Composition containing HP-HMG for use in the treatment of infertility

Abstract

The present invention relates to improved assisted reproductive techniques for women who are expected to have a high ovarian response to controlled ovarian stimulation, including targeting threshold serum hCG levels by the last day of stimulation.

Description

[Technical Field]

[0001] The present invention as described herein relates to assisted reproductive technologies. In particular, described herein are compositions and methods for treating infertility, including methods for controlled ovarian stimulation, which may be especially useful for women who are expected to have a high ovarian response to controlled ovarian stimulation. [Background technology]

[0002] Assisted reproductive technology (ART) procedures generally involve stimulating the development and maturation of eggs, collecting eggs from a woman's ovaries, combining them with sperm in vitro, and implanting them into the woman's uterus (a donor or another woman). The success of ART is hindered by maternal and perinatal risks associated with the stimulation of egg development and maturation, such as ovarian hyperstimulation syndrome (OHSS) and ectopic pregnancy. Other concerns arising in ART include the production of high-quality embryos and euploid blastocysts that support ongoing pregnancy and live birth rates.

[0003] Gonadotropins, such as menotropin (e.g., human menopausal gonadotropin, or hMG), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), have been used for controlled ovarian stimulation (COS), with highly purified menotropin (HP-hMG) and recombinant human FSH (rFSH) being used more recently. HP-hMG primarily provides FSH activity and exogenous LH activity in the form of human chorionic gonadotropin (hCG). The effectiveness of ovarian stimulation protocols can be enhanced by using long gonadotropin hormone-releasing hormone (GnRH) agonists or GnRH antagonists for cycle control. For example, see Devroey et al., Fertility and Sterility 97:561-71 (2012) and Ziebe et al., Human Reproduction 22(9)2404-13 (2007), which reported that the use of HP-hMG in comparison to rFSH derived from Chinese hamster ovary cells (CHO cells) (GONAL-F) was able to influence embryonic morphology in the best quality embryos (based on visual assessment) resulting from HP-hMG stimulation, as well as the observed improved implantation, continuing pregnancy, and live birth rates.

[0004] Because patient responses to ovarian stimulation vary widely, treatment is often individualized. For example, individualization may be based on the expected ovarian response to gonadotropin stimulation, predicting poor, normal, or high response. High-responding women are typically defined as women who produce a large number of developing follicles following a standard protocol of controlled ovarian stimulation (COS). While these patients are generally considered good candidates for ART, high ovarian response may be associated with lower implantation rates and higher miscarriage rates, and therefore a reduced likelihood of successful outcomes compared to normal ovarian response. These high-responding women also have a greater risk of OHSS and its associated complications.

[0005] Attempts to develop improved ART methods for expected high-responders have involved exploring milder stimulation protocols. For example, Rubio et al., Human Reproduction 25(9):2290-97 (2010) reported that reducing the dose of gonadotropin administered to high-responders improved fertilization rates and embryo quality, although lower doses resulted in fewer oocytes. Other attempts have considered whether the specific gonadotropin used affects the outcome. For example, La Marca et al., Fertility and Sterility O-169 (2012) reported that among expected high-responders (subjects with AMH ≥ 5.2 ng / ml), the group stimulated with rFSH (GONAL-F) derived from CHO cells recovered significantly more oocytes, but had a significantly lower live birth rate per cycle compared to the group stimulated with HP-hMG (20% vs. 33% in the MERIT "long agonist" clinical trial; 23% vs. 34% in the MEGASET "antagonist" clinical trial). [Overview of the project] [Problems that the invention aims to solve]

[0006] In particular, improved assisted reproductive technologies are still needed for women who are expected to respond highly to controlled ovarian stimulation. [Means for solving the problem]

[0007] The compositions and methods described herein arise from the surprising and unexpected finding that, in HP-hMG-treated subjects expected to be highly responsive, serum hCG on the final day of stimulation is a key predictor of live birth probability, with higher serum hCG correlated with a higher probability of live birth. In other words, the compositions and methods described herein arise from the surprising and unexpected finding that determining serum hCG in the mid-follicular phase of stimulation and adjusting HP-hMG dosing to achieve a target serum hCG on the final day of stimulation is associated with a higher probability of live birth.

[0008] Provided herein is a method for treating infertility by controlled ovarian stimulation in patients expected to have a high ovarian response to controlled ovarian stimulation, comprising: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation by administering HP-hMG to the selected patients at an initial daily dose of 75 IU to 225 IU; determining whether the patient's serum hCG level is at the target mid-follicular threshold level during the mid-follicular phase of controlled ovarian stimulation; and optionally maintaining or increasing the daily dose of HP-hMG based on whether the patient's serum hCG level is at or below the target mid-follicular threshold level. Typically, the patients are not anovulators. Patients may be 21 to 35 years of age and weigh 18 to 30 kg / m² at the start of treatment. 2The patient may have a BMI of ≥ 1.5 mIU / mL. The method may include increasing the daily dose of HP-hMG when the patient's serum hCG level is below the target mid-phase threshold level. The method may include increasing the daily dose of HP-hMG by 75 IU / day when the patient's serum hCG level is below the target mid-phase threshold level. The method may include maintaining the daily dose of HP-hMG when the patient's serum hCG level is at the target mid-phase threshold level. The target mid-phase threshold level for serum hCG may be ≥ 1.5 mIU / mL. The mid-phase follicular stage of controlled ovarian stimulation may be selected from day 5, day 6, and day 7 of stimulation. The starting daily dose of HP-hMG may be 150 IU / day. The method may further include administering a gonadotropin-releasing hormone antagonist (GnRH antagonist) starting on day 6 of stimulation. The method may further include inducing final follicular maturation by administering human chorionic gonadotropin (hCG), or optionally, a gonadotropin-releasing hormone agonist (GnRH agonist) supplemented with hCG.The method is to (a) retrieve oocytes, fertilize the oocytes, develop the fertilized oocytes to the blastocyst stage, randomly assess the quality / morphology of the blastocysts, and implant fresh blastocysts in the uterus (e.g., randomly selected based on a visual assessment of quality / morphology); (b) retrieve oocytes, fertilize the oocytes, develop the fertilized oocytes to the blastocyst stage, randomly assess the chromosomal quality of the blastocysts, freeze one or more or all blastocysts, and implant thawed frozen blastocysts in the uterus (e.g., euploid blastocysts selected based on chromosomal assessment); (c) retrieve oocytes, freeze unfertilized oocytes, subsequently thaw one or more oocytes, and one or (d) fertilizing multiple or all thawed oocytes, developing the fertilized oocytes to the blastocyst stage, randomly assessing the quality / morphology of the blastocysts, and implanting the blastocysts in the uterus (e.g., randomly selected based on a visual assessment of quality / morphology); or (d) retrieving oocytes, freezing unfertilized oocytes, subsequently thawing one or more frozen oocytes, fertilizing one or more or all thawed oocytes, developing the fertilized oocytes to the blastocyst stage, randomly assessing the chromosomal quality of the blastocysts, freezing one or more or all blastocysts, and implanting the thawed-frozen blastocysts in the uterus (e.g., euploid blastocysts selected based on a chromosomal assessment).

[0009] Also provided herein is a method for treating infertility by controlled ovarian stimulation in patients expected to have a high ovarian response to controlled ovarian stimulation, comprising: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation by administering HP-hMG to the selected patients at an initial daily dose of 75 IU to 225 IU; determining whether the patient's serum hCG level is at the target mid-follicular threshold level during the mid-follicular phase of controlled ovarian stimulation; and optionally administering hCG to the patient based on whether the patient's serum hCG level is at or below the target mid-follicular threshold level. The method may include administering hCG at a daily dose of 5 to 60 IU / day, or equal to 5 to 60 IU / day, when the patient's serum hCG level is below the target mid-follicular threshold level.

[0010] Also provided herein is a method for treating infertility by controlled ovarian stimulation in patients expected to have a high ovarian response to controlled ovarian stimulation, comprising: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation by administering rFSH to the selected patients at a daily dose effective for controlled ovarian stimulation; and administering hCG to the patients at a daily dose of 5-60 IU / day, or equal to 5-60 IU / day, starting in the mid-follicular phase of controlled ovarian stimulation.

[0011] Also provided herein is a composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, wherein the treatment comprises: selecting a patient identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation by administering a daily dose of HP-hMG to the patient from day 1 of the treatment (e.g., 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day); determining whether the patient's serum hCG level is at a target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of controlled ovarian stimulation (e.g., on day 5, 6, or 7 of stimulation); and inducing final follicular maturation when the patient's serum hCG level is at or above a specific threshold level of serum hCG in final follicular maturation resulting in an increased chance of live birth. The specific threshold level of serum hCG at the final follicular maturation that leads to an increased chance of live birth can be selected from 1.5–2.0 mIU / mL, more preferably 1.8 mIU / mL.

[0012] Also provided herein is a composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation in order to increase the likelihood of live birth following fresh embryo or frozen embryo transfer, wherein the treatment comprises: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; and performing controlled ovarian stimulation by administering a daily dose of HP-hMG to the patients from day 1 of the treatment (e.g., 75-450 IU / day, preferably 75-225 IU / day). The procedure includes: determining whether the patient's serum hCG level is at a target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of controlled ovarian stimulation (e.g., on day 5, 6, or 7 of stimulation); and inducing final follicular maturation when the patient's serum hCG level is at or above a specific threshold level of serum hCG in final follicular maturation resulting in an increased chance of live birth. The specific threshold level of serum hCG in final follicular maturation resulting in an increased chance of live birth may be selected from 1.5 to 2.0 mIU / mL, more preferably 1.8 mIU / mL.

[0013] Also provided herein is a composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, wherein the treatment comprises: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation by administering a daily dose of HP-hMG to the selected patients from day 1 of the treatment (e.g., 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day); determining whether the patient's serum hCG level is at the target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of controlled ovarian stimulation (e.g., on day 5, 6, or 7 of stimulation); and optionally maintaining or increasing the daily dose of HP-hMG (e.g., by only 75 IU / day) based on whether the patient's serum hCG level is at or below the target mid-follicular threshold level.

[0014] Also provided herein is a composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, in order to increase the likelihood of live birth following fresh embryo or frozen embryo transfer, wherein the treatment comprises: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; and performing controlled ovarian stimulation by administering a daily dose of HP-hMG to the selected patients from day 1 of the treatment (e.g., 75-450 IU / day, preferably 75-225 IU). The procedure includes: determining whether the patient's serum hCG level is at the target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of controlled ovarian stimulation (e.g., on day 5, 6, or 7 of stimulation); and optionally maintaining or increasing the daily dose of HP-hMG (e.g., by only 75 IU / day) based on whether the patient's serum hCG level is at or below the target mid-follicular threshold level.

[0015] In any of the compositions for use described herein, the patient may have a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) prior to treatment / stimulation; the treatment may further include identifying the patient as having a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) prior to stimulation; the patient is not an anovulator; the patient is 21–35 years of age and / or the patient weighs 18–30 kg / m² at the start of treatment. 2 He has a BMI of [value missing].

[0016] In any of the HP-hMG compositions for use described herein, the composition may comprise 75 to 450 IU of HP-hMG, and controlled ovarian stimulation may comprise administering HP-hMG at an initial dose of 75 to 225 IU of hMG per day, preferably 150 IU / day, for example, from day 1 to at least day 5 of stimulation.

[0017] In any of the HP-hMG compositions for use described herein, treatment of infertility may increase the likelihood of live birth compared to treatment with recombinant FSH derived from CHO cells.

[0018] In any of the compositions for use described herein, the treatment may further include inducing final follicular maturation by administering hCG, or optionally, an hCG-supplemented GnRH agonist, and / or administering a GnRH antagonist, starting on day 6 of stimulation.

[0019] In any of the compositions for use as described herein, the treatment comprises: (a) recovering an oocyte, fertilizing the oocyte, developing the fertilized oocyte to the blastocyst stage, optionally assessing the quality / morphology of the blastocyst, and implanting a fresh blastocyst (e.g., optionally selected based on a visual assessment of quality / morphology) in the uterus; or (b) recovering an oocyte, fertilizing the oocyte, developing the fertilized oocyte to the blastocyst stage, optionally assessing the chromosomal quality of the blastocyst, freezing one or more or all of the blastocysts, and implanting a thawed blastocyst (e.g., a euploid blastocyst selected based on chromosomal assessment) in the uterus; or (c) recovering an oocyte, freezing the unfertilized oocyte, subsequently thawing one or more of the oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocyte to the blastocyst stage, optionally assessing the quality / morphology of the blastocyst, and implanting a blastocyst (e.g., optionally selected based on a visual assessment of quality / morphology) in the uterus; or (d) recovering an oocyte, freezing the unfertilized oocyte, subsequently thawing one or more of the frozen oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocyte to the blastocyst stage, optionally assessing the chromosomal quality of the blastocyst, freezing one or more or all of the blastocysts, and implanting a thawed blastocyst (e.g., a euploid blastocyst selected based on chromosomal assessment) in the uterus, which may further be included.

[0020] Also provided is a composition comprising HP-hMG for use in the treatment of infertility as described herein. Also provided is a composition comprising hCG for use in the treatment of infertility as described herein. Also provided is a composition comprising rFSH for use in the treatment of infertility as described herein.

[0021] Also provided is HP-hMG for use in the preparation of a medicament for treating infertility as described herein. Also provided is hCG for use in the preparation of a medicament for treating infertility as described herein. Also provided is rFSH for use in the preparation of a medicament for treating infertility as described herein.

[0022] The above summary is illustrative and explanatory and is intended to provide further description of the invention. A detailed description is set forth below for a fuller understanding of the invention. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description.

Best Mode for Carrying Out the Invention

[0023] Described herein are reproductive assistance technology methods, for example, methods for treating infertility. In particular, described herein is a controlled ovarian stimulation (COS) method that may be particularly useful for women expected to have a high ovarian response to controlled ovarian stimulation. As shown in Example 1, the method may be useful for increasing the likelihood of live birth, for example, for increasing the live birth rate.

[0024] This invention is based on our unexpected finding that, in subjects expected to be high responders, serum hCG on the final day of controlled ovarian stimulation is an important predictor of live birth probability, with higher serum hCG levels correlated with a higher probability of live birth. As reported in Example 1 below, for every 1 mIU / mL increase in hCG, the likelihood of live birth increased by 38% in subjects treated with HP-hMG. This is the first report of such an effect in expected high responders. Arce and Smitz, Human Fertility, 14(3):192-99 (2011) report a retrospective analysis of normal gonadotropin-treated anovulatory infertile patients treated with HP-hMG or rFSH (GONAL-F) in a low-dose escalation protocol, where serum hCG at the end of stimulation was positively associated with treatment outcomes in normal gonadotropin-treated anovulatory patients. Arce and Smitz, Gynecol. Endocrinol. 29(1):46-50 (2013), report a retrospective analysis of the HP-hMG arm of a long GnRH agonist protocol in women with regular menstrual cycles of 21–35 days and tubal factor or unexplained infertility, or partners with mild semen abnormalities, where serum hCG on day 6 of stimulation was positively associated with treatment outcomes in that patient subgroup. However, prior to this invention, the effect of serum hCG on treatment outcomes in ovulating women expected to have a high ovarian response to controlled ovarian stimulation had not been anticipated or reported.

[0025] Thus, according to several embodiments, the compositions and methods described herein are for increasing the likelihood of live birth by targeting a threshold serum hCG level on the final day of stimulation with HP-hMG, for example, determining serum hCG in the mid-follicular phase of HP-hMG stimulation, and adjusting HP-hMG dosage to achieve the target serum hCG level on the final day of stimulation. While not bound by theory, the results considered herein suggest that hCG derived from HP-hMG (e.g., provided by HP-hMG) contributes positively to the likelihood of live birth, particularly when used in regulated ovarian stimulation of expected high-responders compared to patients treated with rFSH derived from CHO cells as a gonadotropin.

[0026] Also described herein are compositions and methods for increasing the likelihood of live birth and achieving a target serum hCG level on the final day of stimulation by targeting a threshold serum hCG level on the final day of stimulation, for example, by administering hCG initiated during the mid-follicular phase of regulated ovarian stimulation with HP-hMG or rFSH.

[0027] definition The technical and scientific terms used herein have the meanings generally understood by those skilled in the art of assisted reproductive technologies to which the present invention relates, unless otherwise defined. Various methodologies known to those skilled in the art are referenced herein. Unless otherwise specified, any suitable materials and / or methods known to those skilled in the art may be used in carrying out the present invention. However, specific materials and methods are described. The materials, reagents, etc., mentioned in the following description and examples may be obtained from commercial sources unless otherwise noted.

[0028] In this specification, the singular forms "a," "an," and "the" refer to both singular and plural nouns unless explicitly stated otherwise.

[0029] As used herein, the term “about” means that the number or range is not limited to the exact number or range stated, but encompasses a range around the number or range enumerated as understood by those skilled in the art from the context in which the number or range is used. Unless otherwise evident from the context or convention in the art, “about” means plus or minus 10% of a particular term.

[0030] As used herein, the terms “anovulation” or “anovulatory syndrome” refer to a patient whose ovaries do not release oocytes during the menstrual cycle. Therefore, ovulation does not occur. Chronic anovulation is a common cause of infertility. Generally, the patients for whom the compositions and methods described herein are intended are not anovulatory patients.

[0031] As used herein, “continuing pregnancy” refers to a gestational period of 10–11 weeks, for example, a pregnancy with a viable fetus and detectable fetal heartbeat 8–9 weeks after blastocyst / embryo transfer.

[0032] As used herein, “clinical pregnancy” refers to conception and the detection of a detectable fetal heartbeat during the 5-6 week gestational period, for example, 3-4 weeks after blastocyst / embryo transfer.

[0033] As used herein, “woman” refers to an adult female human being. Typically, the women treated by the compositions and methods described herein are 35 years of age or younger and have a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) as measured using the Beckmann-Coulter second-generation assay, as described in Arce et al., Fertility and Sterility 99:1644-53 (2013), or an equivalent AMH level as assessed by a different method, and a weight of 30 kg / m². 2Or has a BMI of less than that. In some embodiments, the women treated by the compositions and methods described herein are identified as being 21 to 35 years old prior to treatment. In some embodiments, the women treated by the compositions and methods described herein are identified as being 35 years old or less, or 34 years old or less prior to treatment. In some embodiments, the women treated by the methods described herein are identified as being 21 to 34 years old, or 21 to 33 years old, or 21 to 32 years old, or 21 to 31 years old prior to treatment. In some embodiments, the women treated by the methods described herein have a BMI of 18 to 30 kg / m 2 prior to treatment. In some embodiments, the women treated by the methods described herein have a BMI of 38 kg / m 2 or less, 36 kg / m 2 or less, 34 kg / m 2 or less, 32 kg / m 2 or less, 30 kg / m 2 or less, or 28 kg / m 2 or less BMI, e.g., 18 to 38, 18 to 36, 18 to 34, 18 to 32, 18 to 30, or 18 to 28 kg / m 2 prior to treatment. In some embodiments, the women treated by the methods described herein have a BMI of 18 to 25 kg / m 2 , 18 to 26 kg / m 2 , 18 to 27 kg / m 2 , 18 to 28 kg / m 2 , 18 to 29 kg / m 2 , or 18 to 30 kg / m 2 prior to treatment.

[0034] As used herein, the term “expected to have a high ovarian response to controlled ovarian stimulation” or “expected high responder” refers to a woman who is likely to develop a large number of follicles or oocytes following a standard protocol of controlled ovarian stimulation (COS), for example, a woman who has an above-average potential to produce 15 or more oocytes. A woman may be identified as an expected high responder if she produced 15 or more oocytes in a previous ART cycle, for example, in a previous COS treatment. Furthermore, or alternatively, a woman may be identified as an expected high responder if she is considered to be at risk of developing OHSS. Furthermore, or alternatively, a woman may be identified as a high-responder if she has a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml), as measured using the Beckmann-Coulter second-generation assay, for example, as described in Arce et al., Fertility and Sterility 99:1644-53 (2013), or an equivalent AMH level assessed by a different method.

[0035] The term “menotropin” includes human menopausal gonadotropin or “hMG,” including “highly purified menotropin” or “HP-hMG,” as used herein. As used herein, the terms “highly purified menotropin” and “HP-hMG” refer to highly purified hMG products that contain both follicle-stimulating hormone (FSH) activity and human chorionic gonadotropin (hCG)-enhanced luteinizing hormone (LH) activity, including hMG products in which the majority of LH activity is provided by hCG, including products in which ≥90% or ≥95% of LH activity is provided by hCG. See, for example, Foutouh et al., Reproductive BioMed.Online, 14(2):145-47 (2007); Wolfenson et al., Reprod.BioMed.Online, 10(4):442-54 (2005). In some embodiments, HP-hMG is an HP-hMG product available under the trademark MENOPUR® from Ferring Pharmaceuticals, Inc., containing LH activity enhanced by FSH and hCG, where ≥95% of the LH activity is provided by hCG (pituitary hCG) as assessed by immunoreactivity. See, for example, Arce and Smitz, Human Fertility, 14(3):192-99 (2011). To be reconstituted for use, one vial of MENOPUR® (75 IU HP-hMG) contains 75 IU of FSH activity and 75 IU of LH activity, where hCG provides approximately 70 IU of LH activity.

[0036] The term "GnRH agonist" as used herein includes gonadotropin-releasing hormone (GnRH) agonists, such as buserelin (e.g., SUPRECUR®), leuprorelin (e.g., leuprolide acetate, e.g., LUPRON®), nafarelin (e.g., SYNAREL®), and triptorelin (e.g., TRELSTAR®).

[0037] The term "GnRH antagonist" as used herein includes gonadotropin-releasing hormone (GnRH) antagonists, such as ganirelix acetate (e.g., ORGALUTRAN®) and cetrorelics acetate (e.g., CETROTIDE®), which block the action of GnRH by competitively blocking GnRH receptors on pituitary gonadotropin-producing cells, thereby preventing gonadotropin production / release and immature ovulation (release of an egg).

[0038] As used herein, the term “effective dose” refers to the dosage determined to provide a specific pharmacological effect when administered to a subject requiring such treatment. It is emphasized that a therapeutically effective dose, even if considered therapeutically effective by those skilled in the art, is not necessarily effective in treating the conditions described herein in a given patient. For convenience, exemplary doses and therapeutically effective doses are provided below for adult female human subjects. Those skilled in the art can adjust such doses as necessary in accordance with standard practice to treat specific subjects and / or conditions / diseases.

[0039] Assisted reproductive technology methods The treatment methods described herein are useful in any reproductive technique involving controlled ovarian stimulation (COS) for in vitro fertilization, including in vitro fertilization by intracytoplasmic sperm injection (ICSI), methods involving fresh transfer of fertilized eggs (e.g., blastocysts / embryos), methods involving freezing fertilized eggs for subsequent implantation, and methods involving freezing unfertilized oocytes for subsequent fertilization.

[0040] As described above, according to several embodiments, the present invention provides a reproductive technology method that involves using a highly purified menotropin (HP-hMG) product containing LH activity, which is promoted by both FSH and hCG, as a gonadotropin for COS in women who are expected to have a high ovarian response to COS and who are undergoing COS. As also noted above, for the purposes of the compositions and methods disclosed herein, a woman may be identified as likely to have a high ovarian response to COS based on having a high ovarian response to a previous ART cycle, e.g., a previous COS treatment, or if she has a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml), e.g., a serum AMH level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) as measured using the Beckmann-Coulter second-generation assay, as described in Arce et al., Fertility and Sterility 99:1644-53 (2013), or an equivalent AMH level as assessed by a different method. Serum AMH levels are an alternative marker for securing functional ovarian follicles, and a positive correlation between serum AMH levels and ovarian response (e.g., oocyte yield) has been reported (ibid.). According to the compositions and methods described herein, women are typically identified as expected high-responders based on their serum AMH levels.

[0041] Thus, according to several embodiments, the assisted reproductive technology treatment methods described herein include: performing controlled ovarian stimulation in a woman expected to have a high ovarian response to controlled ovarian stimulation using HP-hMG to stimulate follicular development; determining serum hCG during stimulation; and adjusting HP-hMG dosage to achieve a target serum hCG on the final day of stimulation. More specifically, the compositions and methods described herein relate to the treatment of infertility by controlled ovarian stimulation in a patient expected to have a high ovarian response to controlled ovarian stimulation, comprising: selecting a patient identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation in the selected patient by administering HP-hMG to the selected patient at an initial daily dose of, for example, 75 IU to 225 IU; determining whether the patient's serum hCG level is at the target mid-follicular threshold level during the mid-follicular phase of controlled ovarian stimulation; and optionally maintaining or increasing the daily dose of HP-hMG based on whether the patient's serum hCG level is at or below the target mid-follicular threshold level. In any embodiment described herein, HP-hMG may be MENOPUR®.

[0042] The procedure may include identifying patients (e.g., women) who are expected to have a high ovarian response to controlled ovarian stimulation, for example, by having a serum AMH level equal to or greater than 35.7 ± 0.5 pmol / L (≧5.0 ± 0.2 ng / ml) as measured using a Beckmann-Coulter second-generation assay, or a comparable AMH level as measured by a different method, before performing controlled ovarian stimulation. Thus, the assisted reproductive technology procedure described herein may include selecting women identified as expected to have a high ovarian response to controlled ovarian stimulation and performing controlled ovarian stimulation, as summarized above and described in more detail below. The method may further include determining that a woman is expected to have a high ovarian response to controlled ovarian stimulation, for example, by determining that the woman has a serum AMH level equal to or greater than 35.7 ± 0.5 pmol / L (≧5.0 ± 0.2 ng / ml) when measured using a Beckmann-Coulter second-generation assay, or a comparable AMH level measured by a different method, before performing controlled ovarian stimulation. In any embodiment, a woman may or may be identified as having a serum AMH level equal to or greater than 35.7 ± 0.5 pmol / L (≧5.0 ± 0.2 ng / ml) when measured using a Beckmann-Coulter second-generation assay, or a comparable AMH level measured by a different method. In any embodiment, the patient (e.g., a woman) is not an anovulatory woman.

[0043] According to several embodiments, the method involves administering HP-hMG in an effective dose to stimulate follicular development, for example, at a dose of approximately 75 IU / day to approximately 450 IU / day, including 150 IU / day or 225 IU / day. HP-hMG administration is typically initiated on the second or third day of the patient's menstrual cycle, with the first day of treatment (also referred herein as the first day of stimulation) being performed on the second or third day of the patient's menstrual cycle. HP-hMG administration is continued daily for a total stimulation period of approximately 1 to approximately 20 days, typically 8 to 12 days, and more specifically, for approximately 9 to 11 days, typically including approximately 10 days, until a desirable level of follicular development is reached.

[0044] HP-hMG can be administered in doses ranging from approximately 75 IU / day to approximately 450 IU / day, including 75 IU / day, 150 IU / day, 225 IU / day, 300 IU / day, 375 IU / day, or 450 IU / day, which may be adjusted during the stimulation period. Typically, the starting dose of HP-hMG is 150 IU / day, but it can range from 75 IU / day to 225 IU / day. Pharmaceutical compositions containing HP-hMG, such as the MENOPUR® product marketed by Ferring Pharmaceuticals, Inc. and formulated for subcutaneous injection, are commercially available.

[0045] For example, it is known in the art to adjust gonadotropin dosage during the stimulation period (e.g., increasing or decreasing HP-hMG or rFSH dosage) based on the target ovarian (follicular) response, which can be assessed by transvaginal ultrasound (TVUS) and serum estradiol levels. It is also known to adjust gonadotropin dosage during the stimulation period when one or both of the patient's serum estradiol levels and the number of follicles > 12 mm are too low or too high. Such assessments and adjustments can be made at any time during the stimulation period, typically during the mid-follicular phase of stimulation, typically on day 5, 6, or 7 of stimulation.

[0046] According to some embodiments of the compositions and methods disclosed herein, HP-hMG administration is adjusted (or is further adjusted) during the stimulation period (e.g., during the mid-follicular phase of stimulation) based on the patient's serum hCG level. Thus, the patient's serum hCG level is determined during the stimulation period (e.g., during the mid-follicular phase of stimulation), and if the serum hCG is below the target level (e.g., below the target mid-follicular level), the dose of HP-hMG is increased (e.g., unless the increased dose is contraindicated by other safety factors, e.g., a high ovarian response). Such assessment and adjustment may be made at any time during the stimulation period that affects serum hCG on the final day of stimulation, for example, during the mid-follicular phase of stimulation, typically 4 to 6 days after stimulation, for example, on day 5, 6, or 7 of stimulation, including day 6 of stimulation.

[0047] Serum hCG can be determined by any means known in the art, including by enzyme-coupled immunosorbent assay (ELISA) or electrochemiluminescence immunoassay, as known in the art. In some embodiments, serum hCG is measured by ELISA with a lower detection limit of 0.5 mIU / mL for hCG. In some embodiments, serum hCG is measured by electrochemiluminescence immunoassay with a lower detection limit of 0.1 mIU / mL for hCG. Serum hCG is typically measured using a blood sample taken from the patient at least 8 hours after the most recent dose of HP-hMG was administered.

[0048] According to the compositions and methods described herein, the target threshold serum hCG on the final day of stimulation may be 1.5–2.0 mIU / mL. The target mid-follicular phase serum hCG threshold level is selected to achieve the target final-day serum hCG threshold level on the final day of stimulation. In some embodiments, the target threshold serum hCG on the final day of stimulation is ≥1.8 mIU / mL (1.8 IU / L). Consistent with such embodiments, the target mid-follicular phase serum hCG (e.g., on day 5, 6, or 7 of stimulation) is selected to achieve the target final-day threshold serum hCG by the final day of stimulation, and thus may be, for example, ≥1.4 mIU / mL, ≥1.5 mIU / mL, ≥1.6 mIU / mL, or ≥1.7 mIU / mL, for example, ≥1.5 mIU / mL. In some embodiments, the target threshold serum hCG on the final day of stimulation is ≥2.0 mIU / mL (2.0 IU / L). In accordance with such embodiments, the target mid-follicular phase serum hCG (for example, on day 5, 6, or 7 of stimulation) is selected to achieve the target end-of-stimulation threshold serum hCG by the end of stimulation, and may be, for example, ≥1.6 mIU / mL, ≥1.7 mIU / mL, ≥1.8 mIU / mL, or ≥1.9 mIU / mL. In some embodiments, the target threshold serum hCG on the end of stimulation is ≥1.5 mIU / mL (1.5 IU / L). In accordance with such embodiments, the target mid-follicular phase serum hCG (for example, on day 5, 6, or 7 of stimulation) is selected to achieve the target end-of-stimulation threshold serum hCG by the end of stimulation, and may be, for example, ≥1.2 mIU / mL, ≥1.3 mIU / mL, or ≥1.4 mIU / mL. In certain embodiments, the target threshold serum hCG on the final day of stimulation is ≥1.8 mIU / mL (1.8 IU / L), and the target follicular mid-phase serum hCG (for example, on day 5, 6, or 7 of stimulation) is ≥1.5 mIU / mL.

[0049] Thus, according to several embodiments, the assisted reproductive technology procedures described herein include: performing controlled ovarian stimulation in identified expected high-responders by administering a daily dose of HP-hMG effective in stimulating follicular development; determining whether the patient's serum hCG level is at the target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) at the mid-follicular phase of the stimulation period (e.g., on day 6 of stimulation); and optionally maintaining or increasing the daily dose of HP-hMG based on whether the patient's serum hCG level is at the target mid-follicular threshold level (e.g., increasing the daily dose of HP-hMG if the patient's serum hCG level is below the target mid-follicular threshold level). The daily dose of HP-hMG may be increased, for example, in increments of 37.5 IU / day or 75 IU / day, typically in increments of 75 IU / day. The increased daily dose may be continued throughout the remainder of the stimulation period (unless, for example, continuing the increased dose becomes contraindicated by other safety factors, such as a high ovarian response).

[0050] In some embodiments, the patient's serum hCG level may be determined again (e.g., 1–3 days after the initial determination), and the method may optionally further include maintaining or increasing the daily dose of HP-hMG based on whether the patient's serum hCG level is at a target level, where the target level for the subsequent determination is selected to achieve the target end-of-day threshold serum hCG by the end of the stimulation period (e.g., ≥1.5, ≥1.6, or ≥1.7 mIU / mL for a target end-of-day threshold of 1.8 mIU / mL). The daily dose of HP-hMG may be increased, for example, in increments of 37.5 IU / day or 75 IU / day, typically in increments of 75 IU / day. The increased daily dose may be continued throughout the remainder of the stimulation period (e.g., unless continuing the increased dose is contraindicated by other safety factors, e.g., a high ovarian response).

[0051] Optionally, the treatment method may include determining serum hCG levels at other stages of the stimulation period, including before stimulation and / or on the final day of stimulation.

[0052] The treatment method described herein is designed to achieve a target threshold serum hCG level on the final day of stimulation (which the inventors have determined to be a fairly predictive factor for live birth), by determining serum hCG levels during the mid-follicular phase of the stimulation period and increasing the daily dose of HP-hMG if the serum hCG level is below the target mid-follicular threshold level. In fact, based on the results reported in Example 1, it was surprisingly and unexpectedly determined that patients expected to be highly responsive with serum hCG ≥ 1.8 mIU / mL on the final day of stimulation had a greater than 85% chance of live birth, while patients with serum hCG < 1.8 mIU / mL on the final day of stimulation had a less than 25% chance of live birth. Furthermore, as reported in Example 1 below, it was surprisingly and unexpectedly found that every 1 mIU / mL increase in serum hCG on the final day of stimulation increased the probability of live birth by only 38%.

[0053] According to known protocols, gonadotropins (e.g., HP-hMG) are administered daily until a desirable level of follicular development is reached. For example, gonadotropins (e.g., HP-hMG) may be administered until three follicles with a diameter of ≥17 mm have developed, as can be determined by TVUS. Typically, the maximum gonadotropin administration period (stimulation period) is 20 days, and the typical administration period is 8–12 days, more specifically, typically about 9–11 days, including about 10 days.

[0054] In some embodiments, the treatment method includes the administration of a GnRH antagonist during a portion of the gonadotropin (e.g., HP-hMG) administration period. For example, the GnRH antagonist may be administered when the largest follicle reaches a diameter of 14 mm and may be continued throughout the remainder of the gonadotropin (e.g., HP-hMG) administration period. For example, the GnRH antagonist may be started and administered on day 5, 6, or 7 of stimulation (e.g., day 6 of stimulation) and may be continued throughout the remainder of the gonadotropin (e.g., HP-hMG) administration period. When the GnRH antagonist is ganirelix acetate (e.g., ORGALUTRAN®), a typical dose is 0.25 mg / day administered subcutaneously.

[0055] In other embodiments, the treatment method includes the administration of a GnRH agonist prior to controlled ovarian stimulation, for example, the administration of triptorelin (typically 0.1 mg / day subcutaneously) or leuprorelin (e.g., leuprolide acetate, e.g., LUPRON®) prior to controlled ovarian stimulation.

[0056] In some embodiments, the treatment method further includes inducing the maturation of final follicular cells. For example, once a desirable level of follicular development is reached, the induction of final follicular cell maturation can be stimulated by methods known in the art, for example, by a bolus injection of human chorionic gonadotropin (hCG). For example, the induction of final follicular cell maturation may be stimulated in patients with ≥3 follicles, each with a diameter ≥17 mm, and typically having an estradiol (E2) level <10,000 pmol / mL. Thus, in some embodiments, the treatment method may include administering hCG to induce the maturation of final follicular cells. The dose of hCG can be 5,000 IU to 10,000 IU. A typical dose of recombinant hCG (e.g., OVITRELLE®, Merck) is 250 μg, usually administered by a single subcutaneous injection (6,500 IU of hCG activity).

[0057] GnRH agonists can be used as an alternative to the use of hCG to induce final follicular maturation. Thus, in some embodiments, the treatment method may include administering a gonadotropin-releasing hormone (GnRH agonist) to induce final follicular maturation. GnRH agonists can be used, for example, in patients who, after COS treatment, have >25 follicles with a diameter of ≥12 mm or a serum estradiol (E2) level of ≥5,000 pmol / L, or >30 follicles with a diameter of ≥12 mm or a serum estradiol (E2) level of ≥5,000 pmol / L, or an estradiol (E2) level of ≥10,000 pmol / L, or ≥20 follicles with a diameter of ≥12 mm or an estradiol (E2) level of ≥15,000 pmol / L, for example, in cases of an excessive response, to induce final follicular maturation. GnRH agonists are typically leuprolide acetate, e.g., LUPRON®, used in doses of 1–4 mg. GnRH agonists are also typically triptorelin acetate, e.g., DECAPEPTYL®, used in doses of 0.2 mg. When using GnRH agonists to induce final follicular maturation, small amounts of hCG, e.g., 500–3000 IU, may also be used. When GnRH agonists are used to induce final follicular maturation, typically a “total freezing” protocol (discussed below) is followed, for example, for safety reasons.

[0058] In some embodiments, the treatment method further includes recovering oocytes and fertilizing the oocytes by a method known in the art, such as ICSI.

[0059] In some embodiments, the treatment method is a fresh transplantation method. For a fresh transplantation method, one or more blastocysts are selected for transplantation. The remaining blastocysts can be frozen (including vitrification) by methods known in the art for future transplantation. Thus, in embodiments of fresh transplantation, the method includes retrieving oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, retrieving blastocysts, optionally selecting blastocysts based on a quality / morphological assessment, and implanting fresh blastocysts (optionally selected, e.g., based on a quality / morphological assessment) in the uterus. In certain embodiments, the compositions and methods described herein are used in a single blastocyst transplantation protocol, where a single blastocyst is used for fresh transplantation. According to those embodiments, the remaining blastocysts can be frozen by methods known in the art for future transplantation.

[0060] In some embodiments, the method is a cryopreservation method. In embodiments of cryopreservation, the method includes retrieving oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, optionally assessing the chromosomal quality of the blastocysts, freezing one, more, or all of the blastocysts, and implanting the thawed-frozen blastocysts (e.g., euploid blastocysts selected based on the chromosomal assessment) in the uterus. For freezing and "total freezing" methods, the selected blastocysts are frozen by methods known in the art for future implantation / transfer.

[0061] In some embodiments, unfertilized oocytes are frozen. In such embodiments, the method includes retrieving oocytes and freezing one or more or all of the retrieved oocytes for future fertilization by a method known in the Art. In such embodiments, the method may subsequently include thawing one or more of the frozen oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, selecting blastocysts arbitrarily based on a qualitative / morphological assessment, and implanting the blastocysts (e.g., arbitrarily selected based on a qualitative / morphological visual assessment) in the uterus. Alternatively, the method may include: collecting oocytes; freezing one or more or all of the collected oocytes for future fertilization; subsequently thawing one or more of the frozen oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; assessing the chromosomes of the blastocysts; freezing the blastocysts; and implanting the thawed-frozen blastocysts (e.g., euploid blastocysts selected based on the chromosome assessment) in the uterus.

[0062] As described above, in some embodiments, the method includes assessing the chromosomal quality of blastocysts or selecting blastocysts based on a chromosomal assessment. This can be done by methods known in the art, such as preimplantation genetic testing for aneuploidy (PGT-A, also known as PGS) or preimplantation genetic diagnosis (PGD), which are used to examine blastocysts (embryos) for genetic and chromosomal information. When PGS or PGD is used, all chromosomes can be assessed, and only blastocysts identified as having a low risk of chromosomal abnormalities are selected for embryo transfer (implantation in the uterus). This replaces the traditional method of selecting embryos by their appearance under a microscope three or five days after development in an incubator.

[0063] As described above, the compositions and methods described herein are particularly useful for increasing the likelihood of live birth, for example, after in vitro fertilization and fresh or frozen transfer, compared to comparable methods using recombinant follicle-stimulating hormone (rFSH) derived from CHO cells (e.g., GONAL-F, EMD Serono) as a gonadotropin.

[0064] Thus, according to some embodiments, a method is provided for treating infertility by controlled ovarian stimulation in patients expected to have a high ovarian response to controlled ovarian stimulation, comprising: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation on the selected patients by administering HP-hMG to them at an initial daily dose of, for example, 75 IU to 225 IU, for example, 150 IU / day; determining whether the patient's serum hCG level is at the target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of controlled ovarian stimulation (e.g., selected from day 5, day 6, or day 7 of stimulation); and optionally maintaining or increasing the daily dose of HP-hMG (e.g., by only 75 IU / day) based on whether the patient's serum hCG level is at the target mid-follicular threshold level. The method also provides for increasing the likelihood of live birth after in vitro fertilization and fresh or frozen transfer in patients expected to have a high ovarian response to controlled ovarian stimulation, comprising: selecting patients identified as likely to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation in the selected patients by administering HP-hMG to them at an initial daily dose of, for example, 75 IU to 225 IU, for example, 150 IU / day; determining whether the patient's serum hCG level is at the target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of controlled ovarian stimulation (e.g., selected from day 5, day 6, or day 7 of stimulation); and optionally maintaining or increasing the daily dose of HP-hMG (e.g., by only 75 IU / day) based on whether the patient's serum hCG level is at the target mid-follicular threshold level. As discussed above, a patient may have a serum anti-Müllerian hormone (AMH) level equal to or greater than 35.7 ± 0.5 pmol / L (≧5.0 ± 0.2 ng / ml); optionally, the method may further include determining whether the patient has a serum anti-Müllerian hormone (AMH) level equal to or greater than 35.7 ± 0.5 pmol / L (≧5.0 ± 0.2 ng / ml).As discussed above, the method may further include, for example, administering a gonadotropin-releasing hormone antagonist (GnRH antagonist) starting on day 6 of stimulation. As discussed above, the method may further include inducing final follicular maturation by administering human chorionic gonadotropin (hCG) or a gonadotropin-releasing hormone agonist (GnRH agonist) (optionally, supplemented with hCG). As discussed above, the method may be a fresh transfer method further including retrieving oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, retrieving blastocysts, optionally selecting blastocysts based on a quality / morphological assessment, and implanting the fresh blastocysts in the uterus. Alternatively, the method may be a cryotransfer method further comprising: retrieving oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; optionally assessing the chromosomal quality of the blastocysts; freezing one or more or all of the blastocysts; and implanting the thawed-frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal assessment) in the uterus. Alternatively, the method may include: retrieving oocytes; freezing one or more or all of the unfertilized oocytes; subsequently thawing one or more of the frozen oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; optionally selecting blastocysts based on quality / morphological assessment; and implanting the blastocysts (e.g., optionally selected based on quality / morphological visual assessment) in the uterus. Alternatively, the method may include: collecting oocytes; freezing one or more or all unfertilized oocytes; subsequently thawing one or more frozen oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; assessing the chromosomes of the blastocysts; freezing the blastocysts; and implanting the thawed-frozen blastocysts (e.g., euploid blastocysts selected based on the chromosome assessment) in the uterus.

[0065] The present invention also provides a composition (e.g., a pharmaceutical composition) comprising HP-hMG for use in the treatment of infertility in patients (e.g., women) expected to have a high ovarian response to controlled ovarian stimulation, wherein the treatment comprises: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation by administering a daily dose of HP-hMG to the selected patients from day 1 of the treatment (e.g., from day 2 or 3 of the patient's menstrual cycle); determining whether the patient's serum hCG level is at a target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of controlled ovarian stimulation; and inducing final follicular maturation when the level of hCG in the patient's serum is at or above a specific threshold level of serum hCG that results in an increased chance of live birth. The specific threshold level of serum hCG in final follicular maturation that results in an increased chance of live birth may be 1.5–2 mIU / mL, more preferably 1.8 mIU / mL.

[0066] The present invention also provides a composition (e.g., a pharmaceutical composition) comprising HP-hMG for use in the treatment of infertility in patients (e.g., women) who are expected to have a high ovarian response to controlled ovarian stimulation, thereby increasing the likelihood of live birth following fresh embryo or frozen embryo transfer, wherein the treatment comprises: selecting a patient identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation by administering a daily dose of HP-hMG to the patient from day 1 of the treatment (e.g., from day 2 or 3 of the patient's menstrual cycle); determining whether the patient's serum hCG level is at a target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of controlled ovarian stimulation; and inducing final follicular maturation when the patient's serum hCG level is at or above a specific threshold level of serum hCG resulting in an increased likelihood of live birth. A specific threshold level of serum hCG that results in an increased chance of live birth on the day of induction of final follicular maturation may be 1.5–2 mIU / mL, more preferably 1.8 mIU / mL.

[0067] The present invention also provides a composition (e.g., a pharmaceutical composition) comprising HP-hMG for use in the treatment of infertility in patients (e.g., women) expected to have a high ovarian response to controlled ovarian stimulation, wherein the treatment comprises: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation by administering a daily dose of HP-hMG to the selected patients from day 1 of the treatment (e.g., from day 2 or 3 of the patient's menstrual cycle); determining whether the patient's serum hCG level is at the target mid-follicular threshold level during the mid-follicular phase of controlled ovarian stimulation; and optionally maintaining or increasing the daily dose of HP-hMG (e.g., in increments of 75 IU / day) based on whether the patient's serum hCG level is at or below the target mid-follicular threshold level. The target mid-follicular level of serum hCG may be 1.3 to 1.7 mIU / mL, more preferably 1.5 mIU / mL.

[0068] Patients may have serum anti-Müllerian hormone (AMH) levels ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) prior to treatment / stimulation. Treatment may include a further step of identifying patients with serum anti-Müllerian hormone (AMH) levels ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml), measured using the Beckmann-Coulter second-generation assay, for example, as described in Arce et al., Fertility and Sterility 99:1644-53 (2013), or equivalent AMH levels assessed by different methods prior to treatment / stimulation.

[0069] In the embodiments of the present invention, the patient is not an anovulator.

[0070] The composition may comprise 75–450 IU of HP-hMG, for example, MENOPUR®. Treatment for infertility may involve administering doses of 75–450 IU of HP-hMG per day (to the patient), including 75 IU / day, 150 IU / day, 225 IU / day, 300 IU / day, 375 IU / day, or 450 IU / day (which may be adjusted during the stimulation period), for a total stimulation period (treatment period) of about 1–20 days, typically 8–12 days, and more specifically, typically about 10 days, for a total stimulation period of about 9–11 days.

[0071] The procedure may include a further step of administering a GnRH antagonist, which is initiated when the largest follicle reaches a diameter of 14 mm and / or on day 5, 6, or 7 of stimulation (e.g., day 6 of stimulation), and continued throughout the remainder of the HP-hMG administration period.

[0072] Treatments for infertility as described herein are associated with a higher likelihood of live birth, in particular, compared to comparable methods of treatment using recombinant follicle-stimulating hormone (rFSH) derived from CHO cells as a gonadotropin (e.g., GONAL-F, EMD Serono).

[0073] The procedure may further include inducing the maturation of the final follicular cells, as described above. Thus, the procedure may include administering hCG (e.g., recombinant hCG) or a GnRH agonist to induce the maturation of the final follicular cells. As discussed above, when inducing the maturation of the final follicular cells using a GnRH agonist, a small amount of hCG may also be used.

[0074] The procedure may further include: retrieving (e.g., collecting) oocytes; fertilizing (e.g., injecting semen) the oocytes; and developing the fertilized oocytes to the blastocyst stage. Fertilization (e.g., injecting semen) may be in vitro fertilization, or optionally, intracytoplasmic sperm injection (ICSI).

[0075] The procedure may be a fresh embryo transfer method comprising: retrieving oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; retrieving blastocysts; optionally selecting blastocysts based on a qualitative / morphological assessment; and implanting fresh blastocysts (optionally selected, e.g., based on a qualitative / morphological assessment) in the uterus. The procedure may be a single blastocyst transfer protocol, in which a single blastocyst is selected for fresh transfer. Optionally, the remaining blastocysts may be frozen by methods known in the art for future transfers.

[0076] The method may be a cryotransfer method comprising: retrieving oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; selectively assessing the chromosomal quality of the blastocysts; freezing one, more, or all of the blastocysts; and implanting the thawed-frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal assessment) in the uterus. For freezing and "total freezing" methods, the selected blastocysts are frozen by methods known in the art for future implantation / transfer.

[0077] The method may involve freezing unfertilized oocytes. Thus, the method may include retrieving oocytes, freezing one or more or all of the retrieved oocytes, subsequently thawing one or more of the frozen oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, randomly selecting blastocysts based on qualitative / morphological assessment, and implanting the blastocysts (e.g., randomly selected based on qualitative / morphological visual assessment) in the uterus. Alternatively, the method may include: collecting oocytes; freezing one or more or all of the collected oocytes; subsequently thawing one or more of the frozen oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; assessing the chromosomes of the blastocysts; freezing the blastocysts; and implanting the thawed-frozen blastocysts (e.g., euploid blastocysts selected based on the chromosome assessment) in the uterus.

[0078] In one example, the treatment includes administering a dose of 150 IU of HP-hMG per day to the patient starting on day 1 of the treatment, determining on day 6 of the treatment whether the patient's serum hCG level is ≥1.5 mIU / mL, and optionally maintaining or increasing the daily dose of HP-hMG (e.g., in increments of 75 IU / day) based on whether the patient's serum hCG level is ≥1.5 mIU / mL, for example, increasing the daily dose of HP-hMG by 75 IU / day if the patient's serum hCG level is <1.5 mIU / mL.

[0079] The present invention also provides a composition (e.g., a pharmaceutical composition) comprising HP-hMG for use in the treatment of infertility in patients (e.g., women) expected to have a high ovarian response to controlled ovarian stimulation, in order to increase the likelihood of live birth following fresh embryo or frozen embryo transfer, wherein the treatment comprises: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation by administering a daily dose of HP-hMG to the selected patients from day 1 of the treatment (e.g., from day 2 or 3 of the patient's menstrual cycle); determining whether the patient's serum hCG level is at the target mid-follicular threshold level during the mid-follicular phase of controlled ovarian stimulation; and optionally maintaining or increasing the daily dose of HP-hMG (e.g., in increments of 75 IU / day) based on whether the patient's serum hCG level is at or below the target mid-follicular threshold level. The target follicular mid-phase threshold level for serum hCG may be 1.3–1.7 mIU / mL, more preferably 1.5 mIU / mL.

[0080] Patients may have serum anti-Müllerian hormone (AMH) levels ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) prior to treatment / stimulation. Treatment may include further steps to identify patients with serum anti-Müllerian hormone (AMH) levels ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) as measured using the Beckmann-Coulter second-generation assay, as described, for example, in Arce et al., Fertility and Sterility 99:1644-53 (2013), or equivalent AMH levels assessed by different methods prior to treatment / stimulation.

[0081] In the embodiments of the present invention, the patient is not an anovulator.

[0082] The composition may comprise 75–450 IU of HP-hMG, for example, MENOPUR®. Treatment for infertility may comprise administering doses of 75–450 IU of HP-hMG per day (to the patient), including 75 IU / day, 150 IU / day, 225 IU / day, 300 IU / day, 375 IU / day, or 450 IU / day (this may be adjusted during the stimulation period), for a total stimulation period (treatment period) of about 1–20 days, typically 8–12 days, and more specifically, typically 9–11 days including about 10 days, until a desired level of follicular development is reached.

[0083] The procedure may include a further step of administering a GnRH antagonist, which is initiated when the largest follicle reaches a diameter of 14 mm and / or on day 5, 6, or 7 of stimulation (e.g., day 6 of stimulation), and continued throughout the remainder of the HP-hMG administration period.

[0084] Treatments for infertility as described herein are associated with a higher likelihood of live birth, in particular, compared to comparable methods of treatment using recombinant follicle-stimulating hormone (rFSH) derived from CHO cells as a gonadotropin (e.g., GONAL-F, EMD Serono).

[0085] The procedure may further include inducing the maturation of the final follicular cells, as described above. Thus, the procedure may include administering hCG (e.g., recombinant hCG) or a GnRH agonist to induce the maturation of the final follicular cells. As discussed above, when inducing the maturation of the final follicular cells using a GnRH agonist, a small amount of hCG may also be used.

[0086] The procedure may further include: retrieving (e.g., collecting) oocytes; fertilizing (e.g., injecting semen) the oocytes; and developing the fertilized oocytes to the blastocyst stage. Fertilization (e.g., injecting semen) may be in vitro fertilization, or optionally, intracytoplasmic sperm injection (ICSI).

[0087] The procedure may be a fresh embryo transfer method comprising: retrieving oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; retrieving blastocysts; selecting blastocysts based on qualitative / morphological assessment; and implanting fresh blastocysts (optionally selected, e.g., based on qualitative / morphological assessment) in the uterus. The procedure may be a single blastocyst transfer protocol, in which a single blastocyst is selected for fresh transfer. Optionally, the remaining blastocysts may be frozen by methods known in the art for future transfer.

[0088] The method may be a cryotransfer method comprising: retrieving oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; selectively assessing the chromosomal quality of the blastocysts; freezing one, more, or all of the blastocysts; and implanting the thawed-frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal assessment) in the uterus. For freezing and "total freezing" methods, the selected blastocysts are frozen by methods known in the art for future implantation / transfer.

[0089] The method may involve freezing unfertilized oocytes. Thus, the method may include retrieving oocytes, freezing one or more or all of the retrieved oocytes, subsequently thawing one or more of the frozen oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, randomly selecting blastocysts based on qualitative / morphological assessment, and implanting the blastocysts (e.g., randomly selected based on qualitative / morphological visual assessment) in the uterus. Alternatively, the method may include: collecting oocytes; freezing one or more or all of the collected oocytes; subsequently thawing one or more of the frozen oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; assessing the chromosomes of the blastocysts; freezing the blastocysts; and implanting the thawed-frozen blastocysts (e.g., euploid blastocysts selected based on the chromosome assessment) in the uterus.

[0090] In one example, the treatment includes administering a dose of 150 IU of HP-hMG per day to the patient starting on day 1 of the treatment, determining on day 6 of the treatment whether the patient's serum hCG level is ≥1.5 mIU / mL, and optionally maintaining or increasing the daily dose of HP-hMG (e.g., in increments of 75 IU / day) based on whether the patient's serum hCG level is ≥1.5 mIU / mL, for example, increasing the daily dose of HP-hMG by 75 IU / day if the patient's serum hCG level is <1.5 mIU / mL.

[0091] In alternative embodiments, the treatment methods described herein include administering hCG when a patient's serum hCG level is below a target level, for example, supplementing HP-hMG with hCG. Suitable hCG products, including NOVAREL® (Ferring Pharmaceuticals, Inc.), PREGNYL® (Merck), and OVIDREL® (EMD Serono), are commercially available. When used for this purpose, hCG is administered in a dose selected to achieve a target end-day threshold serum hCG level by the end of the stimulation period, for example, at a dose of 5–60 IU / day (or an equivalent amount of OVIDREL®, administered in micrograms, for example, 0.20–2.3 μg / day).

[0092] In such embodiments, the assisted reproductive technology treatment method described herein may include: performing controlled ovarian stimulation in identified expected high-responders by administering a daily dose of HP-hMG effective in stimulating follicular development; determining whether the patient's serum hCG level is at the target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of the stimulation period (e.g., on day 5, 6, or 7 of stimulation); and optionally administering hCG (e.g., at a dose of 5–60 IU / day) based on whether the patient's serum hCG level is at the target mid-follicular threshold level. hCG supplementation may be continued throughout the remainder of the stimulation period.

[0093] According to these embodiments, hCG supplementation may be performed in addition to, or as an alternative to, increasing the daily dose of HP-hMG. Thus, for example, if the patient's serum hCG level is not at the target follicular mid-phase threshold level, hCG may be administered, and optionally, the daily dose of HP-hMG may be increased.

[0094] In some embodiments, the patient's serum hCG level may be determined again (e.g., 1–3 days after the initial determination), and the method may optionally further include (i) maintaining or increasing the daily dose of HP-hMG and / or (ii) maintaining or increasing the daily dose of hCG based on whether the patient's serum hCG level is at a target level, where the target level for the subsequent determination is selected to achieve a target end-of-day threshold serum hCG by the end of the stimulation period (e.g., ≥1.5, ≥1.6, or ≥1.7 mIU / mL for a target end-of-day threshold of 1.8 mIU / mL).

[0095] In the variations of the HP-hMG embodiment discussed above, the daily dose of HP-hMG may be increased after the initial determination that the patient's serum hCG level is not at the target follicular mid-phase threshold level (e.g., ≥1.5 mIU / mL), and hCG supplementation may be initiated after the subsequent determination that the patient's serum hCG level is not at the target threshold level, or vice versa.

[0096] Thus, the present invention provides a composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, wherein the treatment comprises: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation by administering a daily dose of HP-hMG to the selected patients from day 1 of the treatment (e.g., 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day); determining whether the patient's serum hCG level is at the target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of controlled ovarian stimulation (e.g., on day 5, 6, or 7 of stimulation); and optionally administering hCG to the patient based on whether the patient's serum hCG level is at or below the target mid-follicular threshold level. The method may include administering hCG at a daily dose of 5-60 IU / day when the patient's serum hCG level is below the target follicular mid-phase threshold level.

[0097] In further alternative embodiments, the treatment methods described herein include, for example, the use of FSH (e.g., rFSH) as a gonadotropin for controlled ovarian stimulation according to protocols known in the art. As used herein, “rFSH” includes recombinant human FSH products approved for use for controlled ovarian stimulation, such as folitropin alpha (GONAL-F, Merck Serono / EMD Serono) and follitropin beta (PUREGON® and FOLLISTIM®, MSD / Schering-Plough) expressed in Chinese hamster ovary (CHO) cell lines, and follitropin delta (REKOVELLE®, Ferring) expressed in human cell lines. For example, rFSH products derived from CHO cells may be administered at doses of 75–450 IU / day, with a typical starting dose of 75–225 IU / day, e.g., 150 IU / day or 225 IU / day, typically 150 IU / day. Human cell-derived rFSH products, such as REKOVELLE®, can be administered in microgram-based doses of 6–24 μg per day, with a typical starting dose of 12–15 μg / day.

[0098] According to such embodiments, hCG supplementation is initiated in the mid-follicular phase to achieve a target day-end serum hCG level (e.g., ≥1.8 mIU / mL) by the end of controlled ovarian stimulation. When used for this purpose, hCG (e.g., NOVAREL®, Ferring Pharmaceuticals, Inc.; PREGNYL®, Merck; or OVIDREL®, EMD Serono) is administered at a dose selected to achieve a target day-end threshold serum hCG level by the end of stimulation, for example, at a dose of 5–60 IU / day (or an equivalent amount of OVIDREL® administered at micrograms, e.g., 0.20–2.3 μg / day).

[0099] In such embodiments, the assisted reproductive technology treatment method described herein may include performing controlled ovarian stimulation in identified expected high-responders by administering a daily dose of rFSH effective in stimulating follicular development during the mid-follicular phase of the stimulation period (e.g., on day 5, 6, or 7 of stimulation) and administering hCG (e.g., at a dose of 5–60 IU / day). hCG supplementation may be continued throughout the remainder of the stimulation period. In some embodiments, the patient's serum hCG level may be determined 1–3 days after the start of hCG supplementation, and the method may optionally further include maintaining or increasing the daily dose of hCG based on whether the patient's serum hCG level is at a target level, where the target level for subsequent determination is selected to achieve a target day-end threshold serum hCG by the final day of stimulation (e.g., ≥1.5, ≥1.6, or ≥1.7 mIU / mL for a target day-end threshold of ≥1.8 mIU / mL).

[0100] Thus, according to the present invention, in a further embodiment, a composition comprising rFSH for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, wherein the treatment comprises: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation by administering a daily dose of rFSH effective in stimulating follicular development to the selected patients from day 1 of the treatment (e.g., 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day, or 6-24 μg / day, preferably 12-15 μg / day, for rFSH products derived from CHO cells); and administering hCG to the patients at a daily dose of 5-60 IU / day, starting from the mid-follicular phase of controlled ovarian stimulation (e.g., starting on day 5, 6, or 7 of stimulation).

[0101] In a related embodiment, a composition comprising hCG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, wherein the treatment comprises: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation by administering a daily dose of rFSH effective in stimulating follicular development to the selected patients from day 1 of the treatment (e.g., 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day, or 6-24 μg / day, preferably 12-15 μg / day, for rFSH products derived from human cell lines); and administering hCG to the patients at a daily dose of 5-60 IU / day, starting from the mid-follicular phase of controlled ovarian stimulation (e.g., starting on day 5, 6, or 7 of stimulation).

[0102] In a related embodiment, a product comprising rFSH and hCG (e.g., in separate containers) for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, wherein the treatment comprises: selecting patients identified as expected to have a high ovarian response to controlled ovarian stimulation; performing controlled ovarian stimulation by administering a daily dose of rFSH effective in stimulating follicular development to the selected patients from day 1 of the treatment (e.g., 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day, or 6-24 μg / day, preferably 12-15 μg / day, for rFSH products derived from human cell lines); and administering hCG to the patients at a daily dose of 5-60 IU / day, starting from the mid-follicular phase of controlled ovarian stimulation (e.g., starting on day 5, 6, or 7 of stimulation).

[0103] Further embodiments of the methods described herein are illustrated in the following examples, which are not limiting in any way. [Examples]

[0104] Example 1 - MEGASET HR Clinical Trial and Retrospective Analysis The following is a list of 18-30 kg / m² sperm collected in a multicenter, randomized, evaluator-blinded, comparative, non-inferiority trial that underwent intracytoplasmic sperm injection and single blastocyst transfer (fresh transfer). 2 This report describes a retrospective analysis of data from 620 women aged 21–35 years with BMI and serum anti-Müllerian hormone (AMH) ≥ 35.7 pmol / L. The trial was named "MENOPUR® in a Gonadotropin-Releasing Hormone (GnRH) Antagonist Cycle With Single-Blastocyst Transfer in a High Responder Subject Population (MEGASET HR)" (ClinicalTrials.gov identifier NCT02554279). Further details can be found at clinicaltrials.gov / ct2 / show / record / NCT02554279 and in Witz et al., Fertility and Sterility, forthcoming (published online on March 29, 2020).

[0105] 1. Research Group The primary eligibility criteria are a regular ovulatory menstrual cycle of 21-45 days in which the patient desires to become pregnant, and a weight of 18-30 kg / m². 2 The subjects were women aged 21–35 years with a body mass index (BMI). Patients / subjects were expected high-response subjects defined in screening as those with a serum anti-Müllerian hormone (AMH) level of ≥5 ng / mL (35.71 pmol / L). Subjects had a documented history of infertility (e.g., inability to conceive for at least 12 months or at least 6 months, even with donor sperm) and serum FSH levels of 1–12 IU / L (both extremes) on day 2 or 3 of the menstrual cycle.

[0106] Exclusion criteria included known stage III-IV endometriosis; a history of subsequent recurrent miscarriages that did not result in live birth (recurrent is defined as two or more consecutive miscarriages); and previous failures of in vitro fertilization (IVF) or assisted reproductive technology (ART) due to a poor response to gonadotropins (a poor response is defined as a history of development of ≤2 mature follicles or 2 previous failed cycle cancellations prior to oocyte retrieval due to a poor response). Anovulatory women were also excluded.

[0107] 2. Research Protocol This was a multicenter, randomized, evaluator-blinded, phase IV clinical trial comparing HP-hMG and rFSH in a GnRH antagonist cycle with forced single blastocyst transfer (fresh transfer) in a high-response population in the United States. The objective of this study was to demonstrate that HP-hMG is at least non-inferior to rFSH in terms of ongoing pregnancy rate (OPR) in potential high-response patients undergoing IVF / ICSI treatment.

[0108] Participants were classified as potential high-ovarian responders based on serum AMH levels ≥5.0 ng / ml (e.g., ≥35.7 pmol / L) as determined by the Beckmann-Coulter second-generation assay, using materials and reagents from the Beckmann-Coulter-DSL assay (Chaska, MN) in a separate reference laboratory (ReproSource, Inc., Woburn, MA). This classification was based on serum AMH levels ≥5.0 ng / ml (e.g., ≥35.7 pmol / L) as described in Arce et al., Fertility and Sterility 99:1644-53 (2013).

[0109] Participants were randomized in a 1:1 ratio to receive cosophageal stimulant (COS) with a 150 IU dose of HP-hMG (N=311; MENOPUR®, Ferring Pharmaceuticals, Inc.) or rFSH (N=309; GONAL-F, EMD Serono) as the gonadotropin in a GnRH antagonist cycle. Treatment began on day 2 or 3 of the menstrual cycle with a 150 IU dose of HP-hMG or rFSH for the first 5 days. From day 6 of stimulation onward, the dosage could be adjusted daily by 75 IU per adjustment as needed, based on follicular response assessed by TVUS. However, the maximum gonadotropin dose was 300 IU / day. Gonadotropin administration could be continued for a maximum of 20 days, and coasting was prohibited.

[0110] When the largest follicle had a diameter of >14 mm, GnRH antagonist (ganirelix acetate) was initiated at a daily dose of 0.25 mg and continued throughout the gonadotropin treatment period.

[0111] As soon as three follicles with a diameter of ≥17 mm were observed on TVUS, a single injection of 250 μg of hCG (human chorionic gonadotropin alpha) was administered to induce final follicular maturation. However, if a subject had an excessive ovarian response (≥30 follicles, each ≥12 mm, and / or estradiol (E2) levels ≥5,000 pg / mL), a GnRH agonist (4 mg of leuprolide acetate) was administered ≥12 hours after the last GnRH antagonist dose, fresh transfer was canceled, and all blastocysts were biopsied; to reduce the risk of OHSS, viable blastocysts were frozen for use in subsequent transfer cycles.

[0112] Oocyte retrieval was performed approximately 36 hours after administration of hCG or GnRH agonist. Oocytes were infused with partner sperm via ICSI 4 ± 1 hours after retrieval. The quality of oocytes, embryos, and blastocysts was assessed. On day 5 following ICSI, a single blastocyst of the best quality according to morphological criteria (Gardner and Schoolcraft scales) was transferred (fresh transfer); all remaining blastocysts were frozen using vitrification.

[0113] The day after oocyte retrieval, progesterone vaginal suppositories (100 mg twice daily - ENDOMETRIN®; Ferring) were started to stimulate the luteal phase, and this continued until the day of the β-hCG test (10-15 days after blastocyst / embryo transfer). Luteal stimulation was able to be continued until continued pregnancy was confirmed.

[0114] Biochemical pregnancy was confirmed by a positive β-hCG test approximately two weeks after blastocyst transfer. Clinical pregnancy was confirmed by TVUS showing at least one intrauterine gestational sac with fetal heartbeat during the 5-6 week gestational period. Continuing pregnancy was confirmed by at least one intrauterine viable fetus during the 10-11 week gestational period.

[0115] For subjects without ongoing pregnancies in fresh cycles, single frozen blastocyst transfer could be initiated within 6 months of randomization in the clinical trial. Euploidy was selected for frozen transfer using PGS results. Frozen-thawed embryo transfer cycle data, including blastocyst transfer information, β-hCG testing, clinical pregnancy, ongoing pregnancy, pregnancy loss rates, and live births, were collected.

[0116] Post-trial follow-up included the collection of delivery information (live birth and neonatal health) for all subjects with continuing pregnancies in fresh cycles or 1-year-after-randomization frozen-thaw embryo replacement cycles. Live birth rates after fresh cycles, as well as cumulative live birth rates after fresh and 6-month-after-randomization frozen-thaw embryo replacement cycles, were evaluated as part of the post-trial follow-up.

[0117] The HP-hMG used was MENOPUR® (provided by Ferring Pharmaceuticals, Inc.), provided as a vial containing dried HP-hMG (75 IU of HP-hMG providing 75 IU of LH activity, including 75 IU of FSH activity and 75 IU of LH activity provided by hCG), and a vial containing a solvent for reconstitution. After reconstitution, each vial contains 75 IU of FSH activity and 75 IU of LH activity, including 75 IU of LH activity provided by hCG.

[0118] The FSH used was recombinant FSH (GONAL-F, EMD Serono) provided as a solution for injection.

[0119] Other drugs used: • Injectable ganirelix acetate manufactured by Merck and provided as a pre-filled syringe (0.5 mL) delivering 0.25 mg of ganirelix. When the largest follicle measured ≥14 mm and / or serum E2 levels were ≥300 pg / mL, ganirelix acetate was initiated at a daily dose of 0.25 mg and continued throughout the gonadotropin treatment period. OVIDREL® (Human Choroidal Gonadotropin Alpha), manufactured by EMD Serono and supplied as a pre-filled syringe (0.5 mL) delivering 250 μg of chorionic gonadotropin alpha, is administered as a single injection as soon as three follicles ≥17 mm in diameter are observed on TVUS. ENDOMETRIN® (progesterone), manufactured by Ferring and supplied as a vaginal suppository administered twice daily via the vagina, delivering 100 mg (200 mg / day) each time.

[0120] The primary endpoint was the rate of continuing pregnancy, defined as the presence of at least one intrauterine pregnancy with a viable fetus and detectable fetal heartbeat during the 10-11 week gestational period. Secondary endpoints were: • Biochemical pregnancy rate (positive β-hCG test) • Clinical pregnancy rate (transvaginal ultrasound showing at least one intrauterine gestational sac with fetal heartbeat during the 5-6 week gestational period) • Early miscarriage (defined as two positive β-hCG tests, but without continued pregnancy during the 10-11 week gestation period in a fresh cycle) ·Live birth rate Follicle development should be assessed using TVUS, follicular levels (total number of follicles, number of follicles ≤9mm, 10-11mm, 12-14mm, 15-16mm, and ≥17mm), and target levels (size of the largest follicle, average follicle size, average size of the three largest follicles, and average number of follicles ≥17mm, ≥15mm, and ≥12mm). • Endocrine profile (serum estradiol [E2], progesterone [P4], hCG, LH) • Retrieved oocytes, fertilization rate, and embryo quality It included.

[0121] 3. Serum assay Blood samples were collected before the start of stimulation, on day 6 of stimulation, and throughout the stimulation period, including the final day of stimulation. Serum was analyzed using ELISA for AMH (Beckman-Coulter 2nd generation), FSH, LH, and hCG; two-dimensional high-performance liquid chromatography and tandem mass spectrometry for estradiol; and liquid chromatography and tandem mass spectrometry for progesterone and testosterone. The limits of detection were as follows: FSH, 0.017 mIU / mL; LH, 0.005 mIU / mL; βhCG, 0.5 mIU / mL; estradiol, 1.0 pgl / mL; progesterone, 10 ng / dL; and testosterone, 2.5 ng / dL.

[0122] 4. Results and Retrospective Analysis The non-inferiority objective for the primary endpoint of continuing pregnancy was met. HP-hMG was associated with numerically higher continuing pregnancy rates compared to rFSH (30.7% vs. 35.5%, P>0.05). The mean number of oocytes per patient (±SD) (22.2±11.54) in the rFSH arm was higher in the hMG arm (15.1±10.12), but the difference in ovarian response was accompanied by a statistically significant increase in the rate of OHSS (9.7% vs. 21.4%; p<0.05).

[0123] For this retrospective analysis, we collected live birth outcomes resulting from all fresh transplants and any frozen transplants that occurred within 6 months of randomization. Logistic regression was performed to separately identify the relationships between each factor (per visit, where necessary) and the live birth rate. The interaction effects of factors by treatment group (HP-hMG, rFSH) were investigated. Results are reported as odds ratios (ORs) and corresponding 95% confidence intervals (CIs) with p-values.

[0124] Retrospective analysis showed that serum hCG on the final day of stimulation had a significant effect on the likelihood of live birth in HP-hMG-treated subjects, with an odds ratio of 1.38 (CI: 1.00, 1.89) (p: 0.048). For every 1 mIU / mL increase in hCG, the likelihood of live birth increased by 38%. Serum hCG on day 6 of stimulation was not a statistically significant predictive factor in the HP-hMG group (p=0.73). hCG could not be detected in the serum of subjects treated with rFSH.

[0125] Retrospective analysis also showed significant serum FSH interactions between treatment groups on day 6. For every 1 IU / mL increase in serum FSH, the odds ratio for live birth was reduced by only 13% in the rFSH-treated group compared to the HP-hMG-treated group, but with an odds ratio of 0.87 (CI: 0.77, 0.98) (p-value: 0.020). This difference between treatment groups was observed despite HP-hMG containing FSH activity, suggesting that the effect seen in the rFSH-treated group may be due to FSH that is not offset by hCG.

[0126] No other significant relationships with live birth were found at the time points / parameters evaluated.

[0127] While not bound by theory, this analysis suggests that hCG derived from HP-hMG (e.g., provided by HP-hMG) positively contributes to the likelihood of live birth when used in controlled ovarian stimulation of expected high-responders. The cause of this relationship is unclear. However, fewer fresh and frozen embryo transfers were required in the HP-hMG-treated group to achieve similar cumulative live birth outcomes compared to the rFSH-treated group.

[0128] Example 2 The following outlines exemplary infertility treatment methods for expected high-response patients. Infertility treatment targeting serum hCG threshold levels on the final day of COS with HP-hMG administration is associated with a higher likelihood of live birth.

[0129] Typically, a medical practitioner (e.g., a physician) oversees the treatment of infertility. Patients are diagnosed, or have been diagnosed, as expected high-responders based on having serum AMH levels of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) by a Beckmann-Coulter second-generation assay, for example, as described in Arce et al., Fertility and Sterility 99:1644-53 (2013), or equivalent serum AMH levels determined by a different method.

[0130] Patients expected to be highly responsive (e.g., those with serum AMH levels of ≥35.7±0.5 pmol / L or ≥5.0±0.2 ng / ml prior to treatment) are selected and administered HP-hMG (e.g., MENOPUR®, available from Ferring Pharmaceuticals, Inc.). As discussed above, MENOPUR® is considered particularly advantageous in this application because it contains hCG-enhanced LH activity.

[0131] Controlled ovarian stimulation is initiated on the second or third day of the patient's menstrual cycle ("Day 1 of stimulation"). The procedure involves administering a daily dose of MENOPUR®, e.g., 150 IU / day, by injection from Day 1 of the procedure (Day 1 of stimulation) to at least Day 5 (Day 5 of stimulation). As discussed below, the dose may be adjusted upward or downward (e.g., in increments of 75 IU of hMG) up to a maximum daily dose of 450 IU of hMG or a minimum daily dose of 75 IU of hMG (e.g., depending on the patient's ovarian response and / or serum hCG). The procedure may be continued for up to 20 days (including Day 20, up to Day 20 of stimulation), but is typically 8 to 12 days, including approximately 10 days.

[0132] When the diameter of the largest follicle is >14 mm as assessed by TVUS, GnRH antagonist (ganirelix acetate) may be initiated at a daily dose of 0.25 mg and continued throughout the gonadotropin stimulation period.

[0133] During the stimulation period, at the mid-follicular phase (e.g., on day 6 of stimulation), the patient's serum hCG level is determined (e.g., by ELISA with a detection limit of at least 0.5 mIU / mL) to determine whether the patient's serum hCG level is at the mid-follicular target level. For this determination, blood is typically collected at least 8 hours after the previous gonadotropin administration. If the serum hCG level is below the target mid-follicular threshold level (e.g., <1.5 mIU / mL), the daily dose of HP-hMG is increased (e.g., only 75 IU / day). The increased daily dose is continued throughout the remainder of the stimulation period (e.g., unless continuing the increased dose is contraindicated by other safety factors, e.g., a high ovarian response) with the aim of achieving the target threshold level of hCG at the end of stimulation (e.g., ≥1.8 mIU / mL by the time three follicles ≥17 mm in diameter are observed on TVUS). The method may optionally include determining serum hCG levels on the final day of stimulation, but by then, if the level is below the desired target threshold level, it may be too late to intervene.

[0134] Final follicular maturation is induced with hCG or a GnRH agonist. As soon as three follicles with a diameter of ≥17 mm are observed on TVUS, a single injection of 250 μg of hCG (human chorionic gonadotropin alfa) may be administered to induce final follicular maturation. Alternatively, a GnRH agonist may be used to induce final follicular maturation in patients with >30 follicles with a diameter of ≥12 mm or serum estradiol (E2) levels ≥5,000 pg / ml, for example, following COS treatment, or in cases of an excessive response to COS. When a GnRH agonist is used, it may be, for example, leuprolide acetate, e.g., LUPRON® at doses of 1-4 mg.

[0135] The method, according to the protocol described above and its variations known in the art, further includes subsequent steps including oocyte retrieval (generally about 36 hours after inducing final follicle maturation), fertilization, blastocyst retrieval, and implantation of the fresh blastocysts in the uterus.

[0136] The above has disclosed compositions, compositions for use, uses and methods as defined by the following numbered paragraphs. 1. A composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, wherein the treatment is: Select patients who are identified as likely to have a high ovarian response to controlled ovarian stimulation; Controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the patient from day 1 of the procedure (for example, 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day); To determine whether the patient's serum hCG level is at the target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of controlled ovarian stimulation (e.g., on day 5, 6, or 7 of stimulation); When the patient's serum hCG level is at or above a specific threshold level for serum hCG in maturation of the final follicular stage, which increases the likelihood of live birth, it is possible to induce final follicular maturation. A composition containing the following:

[0137] 2. A composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, for increasing the likelihood of live birth following fresh embryo or frozen embryo transfer, wherein the treatment is: Select patients who are identified as likely to have a high ovarian response to controlled ovarian stimulation; Controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the patient from day 1 of the procedure (for example, 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day); To determine whether the patient's serum hCG level is at the target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of controlled ovarian stimulation (e.g., on day 5, 6, or 7 of stimulation); When the patient's serum hCG level is at or above a specific threshold level for serum hCG in maturation of the final follicular stage, which increases the likelihood of live birth, it is possible to induce final follicular maturation. A composition containing the following:

[0138] 3. A composition for use according to any one of paragraphs 1 to 2, wherein a specific threshold level of serum hCG in the maturation of the final follicular phase resulting in an increased chance of live birth is selected from 1.5 to 2.0 mIU / mL, more preferably 1.8 mIU / mL.

[0139] 4. A composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, wherein the treatment is: Select patients who are identified as likely to have a high ovarian response to controlled ovarian stimulation; Controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to selected patients from day 1 of treatment (for example, 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day); To determine whether the patient's serum hCG level is at the target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of controlled ovarian stimulation (e.g., on day 5, 6, or 7 of stimulation); Optionally, maintain or increase (e.g., by only 75 IU / day) the daily dose of HP-hMG based on whether the patient's serum hCG level is at or below the target follicular mid-phase threshold level. A composition containing the following:

[0140] 5. A composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, for increasing the likelihood of live birth following fresh embryo or frozen embryo transfer, wherein the treatment is: Select patients who are identified as likely to have a high ovarian response to controlled ovarian stimulation; Controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to selected patients from day 1 of treatment (for example, 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day); To determine whether the patient's serum hCG level is at the target mid-follicular threshold level (e.g., ≥1.5 mIU / mL) during the mid-follicular phase of controlled ovarian stimulation (e.g., on day 5, 6, or 7 of stimulation); Optionally, maintain or increase (e.g., by only 75 IU / day) the daily dose of HP-hMG based on whether the patient's serum hCG level is at or below the target follicular mid-phase threshold level. A composition containing the following:

[0141] 6. A composition for use as described in any of paragraphs 1 to 5, wherein the patient has a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) prior to treatment / stimulation.

[0142] 7. The composition for use according to any of paragraphs 1 to 6, further comprising identifying the patient as having a serum anti-Müllerian hormone (AMH) level ≥ 35.7 ± 0.5 pmol / L (≥ 5.0 ± 0.2 ng / ml) prior to the treatment.

[0143] 8. A composition for use in any of paragraphs 1-7, provided the patient is not anovulatory.

[0144] 9. The patient is between 21 and 35 years old and weighs 18-30 kg / m² at the start of treatment. 2 A composition for use as described in any of paragraphs 1 to 8, having a BMI.

[0145] A composition for use as described in any of paragraphs 1 to 9, comprising 10.75 to 450 IU of HP-hMG.

[0146] 11. A composition for use according to any one of paragraphs 1 to 10, wherein controlled ovarian stimulation comprises administering HP-hMG at an initial dose of 75 to 225 IU per day, preferably 150 IU / day, for example, from day 1 to at least day 5 of stimulation.

[0147] 12. A composition for use according to any of paragraphs 1 to 11, wherein the treatment of infertility increases the likelihood of live birth compared to treatment with recombinant FSH derived from CHO cells.

[0148] 13. A composition for use according to any of paragraphs 1 to 12, further comprising the treatment of inducing final follicular maturation by administering hCG, or optionally, a GnRH agonist supplemented with hCG.

[0149] 14. A composition for use according to any of paragraphs 1 to 13, further comprising administering a GnRH antagonist to be initiated on the 6th day of stimulation.

[0150] 15. The treatment is, The collection of oocytes, the fertilization of oocytes, the development of fertilized oocytes to the blastocyst stage, the random assessment of the quality / morphology of the blastocysts, and the implantation of fresh blastocysts in the uterus (e.g., randomly selected based on a visual assessment of quality / morphology); or Retrieving oocytes, fertilizing oocytes, developing fertilized oocytes to the blastocyst stage, randomly selecting and assessing the chromosomal quality of blastocysts, freezing one, more, or all blastocysts, and implanting thawed and frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal assessment) in the uterus; or Retrieving oocytes, freezing unfertilized oocytes, subsequently thawing one or more oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, randomly assessing the quality / morphology of the blastocysts, and implanting the blastocysts in the uterus (e.g., randomly selected based on a visual assessment of quality / morphology); or The process involves collecting oocytes, freezing unfertilized oocytes, subsequently thawing one or more frozen oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, randomly selecting and assessing the chromosomal quality of the blastocysts, freezing one or more or all of the blastocysts, and implanting the thawed and frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal assessment) in the uterus. A composition for use as described in any of paragraphs 1 to 14, further comprising:

[0151] 16. A method for treating infertility by controlled ovarian stimulation in patients who are expected to have a high ovarian response to controlled ovarian stimulation, Select patients who are identified as likely to have a high ovarian response to controlled ovarian stimulation; Controlled ovarian stimulation will be performed by administering HP-hMG to selected patients at an initial daily dose of 75 IU to 225 IU; To determine whether the patient's serum hCG level is at the target mid-follicular threshold level during the mid-follicular phase of controlled ovarian stimulation; Optionally, maintain or increase the daily dose of HP-hMG based on whether the patient's serum hCG level is at or below the target follicular mid-phase threshold level. Methods that include...

[0152] 17. The method described in paragraph 16, for patients who are not anovulatory.

[0153] 18. The patient is between 21 and 35 years old and weighs 18-30 kg / m² at the start of treatment. 2 The method described in paragraph 16, having a BMI of [specified value].

[0154] 19. The method according to paragraph 16, comprising increasing the daily dose of HP-hMG when the patient's serum hCG level is below the target follicular mid-phase threshold level.

[0155] 20. The method according to paragraph 16, comprising increasing the daily dose of HP-hMG by 75 IU / day when the patient's serum hCG level is below the target follicular mid-phase threshold level.

[0156] 21. The method according to paragraph 16, comprising maintaining a daily dose of HP-hMG when the patient's serum hCG level is at the target follicular mid-phase threshold level.

[0157] 22. The method according to any one of paragraphs 16-21, wherein the target follicular mid-phase threshold level of serum hCG is ≥1.5 mIU / mL.

[0158] 23. The method according to any one of paragraphs 16-21, wherein the mid-follicular phase of controlled ovarian stimulation is selected from day 5 of stimulation, day 6 of stimulation, and day 7 of stimulation.

[0159] 24. The method described in any one of paragraphs 16-21, wherein the starting daily dose of HP-hMG is 150 IU / day.

[0160] 25. The method according to any one of paragraphs 16-21, further comprising administering a gonadotropin-releasing hormone antagonist (GnRH antagonist) starting on day 6 of stimulation.

[0161] 26. The method according to any one of paragraphs 16-21, further comprising inducing final follicular maturation by administering human chorionic gonadotropin (hCG), or optionally, a gonadotropin-releasing hormone agonist (GnRH agonist) supplemented with hCG.

[0162] 27. (a) retrieving oocytes, fertilizing oocytes, developing fertilized oocytes to the blastocyst stage, randomly assessing the quality / morphology of blastocysts, and implanting fresh blastocysts in the uterus (e.g., randomly selected based on a visual assessment of quality / morphology); or (b) retrieving oocytes, fertilizing oocytes, developing fertilized oocytes to the blastocyst stage, randomly assessing the chromosomal quality of blastocysts, freezing one, more or all blastocysts, and implanting thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal assessment) in the uterus; or (c) retrieving oocytes, freezing unfertilized oocytes, subsequently thawing one or more oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, randomly assessing the quality / morphology of the blastocysts, and implanting the blastocysts in the uterus (e.g., randomly selected based on a visual assessment of quality / morphology); or (d) Recovering oocytes, freezing unfertilized oocytes, subsequently thawing one or more frozen oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, randomly assessing the chromosomal quality of the blastocysts, freezing one or more or all of the blastocysts, and implanting the thawed and frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal assessment) in the uterus. The method described in any one of paragraphs 16-21, further including the method described in any one of paragraphs 16-21.

[0163] 28. A method for treating infertility by controlled ovarian stimulation in patients who are expected to have a high ovarian response to controlled ovarian stimulation, Select patients who are identified as likely to have a high ovarian response to controlled ovarian stimulation; Controlled ovarian stimulation will be performed by administering HP-hMG to selected patients at an initial daily dose of 75 IU to 225 IU; To determine whether the patient's serum hCG level is at the target mid-follicular threshold level during the mid-follicular phase of controlled ovarian stimulation; Based on whether the patient's serum hCG level is at or below the target follicular mid-phase threshold level, the administration of hCG to the patient may be optional. Methods that include...

[0164] 29. The method according to paragraph 28, comprising administering hCG at a daily dose of 5-60 IU / day, or equal to 5-60 IU / day, when the patient's serum hCG level is below the target follicular mid-phase threshold level.

[0165] 30. A method for treating infertility by controlled ovarian stimulation in patients who are expected to have a high ovarian response to controlled ovarian stimulation, Select patients who are identified as likely to have a high ovarian response to controlled ovarian stimulation; Controlled ovarian stimulation is performed by administering rFSH to selected patients at a daily dose effective for controlled ovarian stimulation; Initiate controlled ovarian stimulation during the mid-follicular phase and administer hCG to the patient at a daily dose of 5-60 IU / day, or equal to 5-60 IU / day. Methods that include...

Claims

1. A composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, wherein the treatment is Selecting patients identified as likely to have a high ovarian response to controlled ovarian stimulation, wherein the patients likely to have a high ovarian response to controlled ovarian stimulation have a serum anti-Müllerian hormone (AMH) level of ≥35.7 ± 0.5 pmol / L (≥5.0 ± 0.2 ng / ml) prior to the procedure / stimulation; Controlled ovarian stimulation is performed by administering a daily dose of 75-450 IU of HP-hMG to the selected patients from day 1 of the procedure; To determine whether the patient's serum hCG level is ≥ 1.5 mIU / mL, the target follicular mid-phase threshold level, on day 5, 6, or 7 of controlled ovarian stimulation; Based on whether the patient's serum hCG level is at or below the target follicular mid-phase threshold level, the daily dose of HP-hMG may be maintained or increased. A composition containing the following:

2. The composition for use according to claim 1, further comprising the treatment inducing final follicular maturation when the level of hCG in the patient's serum is at or above a specific threshold level of 1.5 to 2.0 mIU / mL.

3. A composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, wherein the patient expected to have a high ovarian response to controlled ovarian stimulation has a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) prior to the treatment / stimulation, and the treatment is Select patients who are identified as likely to have a high ovarian response to controlled ovarian stimulation; Controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the selected patients from the first day of treatment; To determine whether the patient's serum hCG level is at the target mid-follicular threshold level, i.e., ≥1.5 mIU / mL, during the mid-follicular phase of controlled ovarian stimulation; Based on whether the patient's serum hCG level is at or below the target follicular mid-phase threshold level, the daily dose of HP-hMG may be maintained or increased. A composition containing the following:

4. A composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, wherein the treatment is Selecting patients identified as likely to have a high ovarian response to controlled ovarian stimulation, wherein the patients likely to have a high ovarian response to controlled ovarian stimulation have a serum anti-Müllerian hormone (AMH) level of ≥35.7 ± 0.5 pmol / L (≥5.0 ± 0.2 ng / ml) prior to the procedure / stimulation; Controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the patient from the first day of treatment; In the mid-follicular phase of controlled ovarian stimulation, it is necessary to determine whether the patient's serum hCG level is at the target mid-follicular threshold level, i.e., ≥1.5 mIU / mL; When the level of hCG in the patient's serum is at or above a specific threshold level for serum hCG in the maturation of the final follicular cell, which increases the likelihood of live birth, it is possible to induce the maturation of the final follicular cell. A composition containing the following:

5. The composition for use according to claim 4, wherein the specific threshold level of serum hCG in the maturation of the final follicular phase resulting in an increased chance of live birth is selected from 1.5 to 2.0 mIU / mL.

6. The composition for use according to any one of claims 1 to 5, further comprising identifying, prior to stimulation, that the patient has a serum anti-Müllerian hormone (AMH) level ≥ 35.7 ± 0.5 pmol / L (≥ 5.0 ± 0.2 ng / ml).

7. The patient is not anovulatory, and / or is between 21 and 35 years old, and weighs 18-30 kg / m² at the start of treatment. ２ A composition for use according to any one of claims 1 to 6, having a BMI.

8. The composition for use according to any one of claims 1 to 7, wherein the controlled ovarian stimulation comprises administering HP-hMG at a starting dose of 75 to 225 IU of hMG per day.

9. A composition for use according to any one of claims 1 to 8, wherein the treatment for infertility increases the likelihood of live birth compared to treatment with recombinant FSH derived from CHO cells.

10. The composition for use according to any one of claims 1 to 9, further comprising the treatment of inducing final follicular maturation by administering hCG or a GnRH agonist.

11. The composition for use according to any one of claims 1 to 10, further comprising administering a GnRH antagonist to begin on the sixth day of stimulation.

12. A composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, to increase the likelihood of live birth following fresh embryo or frozen embryo transfer, wherein the patient expected to have a high ovarian response to controlled ovarian stimulation has a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) prior to the treatment / stimulation, and the treatment is Select patients who are identified as likely to have a high ovarian response to controlled ovarian stimulation; Controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the patient from the first day of treatment; In the mid-follicular phase of controlled ovarian stimulation, it is necessary to determine whether the patient's serum hCG level is at the target mid-follicular threshold level, i.e., ≥1.5 mIU / mL; When the level of hCG in the patient's serum is at or above a specific threshold level for serum hCG in the maturation of the final follicular cell, which increases the likelihood of live birth, it is possible to induce the maturation of the final follicular cell. A composition containing the following:

13. A composition comprising HP-hMG for use in the treatment of infertility in patients expected to have a high ovarian response to controlled ovarian stimulation, to increase the likelihood of live birth following fresh embryo or frozen embryo transfer, wherein the patient expected to have a high ovarian response to controlled ovarian stimulation has a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) prior to the treatment / stimulation, and the treatment is Select patients who are identified as likely to have a high ovarian response to controlled ovarian stimulation; Controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the selected patients from the first day of treatment; To determine whether the patient's serum hCG level is at the target mid-follicular threshold level, i.e., ≥1.5 mIU / mL, during the mid-follicular phase of controlled ovarian stimulation; Based on whether the patient's serum hCG level is at or below the target follicular mid-phase threshold level, the daily dose of HP-hMG may be maintained or increased. A composition containing the following:

14. The above treatment Recovering oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, and implanting the fresh blastocysts in the uterus; or Retrieving oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, freezing one or more or all blastocysts, implanting the thawed and frozen blastocysts in the uterus; or Retrieving oocytes, freezing unfertilized oocytes, subsequently thawing one or more oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, implanting the blastocysts in the uterus; or The process involves collecting oocytes, freezing unfertilized oocytes, subsequently thawing one or more frozen oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, freezing one or more or all of the blastocysts, and implanting the thawed and frozen blastocysts in the uterus. A composition for use according to any one of claims 1 to 13, further comprising:

15. A composition comprising HP-hMG for use in the treatment of infertility in patients having a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) prior to treatment / stimulation, wherein the treatment is Prior to treatment / stimulation, select patients identified as having a serum anti-Müllerian hormone (AMH) level of ≥35.7 ± 0.5 pmol / L (≥5.0 ± 0.2 ng / ml); Controlled ovarian stimulation is performed by administering a daily dose of 75-450 IU of HP-hMG to the selected patients from day 1 of the procedure; To determine whether the patient's serum hCG level is ≥ 1.5 mIU / mL, the target follicular mid-phase threshold level, on day 5, 6, or 7 of controlled ovarian stimulation; Based on whether the patient's serum hCG level is at or below the target follicular mid-phase threshold level, the daily dose of HP-hMG may be maintained or increased. A composition containing the following:

16. The composition for use according to claim 15, further comprising the treatment inducing final follicular maturation when the level of hCG in the patient's serum is at or above a specific threshold level of 1.5 to 2.0 mIU / mL.

17. A composition comprising HP-hMG for use in the treatment of infertility in patients having a serum anti-Müllerian hormone (AMH) level ≥ 35.7 ± 0.5 pmol / L (≥ 5.0 ± 0.2 ng / ml) prior to treatment / stimulation, wherein the treatment is Prior to treatment / stimulation, select patients identified as having a serum anti-Müllerian hormone (AMH) level of ≥35.7 ± 0.5 pmol / L (≥5.0 ± 0.2 ng / ml); Controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the selected patients from the first day of treatment; To determine whether the patient's serum hCG level is above the target follicular mid-phase threshold level, i.e., ≥1.5 mIU / mL, on the 5th, 6th, or 7th day of controlled ovarian stimulation; Based on whether the patient's serum hCG level is at or below the target follicular mid-phase threshold level, the daily dose of HP-hMG may be maintained or increased. A composition containing the following:

18. A composition comprising HP-hMG for use in the treatment of infertility in patients having a serum anti-Müllerian hormone (AMH) level ≥ 35.7 ± 0.5 pmol / L (≥ 5.0 ± 0.2 ng / ml) prior to treatment / stimulation, wherein the treatment is Prior to treatment / stimulation, select patients identified as having a serum anti-Müllerian hormone (AMH) level of ≥35.7 ± 0.5 pmol / L (≥5.0 ± 0.2 ng / ml); Controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the patient from the first day of treatment; To determine whether the patient's serum hCG level is at the target follicular mid-phase threshold level, i.e., ≥1.5 mIU / mL, on the 5th, 6th, or 7th day of controlled ovarian stimulation; When the level of hCG in the patient's serum is at or above a specific threshold level for serum hCG in the maturation of the final follicular cell, which increases the likelihood of live birth, it is possible to induce the maturation of the final follicular cell. A composition containing the following:

19. The composition for use according to claim 18, wherein the specific threshold level of serum hCG in the maturation of the final follicular phase resulting in an increased likelihood of live birth is selected from 1.5 to 2.0 mIU / mL.

20. The composition for use according to any one of claims 15 to 19, further comprising identifying, prior to stimulation, that the patient has a serum anti-Müllerian hormone (AMH) level of ≥35.7 ± 0.5 pmol / L (≥5.0 ± 0.2 ng / ml).

21. The patient is not anovulatory, and / or the patient is between 21 and 35 years old, and at the start of treatment, the weight is 18-30 kg / m². ２ A composition for use according to any one of claims 15 to 20, having a BMI.

22. The composition for use according to any one of claims 15 to 21, wherein the controlled ovarian stimulation comprises administering HP-hMG at a starting dose of 75 to 225 IU of hMG per day.

23. A composition for use according to any one of claims 15 to 22, wherein the treatment for infertility increases the likelihood of live birth compared to treatment with recombinant FSH derived from CHO cells.

24. The composition for use according to any one of claims 15 to 23, further comprising the treatment of inducing final follicular maturation by administering hCG or a GnRH agonist.

25. The composition for use according to any one of claims 15 to 24, further comprising administering a GnRH antagonist to begin on the sixth day of stimulation.

26. A composition comprising HP-hMG for use in the treatment of infertility in patients having a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) prior to treatment / stimulation, in order to increase the likelihood of live birth following fresh embryo or frozen embryo transfer, wherein the treatment is: Prior to treatment / stimulation, select patients identified as having a serum anti-Müllerian hormone (AMH) level of ≥35.7 ± 0.5 pmol / L (≥5.0 ± 0.2 ng / ml); Controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the patient from the first day of treatment; To determine whether the patient's serum hCG level is at the target follicular mid-phase threshold level, i.e., ≥1.5 mIU / mL, on the 5th, 6th, or 7th day of controlled ovarian stimulation; When the level of hCG in the patient's serum is at or above a specific threshold level for serum hCG in the maturation of the final follicular cell, which increases the likelihood of live birth, it is possible to induce the maturation of the final follicular cell. A composition containing the following:

27. A composition comprising HP-hMG for use in the treatment of infertility in patients having a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) prior to treatment / stimulation, in order to increase the likelihood of live birth following fresh embryo or frozen embryo transfer, wherein the treatment is: Prior to treatment / stimulation, select patients identified as having a serum anti-Müllerian hormone (AMH) level of ≥35.7 ± 0.5 pmol / L (≥5.0 ± 0.2 ng / ml); Controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the selected patients from the first day of treatment; To determine whether the patient's serum hCG level is above the target follicular mid-phase threshold level, i.e., ≥1.5 mIU / mL, on the 5th, 6th, or 7th day of controlled ovarian stimulation; Based on whether the patient's serum hCG level is at or below the target follicular mid-phase threshold level, the daily dose of HP-hMG may be maintained or increased. A composition containing the following:

28. The above treatment Recovering oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, and implanting the fresh blastocysts in the uterus; or Retrieving oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, freezing one or more or all blastocysts, implanting the thawed and frozen blastocysts in the uterus; or Retrieving oocytes, freezing unfertilized oocytes, subsequently thawing one or more oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, implanting the blastocysts in the uterus; or The process involves collecting oocytes, freezing unfertilized oocytes, subsequently thawing one or more frozen oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, freezing one or more or all of the blastocysts, and implanting the thawed and frozen blastocysts in the uterus. A composition for use according to any one of claims 15 to 27, further comprising:

29. The composition for use according to any one of claims 2, 5, 16, and 19, further comprising the treatment inducing final follicular maturation when the level of hCG in the patient's serum is at or above a specific threshold level of 1.8 mIU / mL.

30. A composition for use according to any one of claims 3, 4, 12, 13, 17, 18, 26, and 27, wherein controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the selected patient at a dose of 75 to 450 IU / day starting from the first day of treatment.

31. A composition for use according to any one of claims 3, 4, 12, 13, 17, 18, 26, and 27, wherein controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the selected patient at a dose of 75 to 225 IU / day starting from the first day of treatment.

32. A composition for use according to any one of claims 3, 4, 12, 13, 17, 18, 26, and 27, wherein controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the selected patient at a dose of 150 to 225 IU / day starting from the first day of treatment.

33. A composition for use according to any one of claims 3, 4, 12, 13, 17, 18, 26, and 27, wherein controlled ovarian stimulation is performed by administering a daily dose of HP-hMG to the selected patient at a dose of 150 IU / day starting from the first day of treatment.

34. The composition for use according to any one of claims 3, 4, 12, and 13, wherein the mid-follicular phase of controlled ovarian stimulation is the 5th, 6th, or 7th day of stimulation.

35. The composition for use according to any one of claims 1, 3, 13, 15, 17, and 27, wherein the increase in daily dose is 75 IU / day.

36. The composition for use according to claim 8 or 22, wherein controlled ovarian stimulation comprises administering HP-hMG at an initial dose of 150 IU hMG / day.

37. The composition for use according to any one of claims 8, 22, or 36, wherein controlled ovarian stimulation comprises administering HP-hMG from day 1 to at least day 5 of stimulation.

38. The composition for use according to claim 10 or 24, further comprising the treatment of inducing final follicular maturation by administering a GnRH agonist supplemented with hCG.