. These predictors include age, body mass index (BMI), FSH, and antral follicle count (AFC).

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

[0006] Until recently, the only approved recombinant FSH (rFSH) products for ovarian stimulation, such as follitropin alfa (GONAL-F®, Merck Serono / EMD Serono) and follitropin beta (PUREGON® / Follistim®, MSD / Schering-Plough), were derived from Chinese hamster ovary (CHO) cell lines and had only 2,3 sialylation. The Applicants developed a human cell line-derived rFSH which is the subject of International Patent Application No. PCT / GB2009 / 000978, published as WO 2009 / 127826A. On 13 December 2016, the European Commission (EC) granted marketing authorisation for REKOVELLE® (also known as FE999049, follitropin delta), a human cell line-derived recombinant follicle-stimulating hormone (human rFSH), for use in controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technology (ART), such as in vitro fertilisation (IVF) cycles. REKOVELLE® is the first rFSH derived from a human cell line. The REKOVELLE® (follitropin delta) product is manufactured by the method disclosed in International Patent Application No. PCT / GB2009 / 000978.

[0007] In the context of IVF, the dosage and administration of REKOVELLE (registered trademark) are individualized for each patient and for the purpose of obtaining an ovarian response associated with a favorable safety / efficacy profile, i.e., to achieve an appropriate number of retrieved oocytes and to reduce the interventions necessary to prevent OHSS. REKOVELLE (registered trademark) is administered in micrograms (μg). The individualized dosage can be modeled to achieve 8 - 14 oocytes in an ART cycle based on AMH and body weight. For this purpose, in the first treatment cycle, the individual daily dosage can be determined based on the female's serum AMH concentration (also referred to herein as "serum AMH level") and dependent on the female's body weight. The dosage can be based on the most recent measurement of AMH (i.e., within the last 24 months, or within the last 12 months) measured by the ELECSYS (registered trademark) AMH Plus immunoassay (Roche). The individual daily dosage can be maintained throughout the stimulation period. In women with AMH < 15 pmol / L, the daily dosage of REKOVELLE (registered trademark) can be 12 μg regardless of body weight. In women with AMH ≥ 15 pmol / L, the daily dosage of REKOVELLE (registered trademark) is lower and can range from 0.19 μg / kg to 0.10 μg / kg across AMH concentrations of 15 - ≥ 40 pmol / L, with a maximum dosage of 12 μg in the first cycle. In subsequent treatment cycles, the daily dosage of REKOVELLE (registered trademark) can be maintained or changed according to the patient's ovarian response in the previous cycle. If the patient did not develop OHSS and showed an appropriate ovarian response in the previous cycle, the same daily dosage can be used. If a low ovarian response was shown in the previous cycle, the daily dosage in the subsequent cycle can be increased by 25% or 50% depending on the degree of the observed response. If an excessive ovarian response was shown in the previous cycle, the daily dosage in the subsequent cycle can be decreased by 20% or 33% depending on the degree of the observed response. In patients who developed OHSS or were at risk of OHSS in the previous cycle, the daily dosage for the subsequent cycle can be decreased by 33% from the dosage in the cycle in which OHSS or the risk of OHSS occurred. The maximum daily dosage of REKOVELLE (registered trademark) is generally 24 μg.

[0008] Intrauterine insemination (IUI) is a infertility treatment that directly places sperm into the uterus using a small catheter. It can be used, for example, in situations where vaginal intercourse is not possible (e.g., due to physical disabilities or psychological problems), or for couples experiencing infertility due to medical conditions (e.g., endometriosis or reduced sperm count or quality), or for couples with unexplained infertility. IUI is a minimally invasive and low-cost alternative to in vitro fertilization (IVF) and can be easily performed in a clinic, so it is widely used. The goal of IUI is to improve the chance of fertilization by increasing the number of healthy sperm that reach the fallopian tubes when the woman is most fertile. IUI may be performed on patients undergoing ovarian stimulation to increase the likelihood of a positive outcome. However, unlike controlled ovarian stimulation (COS) used in IVF and ART, where the goal is to obtain 8 - 14 oocytes before inducing ovulation, the goal of IUI is to obtain only 2 - 3 follicles of ≥16 mm in diameter on the day before or on the day of inducing ovulation and to avoid multiple pregnancies.

[0009] An individualized stimulation protocol is needed to provide improved pregnancy outcomes in patients undergoing IUI.

Summary of the Invention

Means for Solving the Problems

[0010] In the proof-of-concept trials described below, the Applicants demonstrated the efficacy of an individualized dosage regimen of REKOVELLE® in IUI based on AMH and body weight. In their first, second, and third cycles, the percentage of treated patients who obtained two or three mature follicles (defined as follicles ≥16 mm on the day before or on the day of induction of ovulation and / or, for example, as seen in the last ultrasound scan before induction) was 34%, 37%, and 47%, respectively. The percentage of patients who reached more than three follicles was 1.9%, 0%, and 1.5%, respectively. Thus, the dosing regimens described herein achieve the desired goals. Only 6 out of 40 clinical pregnancies (15%) were observed to be multiple pregnancies (only twins), indicating that the dosing regimen is a safe approach. The clinical pregnancy rates per IUI cycle according to the intention-to-treat were 16%, 14.3%, and 16.2% for the three IUI cycles, respectively. The cumulative clinical pregnancy rate over the three cycles of patients who completed the trial was 37.7% higher than previous trials using conventional administration of rFSH with only 2,3 sialylation, indicating that this is useful for clinical practice.

[0011] According to some embodiments, a composition comprising follicle stimulating hormone (FSH) for use in the treatment of infertility by intrauterine insemination (e.g., treatment of infertility by controlled ovarian stimulation for intrauterine insemination) in patients having a serum AMH level of <15 pmol / L, e.g., for increasing the pregnancy rate and / or birth rate, e.g., as compared to treatment with rFSH containing only α2,3 sialylation, e.g., as compared to a fixed-dose treatment with rFSH containing only α2,3 sialylation for increasing the pregnancy rate and / or birth rate, is provided, which should be administered at a dose of 0.048 μg to 0.052 μg, e.g., 0.05 μg of recombinant FSH per kg of the patient's body weight per day, or a corresponding dose. This use may include the steps of determining the patient's serum AMH level and administering the dose to a patient having a serum AMH level of <15 pmol / L. In some embodiments, the composition should be administered at a dose of 0.05 μg of recombinant FSH per kg of the patient's body weight per day. In some embodiments, the FSH is recombinant FSH, e.g., recombinant FSH containing α2,3 and α2,6 sialylation, e.g., recombinant FSH containing α2,3 and α2,6 sialylation, wherein 5-20% of the total sialylation is α2,6 sialylation and 80-95% of the total sialylation is α2,3 sialylation. In some embodiments, the FSH is recombinant FSH produced or expressed in a human cell line. This use may include a further step of inducing ovulation (e.g., by administering a dose of 4,000 - 11,000 IU of hCG or a corresponding dose). This use may include a further step of intrauterine insemination. The treatment of infertility by intrauterine insemination may be controlled ovarian stimulation for intrauterine insemination [e.g., (subsequent step) controlled ovarian stimulation for preparing the patient for intrauterine insemination]. The treatment of infertility by intrauterine insemination may include controlled ovarian stimulation (e.g., using rFSH having α2,3 and α2,6 sialylation) aimed at obtaining 2 or 3 mature follicles (defined as follicles ≧16 mm on the day before or on the day of induction of ovulation and / or, e.g., detected in the last ultrasound scan before induction) for the subsequent step of intrauterine insemination.

[0012] According to some aspects, a composition comprising follicle stimulating hormone (FSH) for use in the treatment of infertility by intrauterine insemination (e.g., treatment of infertility by controlled ovarian stimulation for intrauterine insemination) in patients having a serum AMH level of ≧15 pmol / L (e.g., serum AMH of ≧23 pmol / L), for example, for increasing the pregnancy rate and / or birth rate, for example, as compared to treatment with rFSH containing only α2,3 sialylation, for example, as compared to a fixed-dose treatment with rFSH containing only α2,3 sialylation, for increasing the pregnancy rate and / or birth rate, should be administered at a dose of 0.025 - 0.0475 μg of recombinant FSH per kg of patient body weight per day, or a corresponding dose. In some aspects, the patient can be a patient having polycystic ovary syndrome (PCOS). In some aspects, the patient can be a patient having PCOS with a serum AMH of ≧23 pmol / L. According to some aspects, a composition comprising follicle stimulating hormone (FSH) for use in the treatment of infertility by intrauterine insemination (e.g., treatment of infertility by controlled ovarian stimulation for intrauterine insemination) in patients having PCOS with a serum AMH level of ≧15 pmol / L, for example, for increasing the pregnancy rate and / or birth rate, for example, as compared to treatment with rFSH containing only α2,3 sialylation, for example, as compared to a fixed-dose treatment with rFSH containing only α2,3 sialylation, for increasing the pregnancy rate and / or birth rate, should be administered at a dose of 0.025 - 0.0475 μg of recombinant FSH per kg of patient body weight per day, or a corresponding dose. In some aspects, the composition should be administered at a dose of 0.025 - 0.0475 μg of recombinant FSH per kg of patient body weight per day. In some aspects, the FSH is recombinant FSH, for example, recombinant FSH containing α2,3 and α2,6 sialylation, for example, recombinant FSH containing α2,3 and α2,6 sialylation, wherein 5 - 20% of the total sialylation is α2,6 sialylation and 80 - 95% of the total sialylation is α2,3 sialylation.In some embodiments, the FSH is recombinant FSH produced or expressed in a human cell line. This use may include determining the patient's serum AMH level and administering a dose to a patient having a serum AMH level of ≧15 pmol / L. This use may include a further step of inducing ovulation (e.g., by administering a dose of 4,000 to 11,000 IU of hCG or a corresponding dose). This use may include a further step of intrauterine insemination. Treatment of infertility by intrauterine insemination may be controlled ovarian stimulation for intrauterine insemination [e.g., (subsequent step) controlled ovarian stimulation to prepare the patient for intrauterine insemination].

[0013] Treatment of infertility by intrauterine insemination may include controlled ovarian stimulation (e.g., using rFSH having α2,3 and α2,6 sialylation) aimed at obtaining two or three mature follicles (defined as follicles ≧16 mm on the day before or on the day of induction of ovulation and / or detected, for example, in the last ultrasound scan before induction) for a subsequent step of intrauterine insemination. The composition may be for administration at a defined dose of rFSH (e.g., the starting dose of rFSH), from the first day to the sixth day of treatment, i.e., from the first day to the sixth day of stimulation. From the seventh day of treatment (the seventh day of stimulation), the dose of rFSH may be increased (e.g., increased up to a dose of up to 150% of the starting dose, e.g., increased from a dose of 120% to 150% of the starting dose), decreased (e.g., decreased to a dose of 50% of the starting dose, e.g., decreased from a dose of 50% to 80% of the starting dose), or maintained at the starting dose. The dose may be increased, decreased, or maintained based on the patient's ovarian response (e.g., as measured by ultrasound examination). The (e.g., starting) dose disclosed herein may be the dose for the first cycle of IUI. In the second and subsequent cycles of IUI, the "starting dose" may be increased (e.g., increased up to a dose of up to 150% of the starting dose of the first cycle, e.g., increased from a dose of 120% to 150% of the starting dose of the first cycle), decreased (e.g., decreased to a dose of 50% of the starting dose of the first cycle, e.g., decreased from 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 ovulation induction, and / or, e.g., detected in the last ultrasound scan before ovulation induction).

[0014] According to some embodiments, a method for treating infertility by intrauterine insemination (e.g., a method for treating infertility by controlled ovarian stimulation for intrauterine insemination) in a patient having a serum AMH level of <15 pmol / L, the method comprising administering to the patient a dose of recombinant FSH (rFSH) of 0.048 μg to 0.052 μg per kg of the patient's body weight per day, e.g., a dose of 0.05 μg of rFSH per kg of the patient's body weight per day, or a corresponding dose, optionally wherein the rFSH comprises α2,3 and α2,6 sialic acid addition. The method can be a method of increasing one or both of the pregnancy rate and the birth rate, e.g., a method of increasing one or both of the pregnancy rate and the birth rate as compared to treatment with rFSH comprising only α2,3 sialic acid addition, e.g., a method of increasing one or both of the pregnancy rate and the birth rate as compared to a fixed-dose treatment with rFSH comprising only α2,3 sialic acid addition. The method can include determining the patient's serum AMH level before administration and administering an rFSH dose to a patient having a serum AMH level of <15 pmol / L. In some embodiments, the rFSH is administered at a dose of 0.05 μg of rFSH per kg of the patient's body weight per day. In some embodiments, the rFSH comprises α2,3 and α2,6 sialic acid addition, e.g., rFSH comprising α2,3 and α2,6 sialic acid addition, wherein 5 to 20% of the total sialic acid addition is α2,6 sialic acid addition and 80 to 95% of the total sialic acid addition is α2,3 sialic acid addition. In some embodiments, the rFSH is produced or expressed in a human cell line such as the PER.C6® cell line. The method can further include inducing ovulation (e.g., by administering hCG at a dose of 4,000 to 11,000 IU). The method can further include the step of intrauterine insemination. The treatment of infertility by intrauterine insemination can be controlled ovarian stimulation for intrauterine insemination, e.g., controlled ovarian stimulation for preparing the patient for intrauterine insemination (subsequent steps).The treatment of infertility by intrauterine insemination may include controlled ovarian stimulation (e.g., using rFSH having α2,3 and α2,6 sialylation) aimed at obtaining 2 or 3 mature follicles (a "mature follicle" is defined as a follicle of ≧16 mm on the day before or on the day of ovulation induction and / or, for example, detected in the last ultrasound scan before induction).

[0015] According to some embodiments, in patients having a serum AMH level of ≧15 pmol / L (e.g., ≧23 pmol / L of serum AMH), a method of treating infertility by intrauterine insemination (e.g., a method of treating infertility by controlled ovarian stimulation for intrauterine insemination) is provided, which includes administering to the patient a dose of recombinant FSH (rFSH) of 0.025 μg to 0.0475 μg per kg of the patient's body weight per day, or a corresponding dose, and optionally, the rFSH includes α2,3 and α2,6 sialylation. In some embodiments, the patient can be a patient having polycystic ovary syndrome (PCOS). The method can be a method of increasing one or both of the pregnancy rate and the birth rate, e.g., a method of increasing one or both of the pregnancy rate and the birth rate as compared to treatment with rFSH containing only 2,3 sialylation, e.g., a method of increasing one or both of the pregnancy rate and the birth rate as compared to a fixed-dose treatment with rFSH containing only 2,3 sialylation. In some embodiments, the rFSH is administered at a dose of 0.025 to 0.0475 μg of rFSH per kg of the patient's body weight per day based on the patient's serum AMH level as shown below.

[0016] [Table 1]

[0017] In some embodiments, rFSH comprises rFSH with α2,3 and α2,6 sialylation, for example, rFSH comprising α2,3 and α2,6 sialylation, wherein 5-20% of the total sialylation is α2,6 sialylation and 80-95% of the total sialylation is α2,3 sialylation. In some embodiments, rFSH is produced or expressed in a human cell line such as the PER.C6® cell line. The method can include determining the patient's serum AMH level prior to administration and administering an rFSH dose to a patient having a serum AMH level of ≧15 pmol / L. The method can further include inducing ovulation (e.g., by administering hCG at a dose of 4,000-11,000 IU of hCG). The method can further include the step of intrauterine insemination. Treatment of infertility by intrauterine insemination can be controlled ovarian stimulation for intrauterine insemination, for example, controlled ovarian stimulation to prepare the patient for intrauterine insemination (subsequent steps). Treatment of infertility by intrauterine insemination can include controlled ovarian stimulation (e.g., using rFSH having α2,3 and α2,6 sialylation) aimed at obtaining 2 or 3 mature follicles (a "mature follicle" is defined as a follicle of ≧16 mm on the day before or on the day of induction of ovulation and / or detected, for example, in the last ultrasound scan before induction) for the subsequent step of intrauterine insemination.

DETAILED DESCRIPTION OF THE INVENTION

[0018] The present applicants have demonstrated the effectiveness of an individualized dosage regimen of rFSH containing α2,3 and α2,6 sialylation in IUI (e.g., treatment of infertility by controlled ovarian stimulation for intrauterine insemination) based on AMH and body weight (e.g., 5-20% of total sialylation is α2,6 sialylation and 80-95% of total sialylation is α2,3 sialylation). In the 1st, 2nd and 3rd cycles of IUI, the percentage of treated patients who obtained 2 or 3 mature follicles (defined as follicles ≥16 mm on the day before or on the day of induction of ovulation and / or having "mature follicles" detected, for example, in the last ultrasound scan before induction) was 34%, 37%, and 47% respectively. The percentage of patients who reached more than 3 follicles was 1.9%, 0% and 1.5% respectively. Thus, the dosing regimens described herein achieve the desired goals. Only 6 cases of multiple pregnancies were observed among 40 clinical pregnancies (15%), indicating that this dosing regimen is a safe approach. The clinical pregnancy rates per IUI cycle according to the intention to treat were 16%, 14.3%, and 16.2% respectively in 3 IUI cycles. The cumulative clinical pregnancy rate over 3 cycles among the patients who completed the trial was 37.7%, indicating its usefulness for clinical practice.

[0019] Accordingly, provided herein are treatment and dosing regimens constructed for use in treating patients for infertility.

[0020] Definitions The technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the field of assisted reproductive medicine to which the present invention pertains, unless otherwise defined. Various methodologies known to those of ordinary skill are referenced herein. Any suitable materials and / or methods known to those of ordinary skill may be used in practicing the present invention based on the guidance provided herein. However, specific materials and methods are described. The materials, reagents, etc. referenced in the following description and examples are available from commercial sources unless otherwise noted.

[0021] Any definitions and terms defined in this specification are to be understood as having the same meaning and purpose in all aspects and embodiments of the present invention, unless otherwise clearly stated.

[0022] As used herein, the singular forms "a", "an", and "the" include both the singular and plural forms unless clearly stated otherwise to indicate only the singular form.

[0023] As used herein, the term "about" means that a number or range, as understood by one of ordinary skill in the art depending on the context in which the number or range is used, is not limited to the exact number or range recited, but includes the range before and after the recited number or range. Unless otherwise clear from the context or the convention in the art, "about" means plus or minus 10% of the particular term.

[0024] In this specification, the terms "patient", "subject", "female", and "woman" are used interchangeably.

[0025] As used herein, the term "treatment of infertility" includes the treatment of infertility by controlled ovarian stimulation (COS), or a method that includes a step or stage of controlled ovarian stimulation (COS). The term "treatment of infertility" includes the treatment of infertility in a subject having tubal or unexplained infertility, for example, the treatment of infertility in a subject having endometriosis, for example, stage I or stage II endometriosis, and / or the treatment of infertility in a subject having a partner with male factor infertility. The compositions and methods described herein may be for the treatment (and / or controlled ovarian stimulation) of infertility in a subject having endometriosis, for example, for the various stages of endometriosis in the American Society for Reproductive Medicine (ASRM) classification system (stage IV being the most severe; stage I being 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.

[0026] As used herein, the term "treatment of infertility by intrauterine insemination" includes controlled ovarian stimulation for intrauterine insemination. In other words, the treatment of infertility by intrauterine insemination is for the purpose of obtaining two or three mature follicles (defined as follicles ≧16 mm on the day before or the day of induction of ovulation and / or having "mature follicles" detected, for example, in the last ultrasound scan before induction) for a subsequent step of intrauterine insemination, and includes controlled ovarian stimulation (for example, using rFSH having α2,3 and α2,6 sialylation).

[0027] 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 at 6 - 8 weeks confirmed by ultrasound scan. As used herein, the term "ongoing pregnancy" is defined as a viable intrauterine pregnancy of at least 12 weeks confirmed by ultrasound scan. As used herein, the term "pregnancy loss" is defined as the natural death of a pregnancy before 24 weeks of gestation. As used herein, the term "multiple pregnancy rate" is defined as the visualization of two or more embryos with fetal heartbeats by ultrasound at the survival rate at 6 - 8 weeks of pregnancy per total number of clinical pregnancies.

[0028] As used herein, the term "oligoovulation" refers to sporadic or irregular ovulation with a total of 8 or fewer menstrual cycles (menses) per year, and may include women with cycles of ≧31 days. As used herein, the phrases "identified as oligoovulatory" or "diagnosed with oligoovulation" and "oligoovulatory" patients are used interchangeably to refer to patients with 8 or fewer menstrual cycles (menses) in a year, excluding anovulatory patients. Oligoovulation is one of the most common causes of infertility in women.

[0029] As used herein, the term "anovulatory" or "anovulation" refers to a patient in whom the ovaries do not release an oocyte during the menstrual cycle. Thus, ovulation does not occur. Chronic anovulation is a common cause of infertility.

[0030] Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of reproductive age. Clinical features may include androgen excess (with clinical symptoms such as oligomenorrhea, hirsutism, and acne), ovulatory dysfunction (such as infrequent, irregular, and / or long menstrual cycles), and polycystic ovarian morphology. In the UK, the National Institute for Health and Care Excellence (NICE) website states that in adults, when other causes of menstrual disorders and androgen excess have been excluded, PCOS should be diagnosed if two of the following three criteria are present: clinical and / or biochemical signs of androgen excess; infrequent anovulation or anovulation; and the presence of 12 or more follicles (measuring 2-9 mm in diameter) in one or both ovaries and / or an increase in ovarian volume (10 cm 3 3) defined as polycystic ovaries.

[0031] As used herein, "a patient having polycystic ovary syndrome" or "a patient having PCOS" refers to a patient (female) having PCOS, including a patient diagnosed as having PCOS. A patient having PCOS may have two or more of the following criteria (generally, in the diagnosis of PCOS, other causes of menstrual disorders and androgen excess are excluded): clinical and / or biochemical signs of androgen excess; infrequent anovulation or anovulation; and the presence of 12 or more follicles (measuring 2-9 mm in diameter) in one or both ovaries and / or an increase in ovarian volume (10 cm 3A polycystic ovary defined as such. To date (June 2023), PCOS guidelines have indicated that serum AMH levels should not be used as an alternative for the detection of polycystic ovary morphology (PCOS) or as a single test for the diagnosis of PCOS. However, with improved assay standardization and cut-off levels or thresholds established based on large-scale validation in various age and ethnic groups, the AMH assay will become more accurate as a single test for the detection of PCOM and the diagnosis of PCOS. In this specification, the terms "patient with polycystic ovary syndrome" or "patient with PCOS" may additionally refer to patients (women) with PCOS, including those diagnosed with PCOS who have a serum AMH of 23 pmol / L or higher (based on the new ESHRE guidelines).

[0032] As used herein, the term "follicle" means a follicle that is a sac filled with fluid containing an immature egg or oocyte.

[0033] A blastocyst is formed during early development in a human (or other mammal). In humans, blastocyst formation begins approximately 5 days after fertilization. The use of blastocysts in IVF generally involves retrieving (collecting) a number of oocytes from a female that have resulted from a controlled ovarian stimulation cycle, fertilizing (injecting sperm) one or more of the oocytes, and culturing the fertilized egg (oocyte) for 5 days to form a blastocyst (i.e., developing the fertilized oocyte to the blastocyst stage); and transferring the blastocyst into the uterus.

[0034] An embryo is formed during early development in a human (or other mammal). The use of embryos in IVF generally involves retrieving (collecting) a number of oocytes from a female that have resulted from a controlled ovarian stimulation cycle, fertilizing (injecting sperm) one or more of the oocytes, and culturing the fertilized egg (oocyte) for, for example, 3 days to form an embryo (i.e., developing the fertilized oocyte to the embryonic stage); and transferring the embryo into the uterus.

[0035] The treatments described herein are primarily targeted at IUI, but in cases of an overresponse (e.g., production of a greater number of oocytes than desired for IUI), the oocytes can be used in IVF, including being retrieved and frozen for subsequent use in IVF (e.g., used in the "freeze-thaw" cycle of an IVF protocol).

[0036] Dosing regimen The serum concentration of anti-Müllerian hormone (AMH) is currently established as a reliable marker of ovarian reserve. A decrease in AMH levels correlates with a decreased ovarian response to gonadotropins during COS. Furthermore, high levels of AMH are a suitable predictor of an excessive ovarian response and an indicator of the risk of OHSS. In the dosing regimens described herein, in the first (and optionally subsequent) IUI treatment cycles, the individual daily dose is based on the woman's serum AMH concentration (also referred to herein as the "serum AMH level") and is determined depending on the serum AMH concentration and the woman's body weight. This dose is based on the most recent determination of the woman's serum AMH (i.e., determined within the past 24 months, including within the past 12 months) and is measured, for example, by a similar assay such as the ELECSYS® AMH Plus immunoassay (Roche) or the ACCESS AMH Advanced from Beckman Coulter or the UMIPULSE G AMH from Fujirebio. Additionally or alternatively, the serum concentration of the patient's anti-Müllerian hormone (AMH) can be determined using a Beckmann-Coulter Gen 2 assay as described in Arce et al., Fertility and Sterility 99:1644-53 (2013), or an equivalent method.

[0037] The subject may have normal serum FSH levels, e.g., serum FSH levels of 1 - 16 IU / L, e.g., 1 - 15 IU / L, e.g., 1 - 12 IU / L, e.g., 2 - 10 IU / L, in all initial follicular phases. Thus, the compositions or agents or methods described herein may be for the treatment (and / or regulation of ovarian stimulation) of infertility in a subject having (or identified as having) normal serum FSH levels of 1 - 16 IU / L, e.g., 1 - 15 IU / L, e.g., 1 - 12 IU / L, e.g., 2 - 10 IU / L, in all initial follicular phases. Serum FSH can be measured by methods well known in the art and optionally used to identify a patient for treatment.

[0038] The subject may have a BMI > 15 and a BMI < 40 kg / m 2 , e.g., a BMI > 17.5 and a BMI < 38 kg / m 2 , e.g., a BMI > 18 and a BMI < 25 kg / m 2 , e.g., a BMI > 20 and a BMI < 25 kg / m 2 Thus, the compositions or agents or methods described herein may be used for the treatment of infertility in a patient having a BMI > 1 and a BMI < 40 kg / m 2 , e.g., a subject having a BMI > 17.5 and a BMI < 38 kg / m 2 , e.g., a subject having a BMI > 18 and a BMI < 25 kg / m 2 , e.g., a subject having a BMI > 20 and a BMI < 25 kg / m 2 Thus, the compositions or agents or methods described herein may be used for the treatment of infertility in a subject having a BMI > 17.5 and a BMI < 32 kg / m 2 The patient (subject) may have a BMI of 30 kg / m 2 or more, e.g., a BMI of 30 - 40 kg / m 2 BMI can be measured by methods well known in the art and optionally used to identify a patient for treatment.

[0039] According to all aspects described herein, the treatment of infertility described herein preferably is the step of COS or includes the step of COS. In other words, the treatment of infertility is by controlled ovarian stimulation (as described herein) for intrauterine insemination. The cause of infertility can be the female's partner who suffers from male infertility, but it will be understood that according to the present invention, it is the female (woman) who is treated by COS.

[0040] As used herein, "day 1 of treatment" is also referred to as "day 1 of stimulation" and refers to the first day on which the dose of rFSH is administered to the patient. Day 1 of treatment (stimulation) can be on day 1, 2 or 3 of the patient's menstrual cycle, for example, day 2 or 3. In other words, day 1 of treatment (stimulation) can be 1, 2 or 3 days after the start of the patient's menstrual bleeding, for example, 2 or 3 days after, which is consistent with the usage of this term in clinical practice using a GnRH antagonist or GnRH agonist protocol. The term "during treatment" means the days on which rFSH is being administered to the patient.

[0041] In the treatments, agents, methods and uses described herein, the administration of recombinant FSH (rFSH) starts on day 1 of treatment and can continue for 2 to 20 days, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days. The dose administered on day 1 is referred to herein as the "starting dose". The administration of rFSH starts on day 1 of treatment and can continue for 4 to 20 days, for example, 7 to 13 days, for example, 9 to 13 days, for example, 10 to 13 days, for example, 10 to 11 days. The dose can be the same every day. However, the dose can vary, and in fact is more likely to vary, based on the patient's ovarian response (for example, as measured by ultrasound examination).

[0042] Accordingly, a composition or agent as described herein may be for administration at a defined dose of rFSH (e.g., the starting dose of rFSH) from day 1 to day 6 of treatment, i.e., from day 1 to day 6 of stimulation, and a method or use as described herein may include them. From day 7 of treatment (day 7 of stimulation), the dose of rFSH may be increased (e.g., increased up to a dose of up to 150% of the starting dose, e.g., increased from 120% to 150% of the starting dose), decreased (e.g., decreased to a dose of 50% of the starting dose, e.g., decreased from 50% to 80% of the starting dose), or maintained at the starting dose. The dose may be increased, decreased, or maintained based on the patient's ovarian response (e.g., as measured by ultrasound).

[0043] The dose disclosed herein (e.g., the starting dose) may be the dose for the first cycle of IUI. In the second and subsequent cycles of IUI, the "starting dose" may be increased (e.g., increased up to a dose of up to 150% of the starting dose of the first cycle, e.g., increased from 120% to 150% of the starting dose of the first cycle), decreased (e.g., decreased to a dose of 50% of the starting dose of the first cycle, e.g., decreased from 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 (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 induction and / or, e.g., detected in the last ultrasound scan before induction).

[0044] As used herein with respect to administration, "corresponding to" means a dose having the same pharmaceutical effect as the dose recited in the claims or in this specification. For example, a dose of 0.05 μg per day, or a dose corresponding thereto, may be the recited dose of 0.05 μg per day or a pharmaceutically equivalent dose such as a dose of 0.15 μg every three days. It will be understood that this applies to any dose recited herein.

[0045] According to all aspects described herein, recombinant FSH can be recombinant FSH derived from a human cell line, as described in more detail below. In all aspects, the recombinant FSH can be that sold under the trademark REKOVELLE® (hFollitropin delta) (Ferring B.V.). In all aspects, the recombinant FSH can be administered by injection, for example, subcutaneous injection.

[0046] Generally, according to all aspects described herein, a recombinant FSH composition (e.g., a pharmaceutical composition) or agent is administered before or for administration of a high (ovulatory) dose of human chorionic gonadotropin (hCG) (e.g., 4,000 - 11,000 IU of hCG, e.g., 5,000 IU of hCG, 10,000 IU of hCG, etc.; or 150 - 500 μg of recombinant hCG, e.g., 250 μg of recombinant hCG) to induce final follicular maturation (e.g., to induce ovulation). Thus, in some embodiments, the methods described herein further comprise administration of a high (ovulatory) dose of human chorionic gonadotropin (hCG).

[0047] The compositions, uses, and methods described herein can be for and can be effective for intrauterine insemination in patients being treated for infertility.

[0048] The dosages of recombinant FSH enumerated herein may be for the treatment of infertility in the first stimulation protocol (first stimulation "cycle") of a patient (subject) according to the methods and treatment protocols described herein. Accordingly, the present composition may be used in the treatment of infertility in patients (subjects) with no prior history of treatment for infertility by controlled ovarian stimulation; in the treatment of infertility in patients (subjects) who have not previously completed treatment for infertility by controlled ovarian stimulation, or in patients (subjects) who have not received treatment for infertility by controlled ovarian stimulation during the past six months, more preferably in patients (subjects) who have not received treatment for infertility by controlled ovarian stimulation during the past twelve months. For further stimulation cycles (i.e., treatment for infertility by controlled ovarian stimulation) according to the methods and treatment protocols described herein, it will be understood that the dosage may be adjusted according to the actual ovarian response in the first cycle according to the methods and treatment protocols described herein, for example as outlined above.

[0049] Treatment In the proof-of-concept trial described below, the Applicants demonstrated the efficacy of an individualized dosage regimen of REKOVELLE® in IUI based on AMH and body weight. In their first, second and third cycles, the percentage of treated patients who obtained 2 or 3 mature follicles (defined as follicles ≥16 mm on the day before or on the day of induction of ovulation and / or, for example, as seen in the last ultrasound scan before induction) was 34%, 37%, and 47% respectively. The percentage of patients who reached more than 3 follicles was 1.9%, 0% and 1.5% respectively. Thus, the dosing regimen described herein achieves the desired goals. Only 6 of 40 clinical pregnancies (15%) were observed to be multiple pregnancies, indicating that this is a safe approach. The clinical pregnancy rates per IUI cycle according to the intention-to-treat were 16%, 14.3%, 16.2% respectively in 3 IUI cycles. The cumulative clinical pregnancy rate over 3 cycles among patients who completed the trial was 37.7%, demonstrating usefulness for clinical practice.

[0050] In a first aspect, there is provided a composition (e.g., a pharmaceutical composition) comprising recombinant follicle-stimulating hormone (rFSH) (optionally rFSH comprising α2,3 and α2,6 sialic acid additions) for use in the treatment of infertility by intrauterine insemination in a patient having a serum AMH level of <15 pmol / L (e.g., for increasing the pregnancy rate and / or birth rate, e.g., as compared to treatment with rFSH comprising only 2,3 sialic acid addition, e.g., as compared to a fixed-dose treatment with rFSH comprising only 2,3 sialic acid addition for increasing the pregnancy rate and / or birth rate), which should be administered at a dose of 0.048 μg to 0.052 μg, e.g., 0.05 μg of rFSH per kg of the patient's body weight per day, or a corresponding dose, and a corresponding treatment method. In one example, the composition should be administered at a dose of 0.05 μg of rFSH per kg of the patient's body weight per day. This use or method may include the steps of determining the patient's serum AMH level (e.g., using an automated Elecsys® AMH assay from Roche Diagnostics or a similar method) and administering a dose to a patient having a serum AMH level of <15 pmol / L. The patient may be <35 years old, may be 35 - 40 years old, or may be >40 years old. This use and method may include the steps of determining the patient's age and administering rFSH to a patient <35 years old. This use may include the steps of determining the patient's age and administering rFSH to a patient 35 - 40 years old. This use may include the steps of determining the patient's age and administering rFSH to a patient >40 years old. The rFSH may be rFSH comprising α2,3 and α2,6 sialic acid additions, e.g., recombinant FSH comprising α2,3 and α2,6 sialic acid additions, wherein 5 - 20% of the total sialic acid additions are α2,6 sialic acid additions and 80 - 95% of the total sialic acid additions are α2,3 sialic acid additions. The rFSH may be rFSH produced or expressed in a human cell line. This use or method may include a further step of inducing ovulation (e.g., by administering a dose of 4,000 - 11,000 IU of hCG). This use or method may include a further step of intrauterine insemination.Treatment of infertility by intrauterine insemination can be controlled ovarian stimulation for intrauterine insemination (for example, controlled ovarian stimulation to prepare the patient for subsequent steps of intrauterine insemination). Treatment of infertility by intrauterine insemination can include controlled ovarian stimulation (for example, using rFSH having α2,3 and α2,6 sialylation) aimed at obtaining two or three mature follicles (defined as follicles ≧ 16 mm on the day before or on the day of induction of ovulation and / or detected, for example, in the last ultrasound scan before induction) for subsequent steps of intrauterine insemination.

[0051] In a further aspect, there is provided a composition (e.g., a pharmaceutical composition) comprising recombinant follicle stimulating hormone (rFSH) (optionally rFSH comprising α2,3 and α2,6 sialylation) for use in the treatment of infertility by intrauterine insemination in a patient having a serum AMH level of ≧15 pmol / L (e.g., for increasing the pregnancy rate and / or birth rate, e.g., for increasing the pregnancy rate and / or birth rate as compared to treatment with rFSH comprising only 2,3 sialylation, e.g., for increasing the pregnancy rate and / or birth rate as compared to a fixed dose treatment with rFSH comprising only 2,3 sialylation), which composition should be administered at a dose of 0.025 to 0.0475 μg of rFSH per kg of the patient's body weight per day, or a corresponding dose, and a corresponding treatment method. The patient can be a patient having polycystic ovary syndrome (PCOS). In another aspect, there is provided a composition (e.g., a pharmaceutical composition) comprising recombinant follicle stimulating hormone (rFSH) (optionally rFSH comprising α2,3 and α2,6 sialylation) for use in the treatment of infertility by intrauterine insemination in a patient having PCOS and a serum AMH level of ≧15 pmol / L (preferably, serum AMH of ≧23 pmol / L) (e.g., for increasing the pregnancy rate and / or birth rate, e.g., for increasing the pregnancy rate and / or birth rate as compared to treatment with rFSH comprising only 2,3 sialylation, e.g., for increasing the pregnancy rate and / or birth rate as compared to a fixed dose treatment with rFSH comprising only 2,3 sialylation), which composition should be administered at a dose of 0.025 to 0.0475 μg of rFSH per kg of the patient's body weight per day, or a corresponding dose, and a corresponding treatment method.In another aspect, a composition (e.g., a pharmaceutical composition) comprising recombinant follicle-stimulating hormone (rFSH) (optionally, rFSH comprising α2,3 and α2,6 sialic acid additions) for use in the treatment of infertility by intrauterine insemination in patients with PCOS (e.g., patients having a serum AMH level of ≧15 pmol / L, preferably ≧23 pmol / L serum AMH), e.g., for increasing the pregnancy rate and / or birth rate, e.g., as compared to treatment with rFSH comprising only 2,3 sialic acid addition, e.g., as compared to a fixed-dose treatment with rFSH comprising only 2,3 sialic acid addition, for increasing the pregnancy rate and / or birth rate, which should be administered at a dose of 0.025 - 0.0475 μg of rFSH per kg of the patient's body weight per day, or a corresponding dose, and a corresponding treatment method are provided. In one example, the composition should be administered at a dose of 0.025 - 0.0475 μg of rFSH per kg of the patient's body weight per day. This use or method may include the step of determining the patient's serum AMH level (e.g., using an automated Elecsys® AMH assay from Roche Diagnostics or a similar method) and the step of administering the dose to a patient having a serum AMH level of ≧15 pmol / L. The patient may be <35 years old, may be 35 - 40 years old, or may be >40 years old. This use and method may include the step of determining the patient's age and the step of administering recombinant FSH to a patient <35 years old. This use and method may include the step of determining the patient's age and the step of administering rFSH to a patient 35 - 40 years old. This use and method may include the step of determining the patient's age and the step of administering rFSH to a patient >40 years old. The rFSH may be rFSH comprising α2,3 and α2,6 sialic acid additions, e.g., rFSH comprising α2,3 and α2,6 sialic acid additions, wherein 5 - 20% of the total sialic acid additions are α2,6 sialic acid additions and 80 - 95% of the total sialic acid additions are α2,3 sialic acid additions. The rFSH may be rFSH produced or expressed in a human cell line. This use or method may include a further step of inducing ovulation (e.g., by administering a dose of 4,000 - 11,000 IU of hCG).This use or method may include further steps of intrauterine insemination. The treatment of infertility by intrauterine insemination may be controlled ovarian stimulation for intrauterine insemination (e.g., controlled ovarian stimulation to prepare the patient for intrauterine insemination (subsequent steps)). The treatment of infertility by intrauterine insemination may include, for the subsequent steps of intrauterine insemination, controlled ovarian stimulation (e.g., using rFSH having α2,3 and α2,6 sialylation) aimed at obtaining two or three mature follicles (defined as follicles ≧16 mm on the day before or on the day of induction of ovulation and / or detected, for example, in the last ultrasound scan before induction).

[0052] According to the present invention, in another aspect, there is provided a composition (e.g., a pharmaceutical composition) containing follicle-stimulating hormone (FSH) for use in the treatment of infertility by intrauterine insemination in a patient having PCOS, wherein the follicle-stimulating hormone (FSH) contains alpha2,3 and alpha2,6 sialylation. Preferably, the FSH is a recombinant FSH containing 2,3 and α2,6 sialylation, 5-20% of the total sialylation is α2,6 sialylation, and 80-95% of the total sialylation is α2,3 sialylation. The FSH can be a recombinant FSH produced or expressed in a human cell line. The treatment of infertility by intrauterine insemination may be controlled ovarian stimulation for intrauterine insemination. The FSH may be for administration at a daily dose of 3 μg to 7 μg, preferably 3 μg to 5 μg. The patient may have a BMI of 30, 40 kg / m 2 or more.

[0053] A patient having PCOS may have two or more of the following criteria (generally, other causes of menstrual disorders and androgen excess are excluded): clinical and / or biochemical signs of androgen excess; oligovulation or anovulation; and the presence of 12 or more follicles (2-9 mm in diameter when measured) in one or both ovaries and / or an increase in ovarian volume (10 cm 3Polycystic ovaries defined as such (ultrasound). Alternatively or additionally, a patient with PCOS may have a serum AMH of ≥23 pmol / L. This use or method may include the step of identifying (e.g., diagnosing) a patient as being a patient with PCOS. This use or method may include the step of identifying (e.g., diagnosing) a patient as being a patient with PCOS and the step of administering a dosage to a patient with PCOS. A patient may be identified as having PCOS (optionally by a physician) prior to treatment. A patient may be identified as having PCOS (optionally by a physician, e.g., prior to treatment) by assessing whether the patient has two or more of the following criteria (and generally excluding other causes of menstrual disorders and androgen excess as well): clinical and / or biochemical signs of androgen excess; infrequent anovulation or anovulation; and the presence of 12 or more follicles (measuring 2-9 mm in diameter) in one or both ovaries and / or an increase in ovarian volume (10 cm 3 Polycystic ovaries defined as such (ultrasound). Alternatively or additionally, a patient may be identified as having PCOS by assessing whether the patient has a serum AMH of ≥23 pmol / L. Serum AMH may be measured by a similar assay such as the ELECSYS® AMH Plus immunoassay (Roche) or ACCESS AMH Advanced from Beckman Coulter or UMIPULSE G AMH from Fujirebio. Additionally or alternatively, the serum concentration of a patient's anti-Müllerian hormone (AMH) may be determined using the Beckmann-Coulter Gen 2 assay as described in Arce et al., Fertility and Sterility 99:1644-53 (2013), or an equivalent method. AMH should be determined within 24 months, including within 12 months prior to treatment. A serum AMH of ≥23 pmol / L indicates PCOS.

[0054] The composition can be for administration, and the method can include administration with a defined dose of rFSH (e.g., the starting dose of rFSH) from the first day to the sixth day of treatment, i.e., from the first day to the sixth day of stimulation. From the seventh day of treatment (the seventh day of stimulation), the dose of rFSH can be decreased (e.g., decreased to a dose of 50% of the starting dose, e.g., decreased to a dose from 50% to 80% of the starting dose), or maintained at the starting dose. In other embodiments, from the seventh day of treatment (the seventh day of stimulation), the dose of rFSH can be increased (e.g., increased to a dose up to 150% of the starting dose, e.g., increased to a dose from 120% to 150% of the starting dose). The dose can be increased, decreased, or maintained based on the patient's ovarian response (e.g., as measured by ultrasound examination).

[0055] The doses disclosed herein (e.g., the starting dose) can be the doses for the first cycle of IUI. In the second and subsequent cycles of IUI, the "starting dose" can be increased (e.g., increased to a dose up to 150% of the starting dose of the first cycle, e.g., increased to a dose from 120% to 150% of the starting dose of the first cycle, e.g., increased to a dose from 125% to 150% of the dose of the starting cycle), decreased (e.g., decreased to a dose of 50% of the starting dose of the first cycle, e.g., decreased to a dose from 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, decreased, or maintained based on the patient's response to the first cycle (e.g., measured by the number of mature follicles of ≧16 mm obtained in the first cycle, and / or detected in the last ultrasound scan before stimulation, e.g., on the day before or on the day of induction).

[0056] In some examples, in the 3rd and subsequent cycles of IUI, the "starting dose" may increase (e.g., increase up to a dose of up to 150% of the starting dose of the 2nd cycle, e.g., increase from 120% to 150% of the starting dose of the 2nd cycle, e.g., increase from 125% to 150% of the dose of the 2nd cycle), decrease (e.g., decrease to a dose of 50% of the starting dose of the 2nd cycle, e.g., decrease from 50% to 80% (e.g., 67%, 80%) of the starting dose of the 2nd cycle), or be maintained at the starting dose of the 2nd cycle. The dose may be increased, decreased, or maintained based on the patient's ovarian response to the 2nd cycle (e.g., measured by the number of mature follicles ≥16 mm obtained in the 2nd cycle on the day before or on the day of induction and / or detected in the last ultrasound scan before induction).

[0057] As described above, generally, a recombinant FSH composition (e.g., a pharmaceutical composition) or agent is administered before or for administration of a high (ovulatory) dose of human chorionic gonadotropin (hCG) (e.g., 4,000 - 11,000 IU of hCG, e.g., 5,000 IU of hCG, 10,000 IU of hCG, etc.; or 150 - 500 μg of recombinant hCG, e.g., 250 μg of recombinant hCG) to induce final follicular maturation. Thus, in some embodiments, the methods described herein further comprise administration of a high (ovulatory) dose of human chorionic gonadotropin (hCG).

[0058] Additionally or alternatively, the treatment may further comprise monitoring and / or controlling an excessive response to the treatment (e.g., OHSS).

[0059] Recombinant FSH and rFSH compositions As described above, the methods and compositions described herein use recombinant FSH (rFSH). FSH consists of an alpha subunit of 92 amino acids, which is common to other glycoprotein hormones, LH and chorionic gonadotropin (CG), and a beta subunit of 111 amino acids specific to FSH that confers 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 have two sites for N-linked glycosylation, amino acids 52 and 78 of the alpha subunit, and amino acid residues 7 and 24 of the beta subunit. FSH is glycosylated in this way up to about 30% by mass.

[0060] The glycosylation of rFSH products reflects the range of glycosyltransferases present in the host cell line. Commercially available rFSH products derived from modified Chinese hamster ovary (CHO) cells have a more limited range of sugar chain modifications than natural products. Examples of the decreased glycan heterogeneity found in CHO cell-derived rFSH include the absence of bisecting GlcNAc and the decreased content of core fucosylation and acetyl-lactosamine elongation. Furthermore, CHO cells can add sialic acid only using the α2,3 linkage, and rFSH derived from CHO cells contains only α2,3-linked sialic acid and no α2,6-linked sialic acid. Thus, CHO cell-derived rFSH differs from naturally produced FSH (e.g., human pituitary / serum / urinary FSH), which contains glycans with a mixture of α2,3-linked and α2,6-linked sialic acids, in which α2,3-linked sialic acid predominates.

[0061] As described above, the Applicants developed rFSH derived from a human cell line which is the subject of International Patent Application No. PCT / GB2009 / 000978 (published as International Publication No. WO 2009 / 127826 A) and which has also been approved by the EC as REVOKELLE® (also known as follitropin delta, FE 999049). By modifying a human cell line to express both rFSH and α2,3 sialyltransferase, a recombinant FSH having a mixture of both α2,3 and α2,6 linked sialic acids was produced. The amino acid sequence of the human cell line-derived recombinant FSH (e.g., FE999049), which is the subject of International Patent Application No. PCT / GB2009 / 000978 published as International Publication No. WO 2009 / 127826 A, is the native human FSH sequence, but the product has a different glycosylation pattern. The expressed product is highly acidic and has a mixture of both α2,3 and α2,6 linked sialic acids, the latter being provided by the endogenous sialyltransferase activity. It has been found that the sialic acid linkage type, α2,3 or α2,6, can have a dramatic effect on the biological clearance of FSH. Thus, REVOKELLE® (e.g., FE 999049) may be more biologically appropriate compared to a recombinant product derived from CHO cells which has only α2,3 linked sialic acid and a reduced sialic acid content.

[0062] Accordingly, recombinant FSH used in accordance with the methods and compositions described herein can be produced or expressed in human cell lines such as the PER.C6® cell line. Recombinant FSH can be produced or expressed in the PER.C6® cell line (deposited with ECACC under deposit number 96022940), a cell line derived from PER.C6®, or a modified PER.C6® cell line. Recombinant FSH produced or expressed in the PER.C6® cell line will contain some α2,6-linked sialic acid (α2,6 sialylation) resulting from the endogenous sialyltransferase activity (of the cell line), and will likely contain some α2,3-linked sialic acid (α2,3 sialylation) resulting from the endogenous sialyltransferase activity. The cell line may be modified using α2,3 sialyltransferase. The cell line may be modified using α2,6 sialyltransferase. Alternatively or additionally, recombinant FSH may contain α2,6-linked sialic acid (α2,6 sialylation) resulting from the endogenous sialyltransferase activity (of the cell line).

[0063] In the methods and compositions described herein, the recombinant FSH used may include α2,3 and α2,6 sialylation. 1% to 99% of the total sialylation of the recombinant FSH for use according to the invention may be α2,3 sialylation. 1% to 99% of the total sialylation of the recombinant FSH for use according to the invention may be α2,6 sialylation. The recombinant FSH may have 1% to 50% of the total sialylation being α2,6 sialylation and 50% to 99% of the total sialylation being α2,3 sialylation. For example, 80% to 95% of the total sialylation, such as 80% to 90%, such as 82% to 89%, such as 85% to 89% may be α2,3 sialylation. For example, 5% to 20% of the total sialylation, such as 10% to 20%, such as 11% to 18%, such as 11% to 15% may be α2,6 sialylation. In one example, the recombinant FSH has 5% to 20% of the total sialylation being α2,6 sialylation and 80% to 95% of the total sialylation being α2,3 sialylation. In another example, the recombinant FSH has 50% to 80% of the total sialylation being α2,6 sialylation and 20% to 50% of the total sialylation being 2,3 sialylation.

[0064] As used herein, "sialylation" means the amount of sialic acid residues present in the recombinant FSH carbohydrate structure. Consistent with use in the art, α2,3 sialylation means sialylation at the 2,3 position and α2,6 sialylation means sialylation at the 2,6 position. Thus, "X% of the total sialylation may be α2,3 sialylation" refers to the percentage of the total number of sialic acid residues present in FSH (or hCG) that is sialylated at the 2,3 position. The term "X% of the total sialylation that is α2,6 sialylation" refers to the percentage of the total number of sialic acid residues present in FSH (or hCG) that is sialylated at the 2,6 position.

[0065] In all embodiments, the rFSH may exist as a single isoform or as a mixture of isoforms.

[0066] The composition can be a pharmaceutical composition. The pharmaceutical composition is for the treatment of infertility. The treatment of infertility may include COS before IUI. The pharmaceutical composition can be used, for example, in medical indications where known FSH preparations are used in IUI according to the methods and treatment protocols disclosed herein.

[0067] The recombinant FSH, composition, or pharmaceutical composition can be formulated into a composition well-known for subcutaneous administration (for example, for subcutaneous injection). Typical compositions include, in particular, pharmaceutically acceptable carriers such as aqueous solutions, non-toxic excipients such as salts and preservatives, buffers, etc., as described on pages 1405 - 1412 and 1461 - 1487 of Remington’s Pharmaceutical Sciences fifteenth edition (Matt Publishing Company, 1975), and in national formulary XIV fourteenth edition (American Pharmaceutical Association, 1975). For example, the recombinant FSH, composition, or pharmaceutical composition can be formulated for injection such as subcutaneous injection.

[0068] 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 suitable mixtures thereof, vegetable oils (such as olive oil), and organic esters for injection such as ethyl oleate.

[0069] The composition of the present invention may also contain additives such as, but not limited to, preservatives, wetting agents, emulsifiers, surfactants, and dispersants. Antibacterial and antifungal agents may be included to prevent the growth of microorganisms, and examples thereof include m-cresol, benzyl alcohol, parabens, chlorobutanol, phenol, sorbic acid, and the like. When a preservative is included, benzyl alcohol, phenol, and / or m-cresol are preferred, but the preservative is by no means limited to these examples. Furthermore, it may be desirable to include isotonic agents such as sugars, sodium chloride, and amino acids.

[0070] For example, the composition or drug may contain recombinant FSH and one or more of polysorbate 20, L-methionine, phenol, and arginine hydrochloride. Such a composition may be formulated for injection, such as subcutaneous injection. For example, the composition or drug may be the REKOVELLE® formulation (rFSH with excipients phenol, polysorbate 20, L-methionine, sodium sulfate decahydrate, disodium phosphate dodecahydrate, phosphoric acid [concentrated, for pH adjustment], sodium hydroxide [for pH adjustment], and water for injection).

[0071] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or another sterile injectable medium immediately before use. Injectable formulations can be supplied in any suitable container, such as vials, prefilled syringes, injection cartridges, and the like.

[0072] The recombinant FSH, composition or agent can be formulated for single use or multiple uses (multiple doses). When the recombinant FSH, composition or agent is formulated for multiple uses, generally one or more preservatives are included. When a preservative is included, benzyl alcohol, phenol or m-cresol is preferred, but the preservative is in no way limited to these examples. The single-use or multiple-use formulated composition or agent may further contain an amino acid or a combination of amino acids. Generally, the amino acid is arginine and is added, for example, as arginine or more typically as arginine hydrochloride.

[0073] The recombinant FSH, composition or agent may include a container such as a vial, a prefilled cartridge (for example, for single administration or multiple uses), or an injection device such as a "pen" for multiple doses.

[0074] The recombinant FSH, composition or pharmaceutical composition can be a formulation containing rFSH (for example, an injectable formulation).

[0075] The recombinant FSH, composition or agent can be supplied in any suitable package. For example, the composition or agent can include a number of containers (for example, prefilled syringes or vials) containing FSH. The syringes or vials may be packaged in a blister pack or other means of maintaining sterility. Any composition or agent can optionally include instructions for using the FSH formulation.

[0076] The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine practice in the art. GOODMAN and GILMAN’s THE PHARMACOLOGICAL BASIS FOR THERAPEUTICES,7 thSee ed. In a typical embodiment, the recombinant FSH, composition or agent is provided as a composition for parenteral administration. General methods of preparing parenteral formulations are known in the art and are described in REMINGTON; THE SCIENCE AND PRACTICE OF PHARMACY, supra, pages 780-820. The parenteral composition can be provided as a liquid formulation or as a solid that is mixed with a sterile injectable medium immediately prior to administration. The parenteral composition can be provided in unit dosage form to facilitate administration and to ensure uniform dosage.

[0077] 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 herein and claimed.

[0078] Further aspects are described in the following examples, which are not limiting in any way.

Examples

[0079] The following examples use REKOVELLE (registered trademark), follitropin delta, a recombinant FSH expressed in the PER.C6 (registered trademark) cell line modified by the methods disclosed in International Publication No. WO 2013 / 020996 pamphlet and International Publication No. WO 2009 / 127826A pamphlet.

[0080] The holder of the marketing authorization for REKOVELLE (registered trademark) is Ferring Pharmaceuticals A / S of Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark, and REKOVELLE (registered trademark) is available in the UK from Ferring Pharmaceuticals of Drayton Hall, Church Road, West Drayton, UB7 7PS, UK.

[0081] The active substance in REKOVELLE (registered trademark) is holitropin delta (FE999049). REKOVELLE (registered trademark) is highly sialylated, including α2,3 sialylation and α2,6 sialylation. Approximately 85 - 90% of the total sialylation is α2,3 sialylation, and approximately 10 - 15% of the total sialylation is α2,6 sialylation.

[0082] REKOVELLE (registered trademark) is a colorless and clear solution for injection. Each 1 mL of the solution contains 33.3 micrograms of holitropin delta. Other components are phenol, polysorbate 20, L - methionine, sodium sulfate decahydrate, disodium phosphate dodecahydrate, concentrated phosphoric acid, sodium hydroxide, and water for injection.

[0083] Example 1: Personalized IUI Treatment Study (PITS): A proof - of - concept study to evaluate the effect of individualized doses of holitropin delta in intrauterine insemination Clinical trial registration number: NCT03830723 Introduction The PITS study aimed to evaluate the effect of holitropin delta on ovarian response using an individualized dosing regimen in controlled ovarian stimulation for IUI. Secondary objectives were the incidence of cancelled cycles, multiple pregnancies, and the cumulative clinical pregnancy rate over three consecutive cycles.

[0084] Methods Design This was a single - facility, non - blinded, single - cohort prospective study to evaluate the efficacy and safety of individualized doses of follitropin delta for intrauterine insemination. Patients were enrolled at one facility in Canada to receive up to three cycles of IUI. The study protocol received approval from the 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 receiving any procedures related to the study.

[0085] Participants Women enrolled in the study were 18 to 42 years old and had at least one patent fallopian tube confirmed by laparoscopy, hysterosalpingography (HSG), or hystero - sonosalpingography (HSSG), or had had one pregnancy in the past three years and were followed at the birth facility. Additional inclusion criteria were a regular menstrual cycle of 26 to 39 days, the presence of both ovaries, the use of ejaculated sperm (fresh or frozen) from a partner or donor, and a semen analysis considered appropriate for IUI according to the facility's practice standards. The main exclusion criteria were a high risk of OHSS (AMH ≥ 35 pmol / L (4.9 ng / mL)), body weight > 100 kg, a history of uterine abnormalities including severe malformations (unicornuate or bicornuate uterus) or leiomyomas ≥ 5 cm, uncontrolled thyroid or adrenal dysfunction, pituitary tumors, or persistent ovarian cysts or ovarian enlargement > 3 cm not due to PCOS. Other exclusion criteria were the use of hormonal therapy in the past three months before the start of stimulation, a diagnosis of tubal edema, malignancy, breast pathology incompatible with gonadotropin stimulation, hypersensitivity to follitropin delta or any component of the formulation, and the addition of other infertility medications that could affect follicle stimulation and maturation such as growth hormone (GH).

[0086] Procedure All subjects who participated in the trial were treated with individualized daily subcutaneous doses of follitropin delta (REKOVELLE®, Ferring Pharmaceuticals) during the first IUI cycle, as determined based on body weight and serum AMH levels measured within the last 24 months before the start of ovarian stimulation (Table 1).

[0087]

Table 2

[0088] These doses were designed to achieve 2 - 3 mature follicles for IUI.

[0089] In the second and third cycles, the dose of follitropin delta was adjusted (see Table 5), taking into account the number of mature follicles visualized by the final pre - fertilization ultrasound (by transvaginal ultrasound (TVU)) and the age of the participants (Tables 2 and 3), even if adjustments were made during the first cycle. Additionally, if there were more than 4 follicles with a diameter of 13.0 - 15.9 mm, a 33% reduction in the follitropin delta dose from the prescribed initial dose was made to reduce the risk of an excessive response in the next cycle.

[0090]

Table 3

[0091]

Table 4

[0092] Hormotropin delta therapy was initiated on day 3 of the menstrual cycle and the dose was maintained the same for the first 5 days of stimulation. The response to stimulation was monitored via transvaginal ultrasonography (TVU) starting on day 8 (day 6 of stimulation). Six days after stimulation, participants underwent transvaginal ultrasonography every 2 - 3 days (following the expected growth of 2 mm / day of follicles ≥12 mm). The dose adjustment of Hormotropin delta during the cycle was performed according to the predefined criteria described in Table 4. The size of the follicle was calculated from the measurement of the two largest diameters (two-dimensional size) of the follicle.

[0093]

Table 5

[0094] The target ovarian response was defined as 2 - 3 follicles ≥16 mm detected on the day of or the day before induction and / or, for example, at the last ultrasound scan before induction. If only 1 mature follicle had developed, the physician proceeded with IUI according to the standard treatment at the clinic. If more than 3 mature follicles had developed, cancellation or conversion to IVF was considered.

[0095] The induction drug was chorionic gonadotropin alpha (Ovidrel®, EMD Serono) and was administered when clinically necessary. Until day 14 when urine pregnancy tests were performed, luteal phase support with 100 mg progesterone vaginal tablets (Endometrin®, Ferring Pharmaceuticals) twice a day was initiated on the day of IUI for all women participating in the study.

[0096] Definition A positive pregnancy test was defined as a positive urine pregnancy test. Clinical pregnancy was defined as a viable intrauterine pregnancy at 6 - 8 weeks confirmed by ultrasound scan. A continuing pregnancy was defined as a viable intrauterine pregnancy of at least 12 weeks confirmed by ultrasound scan. Pregnancy loss was defined as the natural death of a pregnancy before 24 weeks of gestation. The multiple pregnancy rate was defined as the survival rate at 6 - 8 weeks of pregnancy per total number of clinical pregnancies, where two or more embryos with fetal heartbeats were visualized by ultrasound.

[0097] Outcome The co - primary endpoints of this trial included ovarian response (specifically, the proportion of cycles reaching 2 or 3 mature follicles) and clinical pregnancy rate. The cumulative clinical pregnancy rate in up to 3 IUI cycles, and the proportion of subjects with multiple pregnancies were also tested as secondary endpoints.

[0098] Other secondary endpoints included stimulation duration, total drug dosage, drug dosage adjustment, and endometrial thickness. Safety endpoints included the proportion of patients who aborted a cycle and the reasons for cycle abortion, the incidence of early OHSS (including moderate / severe grades of OHSS), and the conversion rate to IVF.

[0099] Statistical Methods This trial used a single - cohort, forward - looking, non - blinded design. Continuous variables were evaluated for normality of distribution and reported as mean and standard deviation. Differences between continuous variables were evaluated for normally distributed variables by t - test or ANOVA and multivariate regression analysis, or for non - normally distributed variables by the Wilcoxon signed - rank test. Correlations between continuous variables were evaluated by Pearson's correlation test. Effect size was evaluated by Cohen's d test. Categorical variables were represented as percentages and compared by chi - square test or multivariate regression analysis. The results of pregnancy outcomes were evaluated according to the intention - to - treat principle.

[0100] The effect of age on treatment effectiveness was evaluated by the difference in pregnancy outcomes among patients classified into the following age groups: < 35 years old, 35 - 40 years old, and > 40 years old. ANOVA was used to evaluate the differences between different age cohorts for continuous variables, and multivariate logistic regression for categorical variables was evaluated. Statistical tests were performed using SPSS version 26 and R for Cohen's d test.

[0101] Results The mean age of all subjects was 34.46 (±4.5) years old and was stratified as follows: < 35 years old (47.7%), 35 - 40 years old (38.5%), and > 40 years old (13.8%). The mean 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 number of antral follicles was 15 (±8.6). Primary infertility was present in 54.5% of the participants, and the mean number of years of infertility was 2.48 years (±3.57). The causes of infertility were idiopathic in 41.8% of the registered participants, female factors in 19.1%, male factors in 26.3%, and other factors in 12.8%.

[0102] The clinical pregnancy rate per IUI cycle according to the intention-to-treat (ITT) was 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 birth rate according to ITT was 33% (Table 7) (an ad-hoc calculation as it was not part of the study protocol). Only 6 multiple pregnancies were observed, which exceeded 40 pregnancies (15%). All of these were twin pregnancies. The multiple pregnancy rate per IUI cycle was 12.5%, 8.3%, and 27.3% respectively (Table 7).

[0103] [Table 6]

[0104] [Table 7]

[0105]

Table 8

[0106] The percentages of patients who obtained 2 or 3 follicles in the 1st, 2nd, and 3rd cycles were 34%, 37%, and 47% respectively, and the average numbers of mature follicles were 1.4, 1.4, and 1.6 respectively. The percentages of patients who reached more than 3 follicles in the 1st, 2nd, and 3rd cycles were 1.9%, 0%, and 1.5% respectively, demonstrating the safety of the follitropin delta administration regimen. The proportions of patients with cycle cancellations in the 1st, 2nd, and 3rd cycles were 8.5%, 2.4%, and 8.8% respectively (Table 7).

[0107] During the 3 IUI cycles, the reasons for 17 cancellations were 7 no responses, 4 hyperresponses, 2 premature ovulations, 2 ovarian cysts, and 2 withdrawals from the study by the patients. Through the 3 IUI cycles, OHSS was not reported and there was no conversion to IVF.

[0108] In the 1st (3.25 μg ± 0.74) and 3rd (5.20 μg ± 1.89) IUI cycles, no statistically significant differences were observed in the initial dose of follitropin delta. The average total amounts of follitropin delta used in each cycle were 27.7 g (±12.7%), 31.4 g (±12.7%), and 40.1 g (±19.1%) respectively. There were significant differences between the 1st and 2nd IUI cycles and between the 2nd and 3rd IUI cycles (P < 0.05). The follitropin delta dose adjustments between cycles were on average as follows: from the 1st to the 2nd IUI cycle: +25% of the initial dose (44%) and +50% of the initial dose (6%), and from the 2nd to the 3rd IUI cycle: +25% (20%) and +50% (24%) (Table 8). For each IUI cycle, there were no significant differences in the average number of days of follitropin delta stimulation: 8.5 (±3.0), 7.9 (±2.6), and 7.8 (±2.5) respectively.

[0109]

Table 9

[0110] The endometrial thickness increased from the 1st to the 2nd and 3rd IUI cycles, being 9.3 mm (±2.1), 9.5 mm (±2.0), and 10.1 mm (±2.7) per cycle, respectively, and there was a significant difference between the 1st and 3rd IUI cycles (P = 0.04) (Table 8).

[0111] There was no statistically significant correlation among the total amount of follitropin delta administered per cycle, the number of mature follicles, and the clinical pregnancy rate. However, along with the higher amount of follitropin delta used in the 3rd IUI cycle, there was a tendency towards a greater number of mature follicles, as well as higher clinical and multiple pregnancy rates.

[0112] Discussion 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.

[0113] At least, due to the risk of multiple pregnancy in IUI and because the expected (desired) number of mature follicles is not the same, the gonadotropin doses (e.g., FSH dose) for IUI and IVF are not equivalent. To achieve 2 - 3 mature follicles in this trial, the dose used was approximately one - quarter of the dose used in IVF. This is a relatively conservative (low) dose in the 1st cycle designed to be clinically effective for all patients (e.g., obtaining 2 - 3 mature follicles in the desired amount), but it was considered to have a low potential for causing multiple pregnancy in the 1st cycle. By using such a conservative and safe dose for the first insemination, better individualization of the doses for the 2nd and 3rd IUI cycles is made possible.

[0114] In the second and third cycles, the follitropin delta dosage was adjusted taking into account the number of mature follicles reached during the previous insemination cycle and the age of the participant (see the table above). This enhanced the individualized dosing approach. For example, the quality of the oocytes generally declines with age, and the dosing regimens described herein can compensate for quality with quantity.

[0115] The treatment described herein is advantageous compared to previously reported studies using FSH in IUI.

[0116] Gregoriou O, et al. Fertil. Steril. 2008;90:678 - 683 randomized 50 couples (mean age 32 years) who had previously failed three cycles of clomiphene citrate / IUI and administered either FSH / IUI (Gonal F or Puregon, recombinant FSH from CHO cell line administered at a dose of 150 IU every other day) or letrozole / IUI for up to three cycles. The cumulative birth rate was 28% in the FSH / IUI group and 20% in the letrozole / IUI group. In contrast, in the PITS trial reported herein, the observed birth rate was higher (33% vs. 28%).

[0117] Three other randomized clinical trials compared clomiphene citrate (CC) / IUI with gonadotropin (recombinant FSH from CHO cell line) / IUI. Berker B, et al., Arch. Gynecol. Obstet. 2011;284:1561-1566 randomized 93 couples. The ongoing pregnancy rate per cycle was 9.6% with CC / IUI and 15.6% with gonadotropin / IUI, 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 4 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 there was a higher cancellation rate (mainly due to an excessive response) in the gonadotropin / IUI group (8.7%). The AMIGOS trial reported by Diamond MP, et al., Fertil. Steril. 2015;103(4):962-973 compared gonadotropin (follitropin alpha), estrogen antagonist, and aromatase inhibitor treatment in up to 4 IUI cycles. For these three classes of drugs, the cumulative clinical pregnancy rates 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, and the gonadotropin / IUI group included 24 twins and 10 triplets.

[0118] In the PITS trial reported in this specification, compared with these three randomized clinical trials, higher cumulative clinical pregnancy rates (37.7%) and cumulative birth rates (33%) were obtained, and the improvement was achieved with only 3 IUI cycles instead of 4. Additionally, the multiple pregnancy rate in the PITS trial (15%, no triplets) was half of that observed in the Amigos trial (31.8%), and the abortion rate was lower than that observed in the Dankert trial. These results support the safety of the dosing regimens disclosed in this specification. Without wishing to be bound by theory, the use of a novel human-derived recombinant FSH (follitropin delta) that has been shown to produce milder ovarian stimulation in patients with polycystic ovaries (PCO) may be partly involved in the reduction of the multiple pregnancy rate.

[0119] The PITS trial demonstrated that an individualized approach using individualized doses of follitropin delta, with a multiple pregnancy rate at the same level as that observed with oral agents and approximately half the rate reported with other gonadotropins (including other forms of FSH), which supports the use of the dosing regimens disclosed in this specification in clinical practice, results in higher clinical pregnancy rates (e.g., compared to using a fixed-dose rFSH containing only 2,3 sialylation).

[0120] Conclusion The PITS trial reported in this specification is the first to use follitropin delta for stimulation in an intrauterine insemination protocol, confirming the effectiveness and benefits of the individualized dosing regimen of follitropin delta described in this specification.

[0121] Supplement to this Example The PITS findings updated as of June 2023 are consistent with the results reported and discussed above.

[0122]

Table 10

[0123] Therefore, the updated results of the PITS trial also showed higher cumulative clinical pregnancy rates (40.6% compared to 37.7% before the update) and cumulative birth rates (33% compared to 33% before the update) compared to the results of the randomized clinical trials of the above three prior arts, and the improvement was achieved with only 3 cycles of IUI instead of 4. Additionally, the multiple pregnancy rate in the PITS trial [14% (6 / 43), no triplets] was less than half of that observed in the Amigos trial (31.8%) and had a lower discontinuation rate than that observed in the Dankert trial. These results support the safety of the dosing regimens disclosed herein. Without wishing to be bound by theory, the use of the novel human-derived recombinant FSH (follitropin delta), which has been shown to produce milder ovarian stimulation in patients with polycystic ovaries (PCO), may be partly involved in the reduction of the multiple pregnancy rate.

[0124] The PITS trial demonstrated that an individualized approach using individualized doses of follitropin delta, which is associated with the same level of multiple pregnancy rate observed with oral agents and approximately half the rate reported with other gonadotropins (including other forms of FSH), in clinical practice supports the use of the dosing regimens disclosed herein and results in a higher clinical pregnancy rate (e.g., compared to using a fixed dose of rFSH containing only 2,3 sialylation).

[0125] Breakdown of additional data

[0126]

Table 11

[0127] The breakdown demonstrates an improvement in cumulative clinical pregnancy rates (exceeding the Amigos prior art values of 35.5%, 28.3%, and 22.4%) for patients with an AMH of <15 pmol / L (45%) and patients with an AMH of ≥15 pmol / L (using data from patients with an AMH of 15.0 - 22.9 and patients with an AMH of ≥23 pmol / L). Furthermore, the breakdown demonstrates an improvement in cumulative clinical pregnancy rates (exceeding the Amigos prior art values of 35.5%, 28.3%, and 22.4%) for patients with PCOS (AMH of ≥23.0 pmol / L) (36.4%).

[0128] Furthermore, the breakdown demonstrates an improvement in cumulative birth rates (exceeding the Amigos prior art values of 32.2%, 23.3%, and 18.7%) for patients with an AMH of <15 pmol / L (35%) and patients with an AMH of ≥15 pmol / L (using data from patients with an AMH of 15.0 - 22.9 and patients with an AMH of ≥23 pmol / L). Finally, the breakdown demonstrates an improvement in cumulative birth rates (exceeding the Amigos prior art values of 32.2%, 23.3%, and 18.7%) for patients with PCOS (AMH of ≥23.0 pmol / L) (31.8%). There are similarities in the 32.2% results for high AMH and PCOS patients, but the improvement is clear considering the multiple pregnancy rate in this trial (half of the AMIGOS trial).

[0129] The method defined by the following numbered paragraphs is disclosed above in this specification: 1. A method for treating infertility by intrauterine insemination in a patient having a serum AMH level of <15 pmol / L, 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 of rFSH per kg of the patient's body weight per day. 2. The method according to paragraph 1, wherein the composition is administered at a dose of 0.05 μg of rFSH per kg of the patient's body weight per day. 3. The method according to paragraph 1, wherein the rFSH comprises α2,6 sialylation and α2,3 sialylation. 4. The method according to paragraph 3, wherein 5% to 20% of the total sialic acid addition of rFSH is α2,6 sialic acid addition, and 80% to 95% of the total sialic acid addition of rFSH is α2,3 sialic acid addition. 5. The method according to paragraph 1, wherein rFSH is produced or expressed in a human cell line. 6. The method according to paragraph 1, further comprising determining the serum AMH level of the patient before administration. 7. The method according to paragraph 3, which is effective in increasing one or both of the pregnancy rate and the birth rate as compared to a method using rFSH containing only α2,3 sialic acid addition. 8. The method according to paragraph 1, wherein the patient is <35 years old. 9. The method according to paragraph 1, wherein the patient is 35 to 40 years old. 10. The method according to paragraph 1, wherein the patient is >40 years old. 11. The method according to paragraph 1, wherein the treatment of infertility by intrauterine insemination is controlled ovarian stimulation for intrauterine insemination. 12. The method according to paragraph 1, further comprising inducing ovulation of the patient by administering hCG. 13. The method according to paragraph 11, further comprising the step of intrauterine insemination. 14. A method for treating infertility by intrauterine insemination in a patient having a serum AMH level of ≧15 pmol / L, 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 of rFSH per kg of the patient's body weight per day. 15. The method according to paragraph 14, wherein the patient has polycystic ovary syndrome (PCOS). 16. The method according to paragraph 14, further comprising determining the serum AMH level of the patient before administration. 17. The method according to paragraph 14, wherein rFSH comprises α2,6 sialic acid addition and α2,3 sialic acid addition. 18. The method according to paragraph 17, wherein 5% to 20% of the total sialic acid addition of rFSH is α2,6 sialic acid addition, and 80% to 95% of the total sialic acid addition of rFSH is α2,3 sialic acid addition. 19. The method according to paragraph 14, wherein rFSH is produced or expressed in a human cell line. 20. The method according to paragraph 16, which is effective to increase one or both of the pregnancy rate and the birth rate as compared with a method using rFSH containing only α2,3 sialylation. 21. The method according to paragraph 14, wherein the patient is < 35 years old. 22. The method according to paragraph 14, wherein the patient is 35 - 40 years old. 23. The method according to paragraph 14, wherein the patient is > 40 years old. 24. The method according to paragraph 14, wherein the treatment of infertility by intrauterine insemination is controlled ovarian stimulation for intrauterine insemination. 25. The method according to paragraph 14, further comprising inducing ovulation in the patient by administering hCG. 26. The method according to paragraph 25, further comprising the step of intrauterine insemination.

Claims

1. A composition comprising follicle-stimulating hormone (FSH) for use in the treatment of infertility by intrauterine insemination (e.g., for increasing pregnancy rate and / or birth rate) in patients having a serum AMH level of < 15 pmol / L, wherein the composition should be administered at a dose of 0.048 μg to 0.052 μg, e.g., 0.05 μg of recombinant FSH per kg of the patient's body weight per day, or a corresponding dose.

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

3. The composition for use according to claim 1 or 2, wherein the use comprises a step of determining the serum AMH level of the patient and a step of administering the dose to a patient having a serum AMH level of < 15 pmol / L.

4. A composition comprising follicle-stimulating hormone (FSH) for use in the treatment of infertility by intrauterine insemination (e.g., for increasing pregnancy rate and / or birth rate) in patients having a serum AMH level of ≧ 15 pmol / L, wherein the composition should be administered at a dose of 0.025 to 0.0475 μg of recombinant FSH per kg of the patient's body weight per day, or a corresponding dose.

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

6. A composition comprising follicle-stimulating hormone (FSH) for use in the treatment of infertility by intrauterine insemination (e.g., for increasing pregnancy rate and / or birth rate) in patients having PCOS with a serum AMH level of ≧ 15 pmol / L (preferably, serum AMH of ≧ 23 pmol / L), wherein the composition should be administered at a dose of 0.025 to 0.0475 μg of recombinant FSH per kg of the patient's body weight per day, or a corresponding dose.

7. The composition for use according to any one of claims 4 to 6, wherein the composition should be administered at a dose of 0.025 to 0.0475 μg of recombinant FSH per kg of the patient's body weight per day.

8. Said use comprising the steps of determining said serum AMH level of said patient, and administering said dosage to a patient having a serum AMH level of ≧15 pmol / L, a composition for use according to any one of claims 4 to 7.

9. A composition for use according to any one of claims 1 to 8, wherein said patient is <35 years old.

10. A composition for use according to any one of claims 1 to 8, wherein said patient is 35 to 40 years old.

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

12. A composition for use according to any one of claims 1 to 11, wherein said FSH is recombinant FSH.

13. A composition for use according to any one of claims 1 to 12, wherein said FSH is recombinant FSH comprising α2,3 and α2,6 sialic acid addition.

14. A composition for use according to any one of claims 1 to 13, wherein said FSH is recombinant FSH comprising α2,3 and α2,6 sialic acid addition, 5% to 20% of the total sialic acid addition is α2,6 sialic acid addition, and 80% to 95% of the total sialic acid addition is α2,3 sialic acid addition.

15. A composition for use according to any one of claims 1 to 14, wherein said FSH is recombinant FSH produced or expressed in a human cell line.

16. A composition for use according to any one of claims 1 to 15, wherein the treatment of infertility by intrauterine insemination is controlled ovarian stimulation for intrauterine insemination.

17. A composition for use according to any one of claims 1 to 16, wherein the treatment of infertility by intrauterine insemination comprises a further step of inducing ovulation (e.g., by administering a dose of 4,000 to 11,000 IU of hCG or a corresponding dose), and optionally a further step of intrauterine insemination.

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

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

20. A composition containing follicle-stimulating hormone (FSH) for use in the treatment of infertility by intrauterine insemination in a patient having PCOS, wherein the follicle-stimulating hormone (FSH) contains alpha 2,3 and alpha 2,6 sialic acid addition.

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

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

Images