Compositions for controlled ovarian stimulation

Abstract

Disclosed are formulations comprising FSH, such as recombinant FSH, for use in the treatment of infertility in patients with high AMH and low body weight.

Description

[0001] The present invention relates to compositions and pharmaceutical products for the treatment of infertility.

[0002] Assisted reproductive technology (ART) techniques such as in vitro fertilization (IVF) are well known. These ART techniques generally require a controlled ovarian stimulation (COS) step in which a group of follicles are stimulated to full maturity. Standard COS protocols include administering gonadotropins such as follicle-stimulating hormone (FSH) alone or in combination with luteinizing hormone (LH) activity to stimulate follicle development, typically with administration of GnRH analogs before and / or during stimulation to prevent premature LH surges. Pharmaceutical compositions commonly used for COS include recombinant follicle-stimulating hormone (rFSH) (including The products include FSH (Fluoro- and Gonal F), urinary-derived FSH, recombinant FSH+LH preparations, urinary-derived menotrophins [human menopausal gonadotropin (hMG)], and highly purified human menopausal gonadotropin (HP-hMG). IVF can be associated with the risk of ovarian hyperstimulation syndrome (OHSS), which can be life-threatening in severe cases.

[0003] The ability of predicting women's response potential to controlled ovarian stimulation (COS) can allow to develop individualized COS scheme.Such individualized scheme can for example reduce the risk of OHSS in the women who are predicted to have excessive reaction to stimulation, and / or improve the pregnancy outcome of the women who are classified as adverse responders.Currently, the serum concentration of anti-Müllerian hormone (AMH) is determined to be a reliable marker of ovarian reserve.The AMH level that reduces is relevant to the reaction of the ovary to gonadotropin that reduces during COS.In addition, high levels of AMH are good predictors of excessive ovarian reaction and are indicators of OHSS risk.

[0004] In a preliminary study of women under 35 years old undergoing ART, the CONSORT dosing algorithm (combining basal FSH, BMI, age and AFC) was used to predict the optimal FSH starting dose for COS in women at risk of developing OHSS (Olivennes et al., 2009). Individualized dosing resulted in sufficient oocyte yield and good pregnancy rates. However, due to insufficient response, there was a high cancellation rate in the low-dose group (75 IU FSH), and OHSS did occur in a significant proportion of patients.

[0005] Therefore, there is a need for individualized COS regimens that provide an adequate response to stimulation, and / or a reduced risk of OHSS.

[0006] As mentioned above, the standard COS regimen can include the administration of FSH. FSH is naturally secreted by the anterior pituitary gland and has the function of supporting follicle development and ovulation. FSH comprises an α-subunit of 92 amino acids, which is also common to other glycoprotein hormones LH and CG, and a β-subunit of 111 amino acids, which only FSH has, giving the hormone biological specificity (Pierce and Parsons, 1981). Each subunit is post-translationally modified by adding complex carbohydrate residues. Both subunits carry two sites for N-linked glycan binding, with the α-subunit located at amino acids 52 and 78 and the β-subunit located at amino acid residues 7 and 24 (Rathnam and Saxena, 1975, Saxena and Rathnam, 1976). Therefore, FSH is glycosylated to about 30% by mass (Dias and Van Roey.2001.Fox et al. 2001).

[0007] For many years, FSH purified from postmenopausal human urine has been used in infertility treatment to stimulate ovulation in natural fertility and to provide oocytes for assisted reproductive technology. Until recently, the only recombinant FSH (rFSH) products approved for ovarian stimulation, such as follitropin alfa (GONAL-F, Merck Serono / EMD Serono) and follitropin beta (PUREGON / FOLLISTIM, MSD / Schering-Plough), were derived from Chinese hamster ovary (CHO) cell lines.

[0008] There is considerable heterogeneity associated with FSH preparations, which is related to differences in the amounts of the various isoforms present. Individual FSH isoforms exhibit identical amino acid sequences but differ in the extent of their post-translational modifications; particular isoforms are characterized by heterogeneity in carbohydrate branching structure and varying amounts of sialic acid (terminal sugar) incorporation, both of which appear to affect the biological activity of a particular isoform.

[0009] The glycosylation of natural FSH is highly complex. The polysaccharides in pituitary FSH of natural origin can comprise a variety of structures, which can include a combination of one, two, three and four-antennary polysaccharides (Pierce and Parsons, 1981. Ryan et al., 1987. Baenziger and Green, 1988). Polysaccharides can have other modifications: core fucosylation, bisecting glucosamine, chains extended with acetyllactosamine, partial or complete sialylation, sialylation with α2,3 and α2,6 connections, and sulfated galactosamine (Dalpathado et al., 2006) instead of galactose. In addition, there are differences in the distribution of polysaccharide structures at each glycosylation site. In FSH derived from individual serum and from the urine of postmenopausal women, considerable levels of polysaccharide complexity are found (Wide et al., 2007).

[0010] The glycosylation of recombinant FSH products reflects the range of glycosyltransferases present in the host cell line. The range of glycan modifications in commercial rFSH products derived from modified Chinese hamster ovary cells (CHO cells) is more limited than those found in natural products. Examples of reduced glycan heterogeneity found in rFSH derived from CHO cells include the lack of bisecting glucosamine and reduced nuclear fucosylation and acetyllactosamine extension content (Hard et al., 1990). In addition, CHO cells are only able to add sialic acid using α2,3 linkage (Kagawa et al., 1988, Takeuchi et al., 1988, Svensson et al., 1990); rFSH derived from CHO cells only includes α2,3-linked sialic acid and does not include α2,6-linked sialic acid.

[0011] FSH derived from CHO cells is therefore different from naturally occurring FSH (eg human pituitary / serum / urinary FSH), which contains glycans with a mixture of α2,3 and α2,6-linked sialic acids, with the former predominating.

[0012] The applicant has developed recombinant FSH derived from a human cell line, which is the subject of International Patent Application No. PCT / GB2009 / 000978, published as WO2009 / 127826A. Recombinant FSH with a mixture of both α2,3- and α2,6-linked sialic acids is produced by engineering a human cell line to express rFSH and α2,3 sialyltransferase. The expressed product is highly acidic and has a mixture of both α2,3- and α2,6-linked sialic acids; the latter is provided by endogenous sialyltransferase activity. It was found that the type of sialic acid linkage (α2,3- or α2,6-) can significantly influence the bioclearance of FSH. Recombinant FSH with a mixture of both α2,3- and α2,6-linked sialic acids offers two advantages over rFSH expressed in conventional CHO cells: first, the material is more highly sialylated due to the combined activity of the two sialyltransferases; and second, the material more closely resembles native FSH. This may be biologically more appropriate than recombinant products derived from CHO cells that produce only α2,3-linked sialic acid (Kagawa et al., 1988, Takeuchi et al., 1988, Svensson et al., 1990) and have a reduced sialic acid content (Ulloa-Aguirre et al. 1995, Andersen et al. 2004).

[0013] The amino acid sequence of recombinant FSH derived from a human cell line (which is the subject of International Patent Application No. PCT / GB2009 / 000978, published as WO2009 / 127826A) is the native sequence and is identical to native human FSH and existing rFSH products derived from CHO. However, the applicant has found that when used in (e.g., individualized) COS regimens, recombinant FSH products of human origin (i.e., recombinant FSH produced or expressed in a human cell line, e.g., prepared by modifying a human cell line) with a mixture of both α2,3 and α2,6-linked sialic acids can be particularly effective.

[0014] On December 13, 2016, the European Commission (EC) granted The company has granted marketing authorization for follicle-stimulating hormone delta (FSH, also known as FE999049), a human cell line-derived recombinant follicle-stimulating hormone (human rFSH), for controlled ovarian stimulation to develop multiple follicles in women undergoing assisted reproductive technology (ART), such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles. It is the first rFSH derived from a human cell line. The (follicle stimulating hormone delta) product is prepared by the method disclosed in International Patent Application No. PCT / GB2009 / 000978.

[0015] Two randomized, controlled, assessor-blinded, parallel-group, multicenter, phase 2 anti-Müllerian hormone (AMH)-stratified trials were conducted in IVF / ICSI patients, one in Europe and one in Japan, to determine the dose-response relationship of FE 999049 with the number of oocytes retrieved. In both trials, randomization was stratified according to AMH levels at screening; low AMH (5.0-14.9 pmol / L) or high AMH (15.0-44.9 pmol / L). In the European dose-response phase 2 trial, five doses of FE 999049 (ranging from 5.2 μg / day to 12.1 μg / day) were studied, and a reference group of an approved rFSH product (GONAL-F, 150 IU / day) was also included. In a Phase 2 dose-response trial in Japan, three doses of FE 999049 (6 μg / day, 9 μg / day, and 12 μg / day) were studied, along with standard therapy of an approved rFSH product (FOLLISTIM, 150 IU / day). Currently, follicle-stimulating hormone beta (FOLLISTIM) is the only medical product approved in Japan for controlled ovarian stimulation in IVF / ICSI cycles.

[0016] In the European and Japanese Phase 2 trials, the daily dose was fixed throughout the stimulation period. In both trials, a statistically significant dose-response relationship was observed for FE 999049 with respect to the number of oocytes retrieved, both for the overall population and within each AMH randomization stratum. All FE 999049 doses achieved acceptable pregnancy rates. Furthermore, the dose-response curves for FE 999049 observed in the European and Japanese trials were similar.

[0017] This work enables the development of Individualized COS plan for the (follicle-stimulating hormone delta, FE999049) product.

[0018] Applicants have found that in order to be able to select two high quality oocytes for transfer, it is generally necessary to extract from a region of nine oocytes.

[0019] Applicant has found that, for the experimenter with low AMH (AMH<15pmol / L every liter), need the follicle stimulating hormone δ (for example 12 μ g) of quite high dosage to realize this.With this dosage, from 60% experimenter with low AMH, will extract 8 to 14 oocytes.Relative to the treatment (wherein only extracted 8 to 14 oocytes from 33% experimenter) with the experimenter of low AMH treated with 150IU Gonal-f, this is unexpected and significant progress.Applicant has found, do not need to adjust this dosage according to patient's weight.

[0020] However, 60% of the population (and 80% of women under 30 years old who are treated for infertility) have high AMH (i.e., AMH ≥ 15 pmol / L). For these subjects, it is usually quite easy to extract an average of 9 to 11 oocytes; the problem with stimulation protocols is the risk of OHSS. The applicants have found that in patients who were administered a low dose of follicle-stimulating hormone delta, there was a relationship between the oocytes extracted and the subject's weight. This suggests that there may be risks associated with treatment with a fixed dose of FSH (which is common in the art). The applicant has established a relationship between FSH dose and AMH levels and subject weight, which provides an improved safety profile (reduced risk of OHSS) and acceptable or improved oocyte extraction compared to known treatment regimens.

[0021] The dosing of REKOVELLE is individualized for each patient and is designed to achieve an ovarian response associated with a favorable safety / efficacy profile, i.e., to achieve an adequate number of retrieved oocytes and minimize interventions to prevent ovarian hyperstimulation syndrome (OHSS). REKOVELLE is dosed in micrograms.

[0022] For the first treatment cycle, the individual daily dose will be determined based on the woman's serum anti-Müllerian hormone (AMH) concentration and her weight. The dose should be based on a recent AMH value (i.e., within the last 12 months) measured by the following Roche diagnostic test: ELECSYS AMH Plus Immunoassay. The individual daily dose should be maintained throughout the stimulation period.

[0023] For women with AMH <15 pmol / L, the daily dose of REKOVELLE is 12 mcg, regardless of body weight.

[0024] For women with AMH ≥ 15 pmol / L, the daily dose of REKOVELLE was reduced from 0.19 mcg / kg to 0.10 mcg / kg by increasing AMH concentrations (Table 1 below).

[0025] The dose should be rounded to the nearest 0.33 mcg to match the dosing scale on the injection pen. The maximum daily dose for the first treatment cycle is 12 mcg. To calculate the REKOVELLE dose, body weight should be measured without shoes or outer clothing, just before the start of stimulation.

[0026] Table A Dosage Regimen

[0027]

[0028] mcg: microgram

[0029] AMH concentrations should be expressed in pmol / L and should be rounded to the nearest whole number. If the AMH concentration is in ng / mL, the concentration should be converted to pmol / L by multiplying by 7.14 (ng / mL x 7.14 = pmol / L) before use.

[0030] Treatment with REKOVELLE should be started on day 2 or 3 after the start of menstrual bleeding and continued until adequate follicular development (≥3 follicles, ≥17 mm) has been achieved, which is on average by day 9 of treatment (range 5 to 20 days). A single injection of 250 micrograms of recombinant human chorionic gonadotropin (hCG) or 5,000 IU hCG is administered to induce final follicular maturation. In patients with excessive follicular development (≥25 follicles, ≥12 mm), treatment with REKOVELLE should be discontinued, and hCG should not be used to trigger final follicular maturation.

[0031] For subsequent treatment cycles, the daily dose of REKOVELLE should be maintained or modified based on the patient's ovarian response in the previous cycle. If the patient had an adequate ovarian response in the previous cycle without developing OHSS, the same daily dose should be used. If the patient had a low ovarian response in the previous cycle, the daily dose in the next cycle should be increased by 25% or 50%, depending on the observed response. If the patient had a high ovarian response in the previous cycle, the daily dose in the next cycle should be reduced by 20% or 33%, depending on the observed response. For patients who developed OHSS or are at risk for OHSS in the previous cycle, the daily dose in the next cycle should be 33% lower than the dose in the cycle in which OHSS or the risk of OHSS occurred. The maximum daily dose is 24 mcg.

[0032] The efficacy and safety of an individualized dosing regimen of FE 999049 based on a woman's serum AMH and body weight has been demonstrated in the large Phase 3 trial ESTHER-1 (Evidence-Based Stimulation Trial with Human rFSH in Europe and the Rest of the World), conducted in 11 countries across Europe, North America, and Latin America. The ESTHER-1 trial was conducted in 1,326 IVF / ICSI patients who were randomized 1:1 to controlled ovarian stimulation with one of the following treatments: 1) FE999049, with a fixed daily dose throughout the simulation in its individualized dosing regimen, or 2) an approved CHO-derived rFSH product (follicle-stimulating hormone alfa, GONAL-F) at a standard starting dose of 150 IU / day, with subsequent dose adjustments based on the subject's follicular response during stimulation. FE 999049 was shown to be non-inferior to follitropin alfa in its individualized dosing regimen in terms of ongoing pregnancy rate (30.7% vs. 31.6%) and ongoing implantation rate (35.2% vs. 35.8%). For the overall population, there were no statistically significant differences between the treatment groups in the number of retrieved oocytes, with a mean of 10.0 for FE999049 and a mean of 10.4 for follitropin alfa. Nevertheless, compared to follitropin alfa, the individualized FE 999049 dosing regimen resulted in statistically significantly more retrieved oocytes in patients with AMH <15 pmol / L (a low-risk population) (with a mean of 8.0 vs. 7.0), and statistically significantly fewer oocytes in patients with AMH ≥15 pmol / L (a high-risk population) (with a mean of 11.6 vs. 13.3). This alteration in ovarian response was recognized to be of direct clinical relevance to FE 999049 therapy, as statistically significantly fewer patients had an extreme ovarian response, i.e., <4 oocytes in patients with AMH <15 pmol / L (12% vs. 18%) and ≥15 or ≥20 oocytes in patients with AMH ≥15 pmol / L (28% vs. 35%, and 10% vs. 16%) compared to follitropin alfa. Although 37% of patients in the follitropin alfa group had dose adjustments during stimulation relative to the fixed-dose individualized dosing regimen of FE 999049, a statistically significantly greater percentage of patients treated with FE 999049 achieved an adequate ovarian response (defined as 8-14 oocytes for FE999049), i.e., 43% vs. 38%, compared to follitropin alfa. A statistically significantly lower total gonadotropin dose was observed in the FE 999049 group compared to the CHO-derived rFSH product group, with mean values ​​of 90 μg and 104 μg, respectively.

[0033] The most serious risk associated with gonadotropin therapy is ovarian hyperstimulation syndrome (OHSS). Overall, in the Phase 3 ESTHER-1 trial, interventions for the prevention of OHSS and / or early OHSS occurred in 4.4% of FE 999049 cycles and 6.5% of follitropin alfa cycles. Moderate / severe OHSS and / or interventions for the prevention of early OHSS were observed in 3.3% and 5.6% of cycles treated with FE 999049 and follitropin alfa, respectively.

[0034] Previous studies have reported OHSS rates ranging from 5% to 28.3% in Japanese patients. In the Japanese Phase 2 trial of FE999049, the incidence of early moderate / severe OHSS was 19.5% for subjects in the FOLLISTIM group. Despite the variation in reported OHSS rates, the high incidence of OHSS in Japanese IVF / ICSI patients suggests a clear need for treatment options with a safer OHSS profile in Japan. Based on over 1,300 cycles in the Phase 3 ESTHER-1 trial, the personalized dosing regimen of FE 999049 was associated with a statistically significant reduction in the proportion of subjects who required preventive intervention for early OHSS and / or early OHSS, with an incidence of 4.7% in the FE 999049 group and 6.2% in the follitropin alfa group, compared with a standard regimen of a CHO-derived rFSH product.

[0035] Compared with the women of the U.S. and Western Europe, in many Asian populations (such as Japan, China, Korea S and India), many women's weight is lower. Therefore, there is such risk: using the fixed dose that is suitable for the general population in Europe to Asian / Japanese patients may cause these lighter patients to accept too high FSH dosage with regard to dosage / kg body weight. This and then may cause the risk of overreaction and OHSS in these patients. Traditional " fixed dose " FSH regimen may be the factor of some high OHSS incidence rates reported by Japan.

[0036] The dosage regimen listed in Table A alleviates this risk to a certain extent because patients are dosed by body weight. However, very low doses of gonadotropins may be associated with insufficient follicle recruitment and poor ovarian response. Therefore, there is a risk that administration according to the Table A regimen may cause very light high AMH patients to receive FSH dosages that may be suboptimal from the perspective of efficacy. Therefore, it is necessary to effectively administer to lighter high AMH patients (body weight < 60 kg), while reducing the risk of overstimulation and OHSS in these patients (because these patients have high AMH and low body weight, so they may be more likely to experience this risk).

[0037] The applicant identified such patients in the above-mentioned Japanese Phase 2 trial (see also Example 2 below) who (based on AMH and body weight) should have received <6μg FE 999049 according to the individualized FE 999049 dosing regimen listed in Table A, but actually received 6μg FE 999049 or 150IU FOLLISTIM according to the random assignment. This was only a very limited number of patients (5 patients in the 6μg FE 999049 group and 3 patients in the 150IU FOLLISTIM group). Surprisingly, no ovarian response of more than 15 oocytes was observed in any of the 5 patients in the 6μg FE 999049 group, but no such ovarian response was observed in 2 of the 3 patients in the 150IU FOLLISTIM group (66.7%). Also surprising was that excessive follicular development requiring triggering with a GnRH agonist was not observed in any of the 5 patients in the 6 μg FE 999049 group, but was not observed in 1 of the 3 patients (33.3%) in the 150 IU FOLLISTIM group. Early OHSS was reported in 1 of the 5 patients (20.0%) in the 6 μg FE 999049 group and in 1 of the 3 patients (33.3%) in the 150 IU FOLLISTIM group. These data support its safe and effective use in Japanese IVF / ICSI patients, including those weighing <60 kg and with AMH ≥15 pmol / L.

[0038] The applicant has surprisingly found that a minimum dose of 6 μg can be specified taking into account the lower body weight in the Japanese population, with the aim of avoiding insufficient dosing in low-weight Japanese patients and thereby maintaining efficacy in these patients while avoiding side effects such as OHSS. It should be understood that this technical effect is applicable to any Asian population, or in fact to any population including patients with low body weight and high AMH, regardless of the patient's ethnic background.

[0039] According to the present invention, in a first aspect, there is provided such compositions (for example pharmaceutical composition), it is used for the treatment of infertility in the patient (for example female patient) of AMH≥15pmol / L (for example AMH≥16pmol / L, for example AMH≥19pmol / L, for example AMH≥26pmol / L, for example AMH≥28pmol / L, for example AMH≥40pmol / L) and body weight<60kg, described compositions comprises the daily dosage of 6 to 8 μ g recombinant FSH or is equivalent to the daily dosage of 6 to 8 μ g recombinant FSH.Preferably, compositions comprises the daily dosage of 6 to 8 μ g recombinant FSH.More preferably, compositions comprises the daily dosage of 6 μ g recombinant FSH.

[0040] Infertile treatment can include the step (or multiple steps) of determining the serum AMH level of patient and body weight.Infertile treatment can include the step of using described dosage to the patient with the serum AMH level of limitation and body weight.For example, infertile treatment can include the step (or multiple steps) of determining the serum AMH level of patient and body weight, and to AMH≥15pmol / L (for example AMH≥16pmol / L, for example AMH≥19pmol / L, for example AMH≥26pmol / L, for example AMH≥28pmol / L, for example AMH≥40pmol / L) and body weight<60kg [for example body weight<55kg, for example<52kg, for example<50kg, for example<45kg] patient using the step of described dosage.

[0041] The step of determining the patient's serum AMH level can be performed up to twelve months before the first administration of the dosage to the patient. Preferably, the patient's serum AMH level is determined by ELECSYS AMH Plus immunoassay (available from Roche, Switzerland, see www.roche.com ) determine (measure). The step of determining the patient's weight can be performed just before the first administration of the dosage to the patient (e.g., 0 to 2 days before). As is well known, the step of determining the patient's weight can use a bathroom scale.

[0042] Composition (such as pharmaceutical composition) can be used for treating infertility in patients with body weight <59kg, for example <56kg, for example <55kg, for example <52kg, for example <50kg, for example <45kg, for example <42kg, for example <31.5kg. Composition (such as pharmaceutical composition) can be used for treating infertility in patients with body weight of 40 to 59.9kg, for example, for treating infertility in patients with body weight of 45 to 55kg. Composition can be used for treating infertility in patients with AMH≥16pmol / L, for example, AMH≥19pmol / L, for example, AMH≥26pmol / L, for example, AMH≥28pmol / L, for example, AMH≥30pmol / L, for example, AMH≥40pmol / L.

[0043] Preferably, compositions (such as pharmaceutical composition) is used for the treatment of body weight<52kg (such as<50kg, such as<45kg) and AMH≥26pmol / L (such as AMH≥28pmol / L, such as AMH≥30pmol / L, such as AMH≥40pmol / L) patient's infertility.In this example, infertile treatment can comprise the step of determining patient's serum AMH level and body weight, and to the step of applying the dosage to the patient of AMH≥26pmol / L and body weight<52kg.

[0044] According to the present invention, in yet another aspect, such compositions (for example pharmaceutical composition) is provided, it is accredited as AMH≥15pmol / L (for example AMH≥16pmol / L, for example AMH≥19pmol / L, for example AMH≥26pmol / L, for example AMH≥28pmol / L, for example AMH≥40pmol / L) for the treatment of (before treatment) and is accredited as the infertility in the patient (for example female patient) of body weight<60kg, described compositions comprises the daily dosage of 6 to 8 μ g recombinant FSH or is equivalent to the daily dosage of 6 to 8 μ g recombinant FSH.Preferably, compositions comprises the daily dosage of 6 to 8 μ g recombinant FSH.More preferably, compositions comprises the daily dosage of 6 μ g recombinant FSH.

[0045] Infertile treatment can comprise (before treatment) identifying the step of patient's serum AMH level and body weight based on patient.Infertile treatment can comprise the step of applying described dosage to the patient being accredited as the serum AMH level with limitation and body weight.For example, infertile treatment can comprise (before treatment) identifying the step of patient's serum AMH level and body weight based on patient, and to (before treatment) being accredited as AMH≥15pmol / L (for example AMH≥16pmol / L, for example AMH≥19pmol / L, for example AMH≥26pmol / L, for example AMH≥28pmol / L, for example AMH≥40pmol / L) and (before treatment) being accredited as the patient of body weight<60kg[for example body weight<55kg, for example<52kg, for example<50kg, for example<45kg] applying the step of described dosage.

[0046] (Before treatment) the step of identifying the patient based on the patient's serum AMH level and body weight can be performed just before the dosage is applied to the patient for the first time (e.g., 0 to 2 days before). The step of identifying the patient can be based on the serum AMH level previously determined (e.g., the serum AMH level determined at most twelve months before the dosage is applied to the patient for the first time). Preferably, the patient's serum AMH level is determined by ELECSYS AMH Plus immunoassay (available from Roche, Switzerland, see www.roche.com ) determine (measure). The step of identifying the patient can be based on the patient's weight determined just before the first administration of the dosage to the patient (e.g., 0 to 2 days before). As is well known, the step of determining the patient's weight can use a bathroom scale.

[0047] Composition (such as pharmaceutical composition) can be used for treating (before treatment) and be accredited as body weight <59kg, for example <56kg, for example <55kg, for example <52kg, for example <50kg, for example <45kg, for example <42kg, for example <31.5kg in infertility. Composition (such as pharmaceutical composition) can be used for treating (before treatment) and be accredited as body weight is infertility in patient of 40 to 59.9kg, for example, be used for treating infertility in patient of 45 to 55kg in weight. Composition can be used for treating (before treatment) and be accredited as infertility in patient of AMH≥16pmol / L, for example AMH≥19pmol / L, for example AMH≥26pmol / L, for example AMH≥28pmol / L, for example AMH≥30pmol / L, for example AMH≥40pmol / L.

[0048] Preferably, compositions (such as pharmaceutical composition) is accredited as body weight <52kg (such as <50kg, such as <45kg) and (before treatment) is accredited as infertile in the patient of AMH≥26pmol / L (such as AMH≥28pmol / L, such as AMH≥30pmol / L, such as AMH≥40pmol / L) for the treatment of (before treatment).In this example, infertile treatment can comprise (before treatment) based on the serum AMH level of patient and the step of body weight identification patient, and the step of applying described dosage to the patient of being accredited as AMH≥26pmol / L and (before treatment) being accredited as body weight <52kg.

[0049] Preferably, FSH is recombinant FSH (rFSH). Preferably, rFSH (e.g., recombinant FSH derived from a human cell line) includes α2,3- and α2,6-sialylation. 1% to 99% of the total sialylation of the FSH (rFSH) used according to the present invention may be α2,3-sialylation. 1% to 99% of the total sialylation of the FSH (rFSH) according to the present invention may be α2,6-sialylation. Preferably, 80 to 95%, for example, 80 to 90%, for example, 82 to 89%, for example, 85 to 89% of the total sialylation is α2,3-sialylation. Preferably, 5 to 20%, for example, 10 to 20%, for example, 11 to 18%, for example, 11 to 15% of the total sialylation is α2,6-sialylation. Sialylation means the amount of sialic acid residues present in FSH carbohydrate structure, α2,3- sialylation means sialylation at 2,3 positions (as known in the art), and α2,6 sialylation at 2,6 positions (as known in the art). Therefore, "% in total sialylation can be α2,3 sialylation" refers to the sialic acid residues present in FSH at 2,3 positions account for the percentage of total. The term "% in total sialylation is α2,6- sialylation" refers to the sialic acid residues present in FSH at 2,6 positions account for the percentage of total. rFSH can exist as a single isoform or as a mixture of isoforms.

[0050] The compositions can be used to treat infertility in Asian patients (eg, Japanese, Chinese, Korean, Indian patients, eg, patients of Han, Yamato, or Korean ethnicity).

[0051] According to the present invention, in yet another aspect, there is provided a medicine comprising follicle stimulating hormone (FSH), preferably recombinant FSH, for treating infertility in Asian (e.g., Japan, China, Korea S, India) patients; wherein the medicine is administered to (before treatment) and is accredited as serum AMH level ≥ 15pmol / L (e.g., AMH ≥ 16pmol / L, e.g., AMH ≥ 19pmol / L, e.g., AMH ≥ 28pmol / L) and (before treatment) is accredited as an Asian (e.g., Japan, China, Korea S, India) patient whose body weight is less than 60kg; and wherein the medicine is administered with a daily dose of 6 to 8 μg recombinant FSH or a daily dose equivalent to 6 to 8 μg recombinant FSH. Preferably, the daily dose is 6 to 8 μg recombinant FSH. More preferably, the daily dose is 6 μg recombinant FSH.

[0052] Infertile treatment can comprise (before treatment) identifying the step of patient's serum AMH level and body weight based on patient.Infertile treatment can comprise the step of applying described dosage to the patient being accredited as the serum AMH level with limitation and body weight.For example, infertile treatment can comprise (before treatment) identifying the step of patient's serum AMH level and body weight based on patient, and to (before treatment) being accredited as AMH≥15pmol / L (for example AMH≥16pmol / L, for example AMH≥19pmol / L, for example AMH≥26pmol / L, for example AMH≥28pmol / L, for example AMH≥40pmol / L) and (before treatment) being accredited as the patient of body weight<60kg[for example body weight<55kg, for example<52kg, for example<50kg, for example<45kg] applying the step of described dosage.

[0053] (Before treatment) the step of identifying the patient based on the patient's serum AMH level and body weight can be performed just before the dosage is applied to the patient for the first time (e.g., 0 to 2 days before). The step of identifying the patient can be based on the serum AMH level previously determined (e.g., the serum AMH level determined at most twelve months before the dosage is applied to the patient for the first time). Preferably, the patient's serum AMH level is determined by ELECSYS AMH Plus immunoassay (available from Roche, Switzerland, see www.roche.com ) determine (measure). The step of identifying the patient can be based on the patient's weight determined just before the first administration of the dosage to the patient (e.g., 0 to 2 days before). As is well known, the step of determining the patient's weight can use a bathroom scale.

[0054] As used herein, "the first day of treatment" (also referred to as "the first day of stimulation") refers to the first day on which a dose of FSH (e.g., recombinant FSH) is administered to a patient. The first day of treatment (stimulation) can be on day 1, 2, or 3 (preferably day 2 or 3) of the patient's menstrual cycle. In other words, the first day of treatment (stimulation) can be one, two, or three days, preferably two or three days, after the patient begins menstruation (as is well known in the art).

[0055] The dosage of FSH starts on the first day of treatment and continues for two to twenty days, for example, continues for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days. The dosage of FSH starts on the first day of treatment and continues for seven to thirteen days, for example, nine to thirteen days, for example, 10 to 13 days, for example, 10 to 11 days. The dosage of FSH can be administered with a dosage equivalent to the daily dose mentioned above. For example, the composition can be used for administration at a dosage of 18 μg FSH every three days (for example, for administration on days 1, 4 and 7, etc.).

[0056] The composition (e.g., pharmaceutical composition) or drug can be administered after pre-treating the patient with a (different) pharmaceutical composition that suppresses the production of endogenous gonadotropins before the first day of treatment with FSH (e.g., after the subject has been pre-treated with steroids, GnRH agonists, GnRH antagonists, etc.). In this article, the term "pre-treated" or "pre-treatment" refers to administering a pharmaceutical composition that suppresses the production of endogenous gonadotropins before the first day of treatment with FSH and hCG. This is well known in the art. Therefore, the composition (e.g., pharmaceutical composition) or drug can be used for administration 12 to 16 days, e.g., 13 to 15 days, e.g., 14 days after the administration of a GnRH agonist (e.g., Synarel, Lupron, Decapeptyl) (e.g., after the start of administration, e.g., after the start of daily administration). The product can be used for administration together with a GnRH agonist.

[0057] In other examples, the composition (e.g., pharmaceutical composition) or medicament can be administered prior to administration of a GnRH antagonist (e.g., ganirelix, cetrorelix), for example, five or six days before administration of the GnRH antagonist. The product can be administered with a GnRH antagonist.

[0058] Preferably, the composition (e.g., pharmaceutical composition) or medicament is for administration prior to administration of a high (ovulatory) dose of hCG (e.g., 4,000 to 11,000 IU hCG, e.g., 5,000 IU hCG, 10,000 IU hCG, etc.; or 150 to 350 micrograms recombinant hCG, e.g., 250 micrograms recombinant hCG) to induce final follicular maturation.

[0059] The above dosages can be used for infertility treatment in the first stimulation protocol of a patient (subject). It should be understood that for further stimulation cycles, the dosage can be adjusted according to the actual ovarian response in the first cycle.

[0060] Applicants have designed "personalized" COS regimens in which specific doses of recombinant FSH with specific properties are used to treat patients based on their specific AMH levels, thereby increasing the likelihood of an appropriate response to stimulation (e.g., in patients with low response potential), and / or reducing the risk of OHSS (e.g., in patients classified as high or excessive responders).

[0061] Serum levels of AMH can be determined (e.g., measured) by any method known in the art. Serum AMH levels can be measured using the AMHGen-II enzyme-linked immunosorbent assay (kit) (Beckman Coulter, Inc., Webster, Texas). The assay can detect an AMH concentration greater than 0.57 pmol / L, with a quantitative limit of 1.1 pmol / L. Serum AMH levels can be measured using the automatic AMH ACCESS assay (Beckman Coulter, Inc., Webster, Texas). Preferably, the assay is performed using the AMHGen-II enzyme-linked immunosorbent assay (ELISA) from Roche Diagnostics. AMH assay is used to measure serum AMH levels. Other assays can be used.

[0062] Herein, serum AMH values ​​are generally reported in pmol / L. This can be converted to ng / mL using the conversion formula 1 ng / ml AMH = 7.1 pmol / L AMH.

[0063]

[0014] Herein, the terms "patient" and "subject" are used interchangeably.

[0064] As used herein, the term "infertility treatment" includes methods for treating infertility by controlled ovarian stimulation (COS) or a step or stage comprising controlled ovarian stimulation (COS), such as intrauterine insemination (IUI), in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). The term "infertility treatment" includes methods for treating infertility by ovulation induction (OI) or a step or stage comprising ovulation induction (OI). The term "infertility treatment" includes treating infertility in a subject with tubal infertility or unexplained infertility, including treating infertility in a subject with endometriosis (e.g., stage I or II endometriosis), and / or treating infertility in a subject with anovulatory infertility (e.g., WHO type II anovulatory infertility), and / or treating infertility in a subject with a partner suffering from male factor infertility. The product (or composition) can be used for (in) the treatment of infertility (and / or for controlled ovarian stimulation) in a subject with endometriosis (e.g., a subject with stage I or II endometriosis) as defined by the American Society for Reproductive Medicine (ASRM) classification system for different stages of endometriosis (stage IV: most severe; stage I: least severe) [American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67, 817 821.].

[0065] The composition or medicament may be used for (in) the treatment of infertility (and / or controlled ovarian stimulation) in a subject having a normal serum FSH level of 1 to 16 IU / L (eg 1 to 12 IU / L) in the early follicular phase.

[0066] The composition or medicament can be used for the treatment of infertility (and / or controlled ovarian stimulation) in subjects aged 18 to 42 years (e.g., 25 to 37 years). The product can be used for (in) BMI>1 and BMI<35 kg / m 2 Subjects with BMI>18 and BMI<25 kg / m 2 Subjects with BMI>20 and BMI<25 kg / m 2Treatment of infertility (and / or controlled ovarian stimulation) in subjects with

[0067] rFSH can be produced or expressed in human cell lines (e.g., Per.C6 cell line, HEK293 cell line, HT1080 cell line, etc.). This can simplify the preparation method (and make it more effective) because, compared to known methods, manipulation and control of, for example, cell growth medium to maintain sialylation can be less critical. The method can also be more effective because, compared to the production of known rFSH products, almost no alkaline rFSH is produced; more acidic rFSH is produced and the separation / removal of alkaline FSH is less problematic. Cell lines, derived from cell lines or modified rFSH is produced or expressed in cell lines. In some embodiments, the rFSH produced or expressed in a human cell line (e.g., human sialyltransferase, HEK293 cell line, HT1080 cell line, etc.) will comprise some sialic acids (α2,6 sialylation) provided by the endogenous sialyltransferase activity of the cell line and will comprise some sialic acids (α2,3 sialylation) provided by the endogenous sialyltransferase activity of the cell line. α2,3-sialyltransferase can be used to modify the cell line. α2,6-sialyltransferase can be used to modify the cell line. Alternatively or additionally, the rFSH can comprise sialic acids (α2,6 sialylation) provided by the endogenous sialyltransferase activity of the cell line. In this article, the term "recombinant FSH of human origin" refers to recombinant FSH produced or expressed in a human cell line (e.g., recombinant FSH prepared by transforming a human cell line).

[0068] rFSH can be produced using α2,3- and / or α2,6-sialyltransferases. In an example, rFSH is produced using α2,3-sialyltransferase. rFSH can contain α2,6-linked sialic acid (α2,6 sialylation) provided by endogenous sialyltransferase activity.

[0069] The composition can be a pharmaceutical composition. The pharmaceutical composition is used to treat infertility. The treatment of infertility can include assisted reproductive technology (ART), induced ovulation or intrauterine insemination (IUI). The pharmaceutical composition can be used for medical indications such as those in which known FSH preparations are used.

[0070] Composition or medicine can be formulated as known compositions, it is used for the drug administration of any approach, for example oral, rectal, parenteral, transdermal (for example patch technology), intravenous, intramuscular, subcutaneous, intrasternal (intrasusternal), intravaginal, intraperitoneal, local (powder, ointment or drops) or as buccal lozenge or nasal spray.Typical composition comprises pharmaceutical carrier, as aqueous solution, nontoxic excipient, comprises salt and preservative, buffer etc., particularly as at Remington's Pharmaceutical Sciences (Lemington's Pharmaceutical Sciences) the 15th edition (Matt Publishing Company, 1975), 1405 to 1412 pages and 1461-87 pages, and described in national formulary (national prescription) XIV the 14th edition (American Pharmaceutical Association (U.S. Drug Association), 1975).

[0071] Examples of suitable aqueous and non-aqueous pharmaceutical carriers, diluents, solvents or excipients include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. The compositions or medicines of the present invention may also contain additives such as, but not limited to, preservatives, wetting agents, emulsifiers, surfactants and dispersants. Antibacterial and antifungal agents may be included to prevent microbial growth and include, for example, metacresol, benzyl alcohol, parabens, chlorobutanol, phenol, sorbic acid, etc. If preservatives are included, benzyl alcohol, phenol and / or metacresol are preferred; however, preservatives are by no means limited to these examples. In addition, it may be desirable to include isotonic agents (such as sugar, sodium chloride, etc.).

[0072] The composition or medicament may further comprise a salt comprising a pharmaceutically acceptable alkali metal cation selected from the group consisting of: Na + Salt or K + Salt, or a combination thereof. Preferably, the salt is a Na+ salt, such as NaCl or Na2SO4.

[0073] Preferably, the composition or medicament comprises recombinant FSH and one or more of polysorbate 20, L-methionine, phenol, disodium sulfate and sodium phosphate buffer.

[0074] In some cases, in order to achieve prolonged effect, it is desirable to slow down the absorption of FSH (and other active ingredients, if present) from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of FSH then depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, the delayed absorption of the FSH combination administered parenterally is accomplished by dissolving or suspending the FSH combination in an oily excipient. Injectable reservoir forms are prepared by forming a microcapsule matrix of FSH (and other medicaments, if present) in a biodegradable polymer (such as polylactic acid-polyglycolide). Depending on the ratio of FSH to polymer and the properties of the specific polymer employed, the rate at which FSH releases can be controlled. Examples of other biodegradable polymers include polyvinyl pyrrolidone, poly (orthoesters) and poly (anhydrides) etc. Reservoir injectable preparations are also prepared by encapsulating FSH in a liposome or microemulsion compatible with body tissues.

[0075] The injectable formulations can be sterilized, for example, by filtering through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use. The injectable formulations can be supplied in any suitable container, such as a vial, a pre-filled syringe, an injection cartridge, etc.

[0076] The composition or medicament can be formulated for single use or for multiple use (multiple doses). If the composition or medicament is formulated for multiple use, it is preferred to include a preservative. If a preservative is included, benzyl alcohol, phenol and / or m-cresol are preferred; however, the preservative is by no means limited to these examples. The composition or medicament formulated for single use or multiple use may further include a salt comprising a pharmaceutically acceptable alkali metal cation selected from the group consisting of: Na + Salt or K + Salt, or a combination thereof. Preferably, the salt is a Na+ salt, such as NaCl or Na2SO4.

[0077] The composition or medicament may be contained in a container such as a vial, a pre-filled cartridge (eg, for single administration or multiple use), or an injection device such as a "pen" for, eg, administering multiple doses.

[0078] The composition or medicine can be a preparation (e.g., an injectable preparation) comprising FSH (optionally with hCG, LH, LH activity, etc.). If present, LH activity can be derived from LH or human chorionic gonadotropin hCG. If there is more than one active ingredient (i.e., FSH and, for example, hCG or LH), these can be suitable for administration alone or together. If administered alone, administration can be sequential. The composition or medicine can be supplied in any appropriate packaging. For example, the composition or medicine can comprise multiple containers (e.g., pre-filled syringes or vials) containing FSH or hCG or a combination (or combination) of FSH and hCG. The hCG can be recombinant hCG or urine hCG. If the composition or medicine comprises multiple containers (e.g., pre-filled syringes or vials) containing FSH (e.g., recombinant FSH), each container can contain the same amount of FSH. One or more containers can contain different amounts of FSH. The syringes or vials can be packaged in blister packs or other ways to maintain sterility. Any composition or drug may optionally contain instructions for use of FSH (and, for example, hCG, if present) formulations. The pH and exact concentrations of the various components in the pharmaceutical composition can be adjusted according to conventional practice in the art. See GOODMAN and GILMAN'S THE PHARMACOLOGICAL BASIS FOR THERAPEUTICES, 7th edition. In a preferred embodiment, the composition or drug of the present invention can be supplied as a composition for parenteral administration. General methods for preparing parenteral formulations are known in the art and are described in REMINGTON; THE SCIENCE AND PRACTICE OF PHARMACY, supra, on pages 780-820. Parenteral compositions can be supplied as liquid formulations or as solids, which will be mixed with a sterile injectable medium immediately before administration. In a particularly preferred embodiment, parenteral compositions are supplied in dosage unit form for ease of administration and dosage uniformity.

[0079] According to the present invention, in yet another aspect, a method for treating infertility is provided, said method comprising: the daily dosage of 6 to 8 μ g recombinant FSH or the daily dosage being equivalent to 6 to 8 μ g recombinant FSH is applied to AMH≥15pmol / L (for example AMH≥16pmol / L, for example AMH≥19pmol / L, for example AMH≥26pmol / L, for example AMH≥28pmol / L, for example AMH≥40pmol / L) and the step of the patient (for example female patient) of body weight<60kg [for example body weight<55kg, for example<52kg, for example<50kg, for example<45kg, for example<42kg, for example<31.5kg].Preferably, daily dosage is 6 to 8 μ g recombinant FSH.More preferably, daily dosage is 6 μ g recombinant FSH.

[0080] Method described can include the step of determining the serum AMH level of patient and body weight.Method described can include the step of applying described dosage to the patient with the serum AMH level of limitation and body weight.For example, method described can include the step of determining the serum AMH level of patient and body weight, and to AMH≥15pmol / L (for example AMH≥16pmol / L, for example AMH≥19pmol / L, for example AMH≥26pmol / L, for example AMH≥28pmol / L, for example AMH≥40pmol / L) and body weight<60kg (for example body weight<55kg, for example<52kg, for example<50kg, for example<45kg, for example<42kg, for example<31.5kg) patient applying the step of described dosage.

[0081] According to the present invention, in yet another aspect, a method for the treatment of infertility is provided, said method comprising administering to (before treatment) a daily dose of 6 to 8 μ g recombinant FSH or the daily dose being equivalent to 6 to 8 μ g recombinant FSH and being accredited as AMH≥15pmol / L (for example AMH≥16pmol / L, for example AMH≥19pmol / L, for example AMH≥26pmol / L, for example AMH≥28pmol / L, for example AMH≥40pmol / L) and (before treatment) being accredited as the step of the patient (for example female patient) of body weight<60kg (for example body weight<55kg, for example<52kg, for example<50kg, for example<45kg).Preferably, daily dose is 6 to 8 μ g recombinant FSH.More preferably, daily dose is 6 μ g recombinant FSH.

[0082] Described method can comprise (before treatment) identifying the step of patient based on the serum AMH level of patient and body weight.Described method can comprise the step of applying described dosage to the patient being accredited as the serum AMH level with limitation and body weight.For example, described method can comprise (before treatment) identifying the step of patient based on the serum AMH level of patient and body weight, and to (before treatment) being accredited as AMH≥15pmol / L (for example AMH≥16pmol / L, for example AMH≥19pmol / L, for example AMH≥26pmol / L, for example AMH≥28pmol / L, for example AMH≥40pmol / L) and (before treatment) being accredited as body weight<60kg [for example body weight<55kg, for example<52kg, for example<50kg, for example<45kg] patient applying the step of described dosage.

[0083] The method can be used to treat infertility in Asian (eg, Japanese, Chinese, Korean, Indian) patients.

[0084] Preferably, the patient has (is identified as having) a body weight of <52 kg (e.g. <50 kg, e.g. <45 kg) and has (is identified as having) an AMH of AMH ≥26 pmol / L (e.g. AMH ≥28 pmol / L, e.g. AMH ≥30 pmol / L, e.g. AMH ≥40 pmol / L).

[0085] Preferably, FSH is recombinant FSH (rFSH). Preferably, rFSH (e.g., recombinant FSH derived from a human cell line) includes α2,3- and α2,6-sialylation. 1% to 99% of the total sialylation of the FSH (rFSH) used according to the present invention may be α2,3-sialylation. 1% to 99% of the total sialylation of the FSH (rFSH) according to the present invention may be α2,6-sialylation. Preferably, 80 to 95%, for example, 80 to 90%, for example, 82 to 89%, for example, 85 to 89% of the total sialylation is α2,3-sialylation. Preferably, 5 to 20%, for example, 10 to 20%, for example, 11 to 18%, for example, 11 to 15% of the total sialylation is α2,6-sialylation. Sialylation means the amount of sialic acid residues present in FSH carbohydrate structure, α2,3- sialylation means sialylation at 2,3 positions (as known in the art), and α2,6 sialylation at 2,6 positions (as known in the art). Therefore, "% in total sialylation can be α2,3 sialylation" refers to the sialic acid residues present in FSH at 2,3 positions account for the percentage of total. The term "% in total sialylation is α2,6- sialylation" refers to the sialic acid residues present in FSH at 2,6 positions account for the percentage of total. rFSH can exist as a single isoform or as a mixture of isoforms.

[0086] According to the present invention, in one aspect, a kind of compositions is provided, it is used for the treatment of infertility in the patient of AMH≥26pmol / L and body weight<52kg, and described compositions comprises the daily dosage of 6 to 8 μ g Recombinant FSH.Preferably, the patient has (being accredited as having) such body weight: body weight<52kg (for example<50kg, for example<45kg), and has (being accredited as having) such AMH: AMH≥26pmol / L (for example AMH≥28pmol / L, for example AMH≥30pmol / L, for example AMH≥40pmol / L).

[0087] According to the present invention, in yet another aspect, a kind of compositions is provided, it is used for the treatment of infertility in the patient of AMH≥26pmol / L and body weight<61kg, described compositions comprises the daily dosage of 6 to 8 μ g recombinant FSH or is equivalent to the daily dosage of 6 to 8 μ g recombinant FSH.Preferably, the patient has (being accredited as having) such body weight: body weight<52kg (for example<50kg, for example<45kg), and has (being accredited as having) such AMH: AMH≥26pmol / L (for example AMH≥28pmol / L, for example AMH≥30pmol / L, for example AMH≥40pmol / L). Detailed Description of the Invention

[0088] Reference will now be made to the following examples and Figure 1 Describing the present invention in more detail, Figure 1 The weights and AMH of all patients in the Japanese Phase II clinical trial discussed in the retrospective analysis of Example 3 are shown and indicate if the dose regimen listed in Table A above would specify 6 μg (diamonds) or doses ≥6 μg Rekovelle.

[0089] Example 1 - Rekovelle

[0090] It was modified by the method disclosed in WO2013 / 020996 and WO2009 / 127826A Recombinant FSH expressed in cell lines.

[0091] The marketing authorisation holder for DRUG-IN® is Ferring Pharmaceuticals A / S, Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark and is available in the UK from Ferring Pharmaceuticals, Drayton Hall, Church Road, West Drayton, UB7 7PS, UK.

[0092] The active substance in Rekovelle is follicle-stimulating hormone delta (FE999049). Rekovelle is highly sialylated and includes both α2,3- and α2,6-sialylation, with approximately 85% to 90% of the total sialylation being α2,3-sialylation and approximately 10% to 15% of the total sialylation being α2,6-sialylation.

[0093] REKOVELLE is a clear, colorless solution for injection. It is available in a package of one cartridge and three pen-type needles. Each multidose cartridge contains 12 micrograms of follitropin delta in 0.36 milliliters of solution. One milliliter of solution contains 33.3 micrograms of follitropin delta per milliliter of solution. Other ingredients are phenol, polysorbate 20, L-methionine, sodium sulfate decahydrate, disodium phosphate dodecahydrate, concentrated phosphoric acid, sodium hydroxide, and water for injection.

[0094] Example 2 - Randomized, assessor-blind (AMH)-stratified dose-response trial in Japanese IVF / ICSI patients undergoing controlled ovarian stimulation with follitropin delta

[0095] Methods: A randomized, controlled, assessor-blinded, parallel-group, multicenter, phase 2 anti-Müllerian hormone (AMH)-stratified trial was conducted in Japanese IVF / ICSI patients to determine the dose-response relationship of FE 999049 with respect to the number of oocytes retrieved. Randomization was stratified according to AMH levels at screening; low AMH (5.0-14.9 pmol / L) or high AMH (15.0-44.9 pmol / L).

[0096] 158 patients aged 20 to 39 years (mean age 33.7 years) underwent COS using three dose levels of FE 999049, follicle-stimulating hormone delta (Ferring Pharmaceuticals). The doses of FE 999049 were 6 μg / day, 9 μg / day, and 12 μg / day, and standard therapy with an approved rFSH product (FOLLISTIM, MSD, 150 IU / day) was also included as a control. Currently, follicle-stimulating hormone beta (FOLLISTIM) is the only medical product approved in Japan for controlled ovarian stimulation in IVF / ICSI cycles.

[0097] Patients were randomly assigned to a fixed dose of 6 μg / day, 9 μg / day, and 12 μg / day of FE 999049 (n=117) or 150 IU of follicle-stimulating hormone beta (n=41). Randomization was stratified according to AMH level [low AMH = 5.0-14.9 pmol / L; high AMH = 15.0 to 44.9 pmol / L; AMH (Roche Diagnostics). Gonadotropins were initiated on days 2-3 of the menstrual cycle. Ganrelix 0.25 mg / day was added starting on day 6 of stimulation, and final follicular maturation was initiated on the day ≥3 follicles with a diameter ≥17 mm were observed. OHSS was assessed using the Golan classification.

[0098] The daily dose was fixed throughout the stimulation process. A statistically significant dose-response relationship was observed for FE999049 with respect to the number of oocytes retrieved, both for the overall population and within each AMH randomization stratum. Acceptable pregnancy rates were achieved at all FE 999049 doses.

[0099] In this trial, patients were not dosed according to body weight, and no patient received a dose lower than 6 μg / day of FE 999049. Patients in this trial were not identified by a combination of AMH and body weight prior to treatment.

[0100] Example 3 Retrospective Analysis of Phase II Trial

[0101] Compared with the women of the U.S. and Western Europe, in many Asian countries (such as Japan, China, Korea S and India), many women have lower body weight. Therefore, there is such risk: using a fixed dose suitable for the general population of Europe to Asian / Japanese patients may cause low-weight patients to receive high FSH dosage (with regard to dosage / kg body weight). This may then lead to the risk of overreaction and OHSS in these patients. Traditional " fixed dose " FSH regimen may be a factor in some high OHSS incidence rates reported in the Japanese study.

[0102] The dosage regimen listed in Table A above alleviates this risk to a certain extent because patients are dosed by weight. However, very low doses of gonadotropins may be associated with insufficient follicle recruitment and poor ovarian response. Therefore, there is a risk that administration according to the Table A regimen may result in very light high AMH patients receiving FSH dosages that may be suboptimal from the perspective of efficacy. Therefore, it is necessary to effectively administer to lighter high AMH patients (body weight < 60 kg) while reducing the risk of overstimulation and OHSS in these patients (because these patients have high AMH and low body weight, they may be more prone to this risk).

[0103] Overall, there were no safety concerns at the 6 μg dose of FE 999049 in the Japanese Phase 2 trial. The safety profile of patients weighing less than 60 kg in the Japanese Phase 2 trial was retrospectively reviewed. Data from the reference therapy group using FOLLISTIM are also shown as background for the observed results in the 6 μg FE 999049 group. Table 1 shows safety parameters related to ovarian response.

[0104] Table 1 Comparison of Ovarian Response Safety Parameters in Subjects <60 kg Exposed to 6 μg FE 999049 or 150 IU FOLLISTIM - Overall

[0105]

[0106] In patients weighing <60 kg, the total number of patients with early OHSS was 4 (13.8%) in the 6 μg FE 999049 group and 8 (24.2%) in the 150 IU FOLLISTIM group. Early moderate / severe OHSS was reported in 3 (10.3%) patients and 7 (21.2%) patients in the 6 μg FE 999049 and 150 IU FOLLISTIM groups, respectively. In addition, an adequate response of oocyte yield above 8-14 oocytes was observed in only 1 (3.4%) patient in the 6 μg FE 999049 group, compared to 7 (21.2%) patients in the 150 IU FOLLISTIM group. Excessive follicular development requiring GnRH agonist triggering was not observed in any of the patients in the 6 μg FE 999049 group, but did occur in one patient in the 150 IU FOLLISTIM group. Thus, the use of 6 μg FE 999049 appears to improve the safety ovarian response profile in patients weighing <60 kg compared to 150 IU FOLLISTIM.

[0107] Table 1 covers all patients (regardless of AMH level) of body weight<60kg.All patients with AMH<15pmol / L will receive 12 μ g FE 999049.Therefore, the patient can have the calculated dosage of<6 μ g but will receive the situation of 6 μ g and is only applicable to the patient of AMH≥15pmol / L.Table 2 shows the data of the patient of body weight<60kg and AMH≥15pmol / L in Japan 2 phase trials.

[0108] Table 2 Comparison of Ovarian Response Safety Parameters in Subjects <60 kg Exposed to 6 μg FE 999049 or 150 IU FOLLISTIM - High AMH Stratification

[0109]

[0110]

[0111] Among patients weighing <60 kg and with AMH ≥15 pmol / L, the total number of patients with early OHSS was 4 (22.2%) in the 6 μg FE999049 group and 7 (31.8%) in the 150 IU FOLLISTIM group. Moderate / severe OHSS was the most common severity in early OHSS cases and was reported in 3 (16.7%) patients in the 6 μg FE 999049 group and 6 (27.3%) patients in the 150 IU FOLLISTIM group. While only 1 (5.6%) patient in the 6 μg FE 999049 group had 15-19 retrieved oocytes, this was the case for 4 (18.2%) patients in the 150 IU FOLLISTIM group, of which an additional 2 (9.1%) patients had ≥20 oocytes. No patient in the 6 μg FE 999049 group required a trigger with a GnRH agonist due to excessive follicular development, but one patient in the 150 IU FOLLISTIM group required such a trigger. Thus, controlled ovarian stimulation with 6 μg FE 999049 in patients weighing <60 kg and with AMH ≥15 pmol / L was associated with a lower risk of early OHSS and a lower risk of excessive ovarian response compared with controlled ovarian stimulation with 150 IU FOLLISTIM.

[0112] Regarding the distribution of adverse events in patients weighing <60 kg, the frequency of adverse events judged by the investigators to be related to the drug used for controlled ovarian stimulation was 20.7% in the 6 μg FE 999049 group and 33.3% in the 150 IU FOLLISTIM group. In patients weighing <60 kg and with AMH ≥15 pmol / L, the frequency of related adverse events was 27.8% in the 6 μg FE999049 group and 36.4% in the 150 IU FOLLISTIM group.

[0113] From an efficacy perspective, the clinical pregnancy rate per transfer cycle in patients weighing <60 kg was 40.0% in the 6 μg FE999049 group and 21.7% in the standard therapy group. For patients weighing <60 kg and with AMH ≥15 pmol / L, the clinical pregnancy rate per transfer cycle was 38.5% in the 6 μg FE 999049 group and 20.0% in the standard therapy group.

[0114] Finally, Ferring identified patients in the Japanese Phase 2 trial who would have received <6 μg FE 999049 according to the individualized FE 999049 dosing regimen (Table A above) based on AMH and body weight, but in this trial received 6 μg FE 999049 or 150 IU FOLLISTIM according to random assignment. This was a very limited number of patients (5 patients in the 6 μg FE 999049 group and 3 patients in the 150 IU FOLLISTIM group), but the ovarian response safety data were consistent with those presented previously. No ovarian response of more than 15 oocytes was observed in any of the 5 patients in the 6 μg FE 999049 group, but no such ovarian response was observed in 2 of the 3 patients in the 150 IU FOLLISTIM group (66.7%). Excessive follicular development requiring triggering with a GnRH agonist was not observed in any of the five patients in the 6 μg FE 999049 group, but was not observed in one of the three patients (33.3%) in the 150 IU FOLLISTIM group. Early OHSS was reported in one of the five patients (20.0%) in the 6 μg FE 999049 group and in one of the three patients (33.3%) in the 150 IU FOLLISTIM group.

[0115] In other words, the applicants surprisingly found that a minimum dose of 6 μg could be prescribed taking into account the lower body weight in the Japanese population, with the aim of avoiding underdosing of low-weight Japanese patients and thereby maintaining efficacy in these patients while avoiding side effects such as OHSS.

[0116] In addition to the safety and efficacy data from the Japanese Phase 2 trial using 6 μg of FE 999049 supporting the appropriateness of this dose, simulations were performed using a dose-response model that had been estimated from the Japanese Phase 2 trial. The purpose of these simulations was to evaluate the expected difference in oocyte number using the proposed dosing regimen using 6 μg as the minimum dose compared to a dosing regimen that allowed doses < 6 μg. Based on the weight and AMH levels of all 158 randomized patients in the Japanese Phase 2 trial, 18 (11%) would receive the proposed dosing regimen with a dose of 6 μg rather than the calculated dose of < 6 μg. All of these patients weighed less than 52 kg and had AMH greater than 26 pmol / L, as Figure 1 Figure 2 shows the body weight and AMH of all patients in the trial. Figure 1 These 18 patients are shown using small diamonds (instead of rectangles) in the lower right corner of the figure.

[0117] Among the 18 patients with a calculated dose <6 μg, the mean calculated dose was 5.33 μg, thus the recommended dosing regimen had a mean dose that was 13% higher (mean dose 6.0 μg instead of 5.33 μg) compared with the regimen without a minimum dose.

[0118] By using 6 μg as the minimum dose, a beneficial effect on ovarian response is expected. Among patients with a calculated dose < 6 μg, more patients are expected to achieve the goal of 8-14 retrieved oocytes with the recommended dosing regimen of 6 μg as the minimum dose (48.0% of patients compared to 44.8% with the regimen without a minimum dose), as shown in Table 3.

[0119] Table 3 Predicted outcomes in Japanese patients at calculated doses <6 μg FE 999049

[0120]

[0121] Therefore, in addition to the observed data from the Japanese phase 2 trial, model predictions of ovarian response using the proposed dosing regimen further support the appropriateness of the 6 μg minimum dose.

[0122] In summary, the recommended dosing regimen of FE 999049, including the implementation of 6 μg as the minimum dose, is safe and effective and is being used in the Japanese Phase 3 trial. A dedicated analysis of the Phase 3 data from Japanese patients who received a calculated dose < 6 μg will be conducted for PMDA review to support the efficacy and safety of 6 μg FE 999049 in these patients.

[0123] Example 10 - Phase 3 clinical trial in Japan.

[0124] method

[0125] This will be a randomized, assessor-blinded, controlled, parallel-group, multicenter trial evaluating the efficacy and safety of FE 999049 in its individualized dosing regimen when used for the first cycle of controlled ovarian stimulation for IVF / ICSI followed by a gonadotropin-releasing hormone (GnRH) antagonist regimen in Japanese patients aged 20-40 years. The trial has been designed to demonstrate that FE 999049 is non-inferior to the Japanese approved rFSH product (i.e., FOLLISTIM) in terms of the number of oocytes retrieved.

[0126] Subjects will be screened within 60 days prior to the start of stimulation to meet inclusion and exclusion criteria. Subjects will be randomized in a 1:1 ratio to controlled ovarian stimulation with FE 999049 or FOLLISTIM on days 2-3 of the menstrual cycle. Randomization will be stratified by center and according to AMH levels at screening (<15 pmol / L and ≥15 pmol / L).

[0127] Subjects randomized to FE 999049 will have their individual FE 999049 dose based on their AMH level at screening and their weight at the start of stimulation (see below). The FE 999049 daily dose will be fixed throughout the stimulation process. For subjects with AMH<15pmol / L, the FE 999049 daily dose is 12μg, regardless of body weight. For subjects with AMH≥15pmol / L, the FE 999049 daily dose has a continuous scale ranging from 0.19 to 0.10μg / kg, i.e. depending on actual AMH and body weight. This is listed in the table below. The minimum daily dose of FE 999049 allowed is 6μg, and the maximum daily dose of FE999049 allowed is 12μg. Subjects can be treated with FE 999049 for a maximum of 20 days, and coasting is not allowed.

[0128] For subjects randomized to FOLLISTIM, the dosing regimen is in the label (see below). The starting dose of FOLLISTIM is 150 IU and is fixed for the first five stimulation days, after which it can be adjusted in 75 IU increments based on individual response. The maximum daily dose of FOLLISTIM allowed is 375 IU. Subjects can be treated with FOLLISTIM for a maximum of 20 days, and coasting is not allowed.

[0129] During the stimulation period, subjects will be monitored by transvaginal ultrasound on stimulation days 1 and 6 and at least every two days thereafter. Daily visits are mandatory when 3 follicles ≥15 mm are observed. To prevent a premature luteinizing hormone (LH) surge, a GnRH antagonist will be started on stimulation day 6 at a daily dose of 0.25 mg and continued throughout the stimulation period. When ≥3 follicles ≥17 mm in diameter are observed, a trigger for final follicular maturation will be administered with 5,000 IU urinary human chorionic gonadotropin (hCG). In the event of excessive follicular development (defined as ≥25 follicles ≥12 mm in diameter), the cycle should be canceled (Note: In the event of 25-35 follicles ≥12 mm in diameter, a GnRH agonist can be administered as a trigger for final follicular maturation). In the event of poor follicular development (defined as the failure of the investigator to achieve ≥3 follicles ≥17 mm in diameter by day 20), the cycle should be canceled.

[0130] Oocyte retrieval will occur 36 hours (± 2 hours) after triggering final follicular maturation, and the oocytes can be fertilized by IVF or ICSI. Fertilization and embryo development will be evaluated from oocyte retrieval to the day of transfer. One of the best quality blastocysts will be transferred on day 5 after oocyte retrieval, and the remaining blastocysts can be cryopreserved. For subjects who use GnRH agonists for triggering final follicular maturation, transfer will not occur, and blastocysts can be cryopreserved on day 5. According to the statement of the Japan Society of Obstetrics and Gynaecology (JSOG), all cryopreserved blastocysts can be used by subjects after the trial is completed.

[0131] Vaginal progesterone tablets (LUTINUS, Ferring Pharmaceuticals) 100 mg were provided three times daily for luteal phase support from the day following oocyte retrieval until the day of clinical pregnancy presentation. Luteal phase support was provided only to subjects scheduled for transfer and could be terminated earlier in the absence of transfer or a negative βhCG test. βhCG testing was performed 13-15 days after transfer, followed by transvaginal ultrasound 5-6 weeks after transfer to assess clinical and critical pregnancy.

[0132] Blood samples will be collected during the trial to evaluate endocrine properties as well as clinical chemistry and hematology parameters. Endocrine parameters will be measured at screening, on day 1 of stimulation, on day 6 of stimulation, and at the end of stimulation. Clinical chemistry and hematology parameters will be evaluated at screening, at the end of stimulation, and at the end of the trial. Subjects will be evaluated three times daily for local tolerance to FE 999049 after subcutaneous administration: immediately after injection, 30 minutes after injection, and 24 hours after injection. Injection site reactions will be evaluated throughout the stimulation process and recorded in a diary by the subjects.

[0133] If a trial procedure and / or evaluation is to be carried out on a Sunday, public holiday or outside clinic opening hours, the procedure and / or evaluation may be postponed to the next working day (up to one day after the original appointment schedule) or cancelled, if appropriate.

[0134] During mandatory follow-up, pregnancy progress and outcome data will be collected for subjects with critical pregnancies. Data on ongoing pregnancies (10-11 weeks after transfer) and pregnancy outcomes as well as neonatal health at birth and 4 weeks after birth will be collected. Pregnancy follow-up does not include any intervention, but only data collection. Pregnancy follow-up data will be based on reports obtained from the subject's gynecologist / obstetrician and the subject's Maternal and Child Health Handbook. The data will be obtained through the trial site via the subject's gynecologist / obstetrician, the subject himself or other sources (when applicable). Ferring intends to submit the J-NDA after the main part of the trial is completed (i.e., until the clinical pregnancy visit), and the available pregnancy follow-up data will be included in the J-NDA at that time. Pregnancy follow-up data can be submitted after completion.

[0135] Number of subjects

[0136] Approximately 328 subjects will be randomized in a 1:1 ratio to FE 999049 and FOLLISTIM.

[0137] Inclusion / Exclusion Criteria

[0138] Women who are suitable for IVF and / or ICSI treatment, undergoing their first IVF / ICSI cycle, and diagnosed with tubal infertility, unexplained infertility, infertility associated with endometriosis stage I / II, or with a partner diagnosed with male factor infertility will be included in the trial. Participants will be aged 20-40 years with a body mass index (BMI) of 17.5-32.0 kg / m2.

[0139] Women with stage III / IV endometriosis, a history of recurrent miscarriage, or contraindications to controlled ovarian stimulation with gonadotropins will be excluded from participation in the trial.

[0140] A complete list of inclusion and exclusion criteria is provided below.

[0141] Inclusion criteria

[0142] 1. Sign the informed consent form before any trial-related procedures.

[0143] 2. Have good physical and mental health.

[0144] 3. Japanese women aged 20 to 40 years. Subjects must be at least 20 years old (including their 20th birthday) when they sign the informed consent form and no older than 40 years old (until the day before their 41st birthday) at the time of randomization.

[0145] 4. Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I / II (as defined by the revised American Society for Reproductive Medicine (ASRM) classification), or with a partner diagnosed with male factor infertility who are candidates for in vitro fertilization (IVF) and / or intracytoplasmic sperm injection (ICSI) treatment using ejaculated sperm from the male partner.

[0146] 5. Infertility for at least 1 year before random assignment (not applicable to tubal infertility or severe male factor infertility).

[0147] 6. The trial cycle will be the subject's first controlled ovarian stimulation cycle for IVF / ICSI.

[0148] 7. Regular menstrual cycles of 24-35 days (inclusive), presumably ovulatory.

[0149] 8. A uterine function consistent with expected normal function (e.g., no clinically disturbing signs of uterine fibroids (defined as submucosal or intramural fibroids greater than 3 cm in diameter, without polyps and without congenital structural abnormalities, which are associated with a decreased chance of pregnancy)) as documented by hysterosalpingography, hysteroscopy, saline infusion ultrasound, or transvaginal ultrasound within 1 year prior to screening. This also includes women who have been diagnosed with any of the above medical conditions but have had them surgically corrected within 1 year prior to screening.

[0150] 9. Within 1 year prior to screening, transvaginal ultrasound documented the presence and adequate visualization of both ovaries without obvious signs of abnormalities (e.g., absence of endometrioma greater than 3 cm or ovarian enlargement that would contraindicate the use of gonadotropins), as well as the fallopian tubes and surrounding tissue without obvious signs of abnormalities (e.g., absence of hydrosalpinx). Both ovaries must be accessible for oocyte retrieval.

[0151] 10. Early follicular phase (cycle days 2-4) serum FSH level of 1 to 15 IU / L (results obtained within 3 months before screening).

[0152] 11. Negative serum hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) antibody tests within 1 year prior to screening.

[0153] 12. Body mass index (BMI) at screening is 17.5 to 32.0 kg / m2 (inclusive of both endpoints).

[0154] 13. Willing to accept transfer of one blastocyst.

[0155] Exclusion criteria

[0156] 1. Known endometriosis stage III-IV (as defined by the revised ASRM classification).

[0157] 2. One or more follicles (including cysts) >10 mm observed based on transvaginal ultrasound before the start of stimulation on stimulation day 1 (puncture of cysts is allowed before randomization).

[0158] 3. Known history of recurrent miscarriage (defined as three consecutive miscarriages after ultrasound confirmation of pregnancy (excluding ectopic pregnancy) and before the 24th week of gestation).

[0159] 4. Known abnormal karyotype of the subject or his partner. In cases where sperm production is severely impaired (concentration < 1 million / mL), a normal karyotype (excluding Y chromosome microdeletions) must be documented.

[0160] 5. Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events.

[0161] 6. Known porphyria.

[0162] 7. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes mellitus).

[0163] 8. Known hereditary or acquired thrombophilia diseases.

[0164] 9. Any known endocrine or metabolic abnormality (pituitary, adrenal, pancreatic, liver or kidney) that may impair participation in the trial, except for controlled thyroid function disorders.

[0165] 10. Known presence of anti-FSH antibodies (based on information available in the subject's medical records).

[0166] 11. Known tumor of the ovary, breast, uterus, adrenal gland, pituitary gland, or hypothalamus, which would contraindicate the use of gonadotropins.

[0167] 12. Any abnormal findings in clinical chemistry, hematology, or vital signs at screening that are judged by the investigator to be clinically relevant.

[0168] 13. Known moderate or severe renal or hepatic impairment.

[0169] 14. Currently breastfeeding.

[0170] 15. Undiagnosed vaginal bleeding.

[0171] 16. Known clinically significant abnormal cervical cytology observed within 3 years prior to screening (unless clinical significance has been resolved).

[0172] 17. Findings from laboratory analysis at screening that exclude gonadotropin stimulation.

[0173] 18. Screening findings during gynecological examination that exclude gonadotropin stimulation.

[0174] 19. Findings during the screening gynecological examination that are associated with a decreased chance of pregnancy, such as congenital uterine anomalies or retained intrauterine devices.

[0175] 20. Pregnancy (must be confirmed by a negative urine pregnancy test at screening and before randomization) or contraindications to pregnancy.

[0176] 21. Known currently active pelvic inflammatory disease.

[0177] 22. Use of hormonal preparations (except thyroid medications) or fertility regulators, including dehydroepiandrosterone (DHEA), metformin, and cycle planning using oral contraceptives, progestogens, or estrogen preparations, during the last menstrual cycle before screening.

[0178] 23. Known history of chemotherapy (except during pregnancy) or radiotherapy.

[0179] 24. Current or past (1 year before randomization) alcohol abuse and / or current (last month) alcohol intake exceeding 14 units per week.

[0180] 25. Current or past (3 months before randomization) smoking habit of more than 10 cigarettes / day.

[0181] 26. Hypersensitivity to any drug substance or excipient in the medicinal product used in the investigational study.

[0182] 27. Hypersensitivity to any drug substance or excipient in GnRH or any GnRH analog / derivative.

[0183] 28. Participated in experiments before.

[0184] 29. Currently participating in another trial, including the follow-up period.

[0185] 30. Use of any unregistered study drugs within the last 3 months before screening.

[0186] On days 2-3 of the menstrual cycle, subjects will be randomized in a 1:1 ratio to treatment with FE 999049 or FOLLISTIM, and controlled ovarian stimulation will begin.

[0187] FE 999049 dosing regimen

[0188] Subjects randomized to FE 999049 will have their individual dose based on their AMH level at screening and their weight at randomization. For subjects with AMH <15 pmol / L, the daily dose of FE 999049 is 12 μg, regardless of body weight. For subjects with AMH ≥15 pmol / L, the daily dose of FE 999049 has a continuous scale ranging from 0.19 to 0.10 μg / kg, i.e., depending on actual AMH and body weight.

[0189] The daily dose of FE 999049 will be fixed throughout the stimulation process. The minimum daily dose of FE 999049 allowed is 6 μg. The maximum daily dose of FE 999049 allowed is 12 μg. Dosing will continue until the criteria for triggering final follicular maturation have been met. Subjects can be treated with FE 999049 for a maximum of 20 days. Coasting is not allowed.

[0190] The following table details the complete FE 999049 dosing regimen:

[0191]

[0192] AMH concentrations will be rounded to the nearest whole number.

[0193] Subjects can be treated for up to 20 days.

[0194] FE 999049 is administered as a single daily subcutaneous injection in the abdomen. The dose should not be divided into two injections. To minimize local injection site reactions, it is recommended to periodically change the injection site.

[0195] The first FE 999049 injection will be administered in an outpatient setting and will be administered by the trial medical representative or by the subject under the supervision of the trial medical representative. Subsequent injections can be administered at home or in an outpatient setting. The trial medical representative will provide the subject with instructions on how to administer FE 999049.

[0196] Calculation of the FE 999049 dose and setting the dose on the FE 999049 prefilled pen

[0197] The subject's serum AMH concentration will be obtained from a blood sample collected at screening and will be determined by a central laboratory using a Roche Diagnostics AMH concentrations will be analyzed using an AMH assay. AMH concentrations will be provided directly to the eCRF from a central laboratory. Subjects' weight will be measured at randomization using a calibrated scale without shoes or a jacket. Weight results will be entered into the eCRF. The FE 999049 dosing algorithm, programmed into the eCRF, calculates the FE 999049 dose based on the subject's AMH and weight.

[0198] The FE 999049 prefilled injection pen is intended for subcutaneous administration of FE 999049. It is a non-sterile, disposable device with an integrated, non-replaceable 3 mL cartridge containing the liquid FE 999049 drug product. Each cartridge holds multiple doses, the size of which is adjustable by the user. The dose can be set from 0.33 μg to 20.0 μg in 0.33 μg increments. The FE 999049 prefilled injection pen has a dosing scale that counts from 0 to 20 μg. Each number is separated by two lines, each representing 0.33 μg. The prefilled injection pen can be set to round the dose to the nearest 0.33 μg. It may be necessary to round the calculated dose, such as in this example, a subject weighing 75.0 kg has an AMH level of 35 pmol / L. The calculated dose for this subject is 8.25 μg (0.11 μg / kg * 75.0 kg), which is then rounded to 8.33 μg, which is 8 μg + 1 line on the pen. The eCRF will provide the calculated dose in the output, which matches the number and line on the prefilled injection pen; that is, any rounding will be automatically completed before providing the subject's calculated dose.

[0199] Trial medical representatives will be instructed and trained in the proper use of the pre-filled pens so that correct instructions can be provided to subjects.

[0200] 5.1.2 FOLLISTIM Dosing Regimen

[0201] For subjects randomized to FOLLISTIM, the dosing regimen is in the label. The starting dose of FOLLISTIM is 150 IU and is fixed for the first five stimulation days, after which it can be adjusted in 75 IU increments based on individual response. The maximum daily dose of FOLLISTIM allowed is 375 IU. Dosing will continue until the criteria for triggering final follicular maturation have been met. Subjects can be treated with FOLLISTIM for a maximum of 20 days. Coasting is not allowed. The table below details the FOLLISTIM dosing regimen.

[0202]

[0203] Subjects can be treated for up to 20 days.

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Claims

1. A composition for the treatment of infertility in a patient with AMH≥15pmol / L and body weight<60kg, the composition comprising a daily dose of 6 to 8 μg recombinant FSH or being equivalent to a daily dose of 6 to 8 μg recombinant FSH.

2. The composition for use in the treatment of claim 1, wherein the treatment of infertility comprises determining the serum AMH level and body weight of the patient.

3. A composition for treating infertility in patients with AMH≥15 pmol / L and body weight <60 kg, the composition comprising a daily dose of 6 to 8 μg recombinant FSH or being equivalent to a daily dose of 6 to 8 μg recombinant FSH.

4. The composition for use in the treatment of claim 3, wherein the treatment of infertility comprises a step of identifying the patient based on the patient's serum AMH level and body weight.

5. A composition for use in treatment according to any preceding claim, for treating a patient having or identified as having a body weight of <59 kg, such as <56 kg, such as <55 kg, such as <52 kg, such as <50 kg, such as <45 kg, such as <42 kg, such as <31.5 kg.

6. according to the compositions for the treatment of any preceding claim, it is used for the treatment of and has following AMH or is accredited as the patient with following AMH: AMH≥16pmol / L, for example AMH≥19pmol / L, for example AMH≥26pmol / L, for example AMH≥28pmol / L, for example AMH≥30pmol / L, for example AMH≥40pmol / L.

7. A composition for use in treatment according to any preceding claim, for use in treating patients identified as having a body weight < 52 kg and an AMH ≥ 26 pmol / L.

8. The composition for use in treatment according to claim 7, wherein the treatment of infertility comprises: The step of identifying the patient based on the patient's serum AMH level and body weight, and the step of administering the dose to the patient with AMH≥26pmol / L and body weight<52kg.

9. A composition for use in therapy according to any preceding claim, for use in the treatment of infertility in Asian patients.

10. A composition for use in treatment according to any preceding claim, comprising a daily dose of 6 μg recombinant FSH.

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

12. A composition for use in treatment according to any preceding claim, wherein the recombinant FSH comprises α2,3- and α2,6-sialylation.

13. A medicine for the treatment of infertility in Asian (e.g., Japanese) patients, comprising recombinant follicle-stimulating hormone (FSH); wherein the medicine is administered to Asian (e.g., Japanese) patients identified as having serum AMH levels ≥15 pmol / L and weighing less than 60 kg; and wherein the medicine is administered at a daily dose of 6 to 8 μg recombinant FSH or a daily dose equivalent to 6 to 8 μg recombinant FSH.

14. The medicament for use in treatment according to claim 14, wherein the treatment of infertility comprises: a step of determining the serum AMH level and body weight of the patient, and a step of administering the dose to the patient having the defined serum AMH level and body weight.

15. A method for treating infertility, said method comprising administering a daily dose of 6 to 8 μg Recombinant FSH or being equivalent to a daily dose of 6 to 8 μg Recombinant FSH to a patient (e.g., female patient) accredited as AMH≥15pmol / L (e.g., AMH≥16pmol / L, e.g., AMH≥19pmol / L, e.g., AMH≥26pmol / L, e.g., AMH≥28pmol / L, e.g., AMH≥40pmol / L) and accredited as body weight<60kg (e.g., body weight<55kg, e.g., <52kg, e.g., <50kg, e.g., <45kg).

16. A composition for treating infertility in patients with AMH≥26 pmol / L and body weight <52 kg, said composition comprising a daily dose of 6 to 8 μg recombinant FSH.

17. A composition for treating infertility in a patient with AMH≥26 pmol / L and body weight <61 kg, comprising a daily dose of 6 to 8 μg recombinant FSH or a daily dose equivalent to 6 to 8 μg recombinant FSH.

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