EA046202B1 - COMPOSITION FOR CONTROLLED OVARIAN STIMULATION - Google Patents

Description

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

Assisted reproductive technology (ART) techniques such as in vitro fertilization (IVF) are well known. These ART techniques usually require a stage of controlled ovarian stimulation (COS), in which a group of follicles is stimulated to full maturity. Standard COS regimens include administration of gonadotropins such as follicle-stimulating hormone (FSH), alone or in combination with luteinizing hormone (LH) to stimulate follicular development, usually with administration of a GnRH (gonadotropin-releasing hormone) analogue before and/or during stimulation to preventing premature release of LH. Pharmaceutical compositions commonly used for COS include recombinant follicle stimulating hormone (rFSH) including Rekovelle® and Gonal F, urine-derived FSH, recombinant FSH+LH formulations, urine-derived menotrophin [human menopausal gonadotropin (hMG)], and highly purified human menopausal gonadotropin (HP-hMG). IVF may be associated with a risk of ovarian hyperstimulation syndrome (OHSS), which can be life-threatening in severe cases.

The ability to predict women's likely response to controlled ovarian stimulation (COS) may allow the development of individualized COS protocols. Such individualized protocols may, for example, reduce the risk of OHSS in women predicted to have an overresponse to stimulation and/or improve pregnancy outcomes in women classified as underresponders. Serum anti-Mullerian hormone (AMH) concentration is now considered a reliable marker of ovarian reserve. Decreased AMN levels correlate with decreased ovarian response to gonadotropins during COS. In addition, high AMN levels are a good predictor of excess ovarian response and an indicator of OHSS risk.

In a pilot study of women under 35 years of age undergoing ART, the CONSORT dosing algorithm (including basal FSH, BMI (body mass index), age, and AFC (antral follicle count)) was used to predict the optimal starting dose of FSH for COS in women at risk of developing OHSS (Olivennes et al., 2009). Individualization of the dose allowed us to achieve adequate egg yield and a good pregnancy rate. However, there were high rates of discontinuation in the low dose group (75 IU (International Units) FSH) due to inadequate response, and OHSS did occur in a significant proportion of patients.

Therefore, there is a need for customized COS protocols that ensure adequate response to stimulation and/or reduced risk of OHSS.

As stated above, standard COS protocols may include administration of FSH. FSH is naturally secreted by the anterior pituitary gland and serves to support follicular development and ovulation. FSH contains a 92 amino acid alpha subunit, also common to the other glycoprotein hormones LH and CG (human chorionic gonadotropin), and a 111 amino acid beta subunit unique to FSH, which confers biological specificity to the hormone (Pierce and Parsons, 1981). Each subunit undergoes post-translational modification by the addition of complex carbohydrate residues. Both subunits carry 2 sites for N-linked glycan attachment, the alpha subunit at amino acids 52 and 78 and the beta subunit at amino acid residues 7 and 24 (Rathnam and Saxena, 1975, Saxena and Rathnam, 1976). Thus, FSH is glycosylated to approximately 30% by weight (Dias and Van Roey, 2001, Fox et al., 2001).

FSH, isolated from the urine of postmenopausal women, has been used for many years to treat infertility; both to promote ovulation during natural reproduction and to provide eggs for assisted reproduction technologies. Until recently, the only approved recombinant FSH (rFSH) products for ovarian stimulation, such as follitropin alpha (GONAL-F, Merck Serono/EMD Serono) and follitropin beta (PUREGON/FOLLISTIM, MSD/Schering-Plough), were derived from a cell line Chinese hamster ovary (CHO).

There is significant heterogeneity associated with FSH preparations, which is due to differences in the amounts of different isoforms present. Individual FSH isoforms have identical amino acid sequences but differ in the degree of their post-translational modification; specific isoforms are characterized by heterogeneity of carbohydrate branching structures and varying amounts of sialic acid (terminal sugar) incorporated, both of which appear to influence the specific biological activities of the isoforms.

Glycosylation of natural FSH is very complex. Glycans in naturally occurring pituitary FSH can contain a wide range of structures, which may include combinations of single-, double-, triple-, and quadruple-branched glycans (Pierce and Parsons, 1981, Ryan et al., 1987, Baenziger and Green, 1988). Glycans may bear additional modifications: backbone fucosylation, glucosamine at branch points, chain extension by acetyllactosamine, partial or complete sialylation, sialylation with α2,3 and α2,6 linkages, and substitution of galactose with sulfated galactosamine (Dalpathado et al., 2006). In addition, there are differences in the distribution of glycan structures among the individual

- 1 046202 glycosylation sites. Comparable levels of glycan complexity were found in FSH obtained from the serum of individuals and from the urine of postmenopausal women (Wide et al., 2007).

Glycosylation of recombinant FSH products reflects the spectrum of glycosyltransferases present in the host cell line. Commercially available rFSH products derived from genetically modified Chinese hamster ovary cells (CHO cells) have a more limited range of glycan modifications than those found in naturally occurring products. Examples of reduced glycan heterogeneity found in CHO cell-derived rFSH include the absence of glucosamine at branch points and reduced amounts of backbone fucosylation and acetyl-lactosamine extension (Hard et al., 1990). In addition, CHO cells are able to add sialic acid only using α2,3 linkages (Kagawa et al., 1988, Takeuchi et al., 1988, Svensson et al., 1990); rFSH derived from CHO cells contains only α2,3-linked sialic acid and does not include α2,6-linked sialic acid.

Thus, CHO cell-derived FSH differs from naturally occurring FSH (e.g., human pituitary/serum/urine FSH), which contains glycans with a mixture of α2,3- and α2,6-linked sialic acid, with the former predominating.

The inventors of the present invention have developed a recombinant FSH derived from a human cell line, which is the subject of international patent application No. PCT/GB2009/000978, published as WO 2009/127826 A. Recombinant FSH with a mixture of both α2,3 and α2,6-linked sialic acid was produced by engineering a human cell line to express both rFSH and α2,3-sialyltransferase. The expressed product is highly acidic and contains a mixture of both α2,3- and α2,6-linked sialic acids; the latter are provided by endogenous sialyltransferase activity. It has been found that the type of sialic acid attachment, α2,3- or α2,6-, can have a significant effect on the biological clearance of FSH. Recombinant FSH with a mixture of α2,3- and α2,6-linked sialic acid has two advantages over rFSH expressed in conventional CHO cells: first, the material is more highly stalated due to the combined activities of the two sialyltransferases; and secondly, the material is more similar to natural FSH. This is likely to be more biologically acceptable compared to recombinant products derived from CHO cells, which produce only α2,3-linked sialic acid (Kagawa et al., 1988, Takeuchi et al., 1988, Svensson et al., 1990) and have reduced sialic acid content (Ulloa-Aguirre et al. 1995, Andersen et al. 2004).

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 WO 2009/127826 A, is the native sequence and is identical to natural human FSH and existing rFSH products originating from CHO. However, the present inventors have discovered that recombinant FSH products of human origin (i.e., recombinant FSH produced or expressed in a human cell line, e.g., produced by an engineered human cell line) that have a mixture of both α2,3 and α2,6 -linked sialic acid may be particularly effective when used in COS protocols (eg, individualized).

December 2016 The European Commission (EU) granted marketing authorization to REKOVELLE® (follitropin delta, also known as FE999049), a recombinant follicle stimulating hormone derived from a human cell line (human rFSH), for use in controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART), such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). REKOVELLE® is the first rFSH derived from a human cell line. The product REKOVELLE® (follitropin delta) is obtained by the methods disclosed in international patent application No. PCT/GB2009/000978.

Two randomized, controlled, rater-blinded, parallel-group, multicenter, phase 2 studies stratified by anti-Mullerian hormone (AMH) were conducted in patients undergoing IVF/ICSI, one in Europe and one in Japan, to establish the relationship dose-response for FE 999049 and number of eggs collected. In both studies, randomization was based on stratification by AMN level at screening; low AMN (5.0-14.9 pmol/L) or high AMN (15.0-44.9 pmol/L). The European phase 2 dose-response study examined five doses of FE 999049 ranging from 5.2 µg/day to 12.1 µg/day and included a control group of the approved rFSH product (GONAL-F, 150 IU/day). day). The Japanese phase 2 study examined three doses of FE 999049 (6 μg/day, 9 μg/day, and 12 μg/day) to establish a dose-response relationship and also included an approved rFSH product (FOLLISTIM, 150 IU/day) as standard of care . Currently, follitropin beta (FOLLISTIM) is the only drug approved in Japan for controlled ovarian stimulation in IVF/ICSI cycles.

In European and Japanese phase 2 studies, the daily dose was fixed throughout the stimulation period. In both studies, a statistically significant relationship was observed

- 2 046202 dose-response bridge for FE 999049 in relation to the number of eggs collected for the entire population and for each AMN randomization group. Acceptable pregnancy rates were achieved at all doses of FE 999049. Additionally, the observed dose-response profile of FE 999049 was similar in the European and Japanese studies.

This work allowed the development of individualized COS protocols for dosing the product REKOVELLE® (follitropin delta, FE999049).

The present inventors have discovered that to be able to select two high quality eggs for transfer, it is usually necessary to collect about nine eggs.

The present inventors have found that for subjects having a low AMN (AMN less than 15 pmol/L), a sufficiently high dose of follitropin delta (eg, 12 μg) is required to achieve this. At this dose, 8-14 eggs will be collected from 60% of patients with low AMN. This is an unexpected and significant improvement over the treatment of low AMN subjects treated with 150 IU Gonal-f, where 8 to 14 eggs were collected from only 33% of subjects. The authors found that there is no need to adjust this dose according to the patient's body weight.

However, 60% of the population (and 80% of women under 30 years of age treated for infertility) have high AMN levels (i.e., AMN 15 pmol/L or more). For these subjects, it is usually quite easy to obtain an average of 9 to 11 eggs; the problem with stimulation protocols is the risk of OHSS. The present inventors have discovered that in patients receiving low doses of follitropin delta, there is a relationship between the eggs collected and the subject's body weight. This means that there may be a risk associated with fixed dose FSH treatment (as is common in this area). The present inventors have established a relationship between FSH dose and AMN level and subject weight, which provides an improved safety profile (reduced risk of OHSS) with acceptable or improved egg retrieval compared to known treatment protocols.

REKOVELLE dosing is individualized for each patient and is aimed at achieving an ovarian response associated with a favorable safety/efficacy profile, i.e., targeting sufficient egg retrieval and reducing interventions to prevent ovarian hyperstimulation syndrome (OHSS). REKOVELLE is dosed in micrograms.

For the first cycle of treatment, the individual daily dose will be determined based on the woman's serum anti-Mullerian hormone (AMH) concentration and body weight. The dose should be based on a recent AMN determination (i.e. within the last 12 months) measured using the following diagnostic test from Roche: ELECSYS AMN Plus immunoassay. The individual daily dose should be maintained throughout the stimulation period.

For women with AMN less than 15 pmol/l, the daily dose of REKOVELLE is 12 mcg, regardless of body weight.

For women with an AMN of 15 pmol/L or more, the daily dose of REKOVELLE is reduced from 0.19 to 0.10 mcg/kg as the AMN concentration increases (Table 1, below).

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

Table A

Dosage schedule

AMN (pmol/l) less 15 15-16 17 18 19-20 21-22 23-24 25-27 28-32 33-39 40 or more Fixed daily dose of REKOVELLE 12.0 mcg 0.19 µg/kg 0.18 µg/kg 0.17 µg/kg 0.16 µg/kg 0.15 µg/kg 0.14 µg/kg 0.13 µg/kg 0.12 µg/kg oh and µg/kg 0.10 µg/kg

mcg: micrograms.

AMN concentration is expressed in pmol/L and rounded to the nearest whole number. If the AMN concentration is expressed 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.

Treatment with REKOVELLE should begin on days 2 or 3 after the onset of menstrual bleeding and continue until sufficient follicular development is achieved (3 or more follicles 17 mm or more), which on average is achieved by the ninth day of treatment (from 5 to 20 days). To induce final follicular maturation, a single injection of 250 μg of recombinant human chorionic gonadotropin (hCG) or 5000 IU hCG is administered. In patients with

- 3 046202 with measured follicular development (25 or more follicles 12 mm or more), treatment with REKOVELLE should be discontinued and final follicular maturation should not be initiated with hCG.

For subsequent treatment cycles, the daily dose of REKOVELLE should be maintained or modified depending 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. In case of decreased ovarian response in the previous cycle, the daily dose in the subsequent cycle should be increased by 25 or 50% depending on the degree of response observed. In case of increased ovarian response in the previous cycle, the daily dose in the subsequent cycle should be reduced by 20 or 33% depending on the degree of response observed. In patients who developed OHSS or were at risk of OHSS in a previous cycle, the daily dose for the subsequent cycle was 33% lower than the dose in the cycle in which OHSS or risk of OHSS was observed. The maximum daily dose is 24 mcg.

The efficacy and safety of the individualized dosing regimen of FE 999049, based on the woman's serum AMN and body weight, was confirmed in the large phase 3 ESTHER-1 study (Evidence-Based Study of Human rFSH Stimulation in Europe and the Rest of the World), conducted in 11 countries, including Europe, Northern America and Latin America. The ESTHER-1 study was conducted in 1326 patients undergoing IVF/ICSI who were randomized 1:1 to controlled ovarian stimulation with one of the following treatments: 1) FE 999049 on an individual dosing schedule with a daily dose fixed throughout stimulation, or 2) an approved CHO cell-derived product, rFSH (follitropin alfa, GONAL-F), at a standard starting dose of 150 IU/day, followed by dose adjustment based on the response of the subject's ovaries during stimulation. FE 999049 was shown to be non-inferior to follitropin alfa in an individualized dosing regimen with regard to rates of ongoing pregnancy (30.7% vs. 31.6%) and ongoing implantation (35.2% vs. 35.8%). For the entire population, there were no statistically significant differences between treatment groups in terms of the number of eggs collected, with mean values of 10.0 for FE 999049 and 10.4 for follitropin alfa. However, the individualized dosing regimen of FE 999049 compared with follitropin alfa resulted in a statistically significant increase in the number of oocytes collected in patients with AMN less than 15 pmol/L (population at risk for reduced response) with a mean of 8.0 versus 7.0 and statistically significantly fewer eggs in patients with AMN 15 pmol/L or more (population at risk for increased response) with a mean of 11.6 versus 13.3. The immediate clinical significance of this shift in ovarian response with FE 999049 was revealed by the statistically significant lower number of patients with extreme ovarian response compared with follitropin alfa, i.e. less than 4 eggs among patients with AMN less than 15 pmol/L (12% vs 18% ) and 15 or more or 20 or more eggs among patients with AMN 15 pmol/L or more (28% vs. 35% and 10% vs. 16%). The percentage of patients with adequate ovarian response, defined for FE 999049 as 8-14 eggs, was achieved in significantly more patients receiving FE 999049 compared with patients receiving follitropin alfa, i.e. 43% versus 38%, despite dose adjustments during stimulation in 37% of patients in the follitropin alfa group compared with the individual fixed-dose dosing regimen of FE 999049. Total gonadotropin dose was statistically significantly lower in the FE 999049 group compared with the CHO cell-derived rFSH group, with mean values 90 mcg and 104 mcg, respectively.

The most serious risk associated with gonadotropin treatment is ovarian hyperstimulation syndrome (OHSS). Overall, in the phase 3 ESTHER-1 studies, OHSS and/or preventative interventions for early OHSS occurred in 4.4% of cycles using FE 999049 and 6.5% of cycles using follitropin alfa. Moderate/severe OHSS and/or preventive interventions for early OHSS occurred in 3.3 and 5.6% of treatment cycles with FE 999049 and follitropin alfa, respectively.

Previous studies have shown that OHSS levels in Japanese patients range from 5 to 28.3%. In the phase 2 FE 999049 study in Japan, the proportion of subjects with early moderate/severe OHSS was 19.5% in the FOLLISTIM group. Despite differences in OHSS incidence rates, the high incidence of OHSS in Japanese patients undergoing IVF/ICSI suggests that there is a clear need to select a treatment option with a safer profile regarding OHSS in Japan. Based on results from more than 1,300 cycles in the phase 3 ESTHER-1 study, the customized dosing regimen of FE 999049 was associated with a statistically significant reduction in the proportion of subjects with early OHSS and/or preventive interventions for early OHSS compared with the standard regimen of the CHO cell-derived rFSH product , while they occurred with a frequency of 4.7% in the group receiving FE 999049, and 6.2% in the group receiving follitropin alfa.

In many Asian populations (eg, Japan, China, South Korea, and India), many women have low body weight compared to women in the United States and Western Europe. Therefore, there is a risk that administering a fixed dose suitable for the European population to Asian/Japanese patients may result in these lower body weight patients becoming sexier.

- 4 046202 chat dose of FSH, which is excessively high per 1 kg of body weight. This, in turn, may lead to a risk of overresponse and OHSS in these patients. Traditional fixed-dose FSH protocols may be responsible for some of the high OHSS rates reported in Japan.

The dosing protocol given in table. And, it somewhat reduces this risk because patients are dosed based on body weight. However, very low doses of gonadotropins are potentially associated with insufficient follicular recruitment and poor ovarian response. Therefore, there is a risk that dosing in accordance with the table. This may result in patients with very low body weight and high AMN receiving a dose of FSH that may not be optimal for efficacy. Therefore, there is a need for effective dosing in low body weight patients (body weight less than 60 kg) with high AMN to simultaneously reduce the risk of overstimulation and OHSS in these patients (who may be more predisposed to this risk because they have a high AMN and low body weight).

The present inventors identified patients in the Japanese phase 2 study mentioned above (see also Example 2 below) who (based on AMN and body weight) would receive less than 6 μg of FE 999049 according to the individualized FE 999049 dosing regimen shown in Table . Ah, but actually received either 6 mcg FE 999049 or 150 IU FOLLISTIM according to randomization. This was only a very limited number of patients (5 patients in the 6 mcg FE 999049 group and 3 patients in the 150 IU FOLLISTIM group). Surprisingly, an ovarian response with maturation of 15 oocytes or more was observed in none of the 5 patients in the 6 mcg FE 999049 group, but in 2 of 3 patients (66.7%) in the 150 IU FOLLISTIM group. It is also surprising that excess follicular development requiring triggering with a GnRH agonist was observed in none of the 5 patients in the 6 mcg FE 999049 group, but in 1 of 3 patients (33.3%) in the 150 IU FOLLISTIM group . Early OHSS was observed in 1 of 5 patients (20.0%) in the 6 mcg FE 999049 group and in 1 of 3 patients (33.3%) in the 150 IU FOLLISTIM group. These data support the safety and efficacy of 6 mcg FE 999049 in Japanese patients undergoing IVF/ICSI, including patients weighing less than 60 kg and AMN 15 pmol/L or more.

The inventors of the present invention have unexpectedly discovered that, given the lower body weight in the Japanese population, a minimum dose of 6 μg can be specified to avoid underdosing in Japanese patients with low body weight and thus maintain effectiveness in these patients, avoiding side effects such as like OHSS. It is clear that this technical effect applies to any Asian population or to any population that includes patients with low body weight and high AMN, regardless of the ethnic origin of the patient.

According to the present invention, in a first aspect, there is provided a composition (for example, a pharmaceutical composition) for use in the treatment of infertility in a patient (for example, a female patient) having an AMN of 15 pmol/L or more (for example, an AMN of 16 pmol/L or more, for example, an AMN 19 pmol/L or more, for example AMN 26 pmol/L or more, for example AMN 28 pmol/L or more, for example AMN 40 pmol/L or more) and body weight less than 60 kg, wherein the composition contains a daily dose of, or daily dose equivalent to 6-8 μg of recombinant FSH. Preferably, the composition contains a daily dose of 6 to 8 μg of recombinant FSH. More preferably, the composition contains a daily dose of 6 μg of recombinant FSH.

Treatment of infertility may include the step (or steps) of determining the patient's serum AMN level and body weight. Treatment of infertility may include the step of administering a dose to a patient having a certain serum AMN level and a certain body weight. For example, treating infertility may include the step (or steps) of determining a serum AMN level and body weight of a patient and the step of administering a dose to a patient having an AMN of 15 pmol/L or more (eg, an AMN of 16 pmol/L or more, e.g., an AMN of 19 pmol /L or more, for example AMN 26 pmol/L or more, for example AMN 28 pmol/L or more, for example AMN 40 pmol/L or more) and body weight less than 60 kg [for example, body weight less than 55 kg, for example less than 52 kg, for example less than 50 kg, for example less than 45 kg].

The step of determining the level of AMN in the patient's serum can be carried out up to twelve months before the first dose of the patient. Preferably, the level of AMH in the patient's serum is determined (measured) using the ELECSYS AMH Plus immunoassay (available from Roche, Switzerland, see www.roche.com). The step of determining the patient's body weight can be carried out immediately before (for example, 0-2 days), the first dose is administered to the patient. At the stage of determining the patient's body weight, scales can be used, as is well known.

The composition (for example, a pharmaceutical composition) can be used for the treatment of infertility in a patient weighing less than 59 kg, for example less than 56 kg, for example less than 55 kg, for example less than 52 kg, for example less than 50 kg, for example less than 45 kg, for example less than 42 kg , for example less than 31.5 kg. The composition (eg, a pharmaceutical composition) can be used to treat infertility in a patient weighing 40 to 59.9 kg, for example, treating infertility in a patient weighing 45 to 55 kg. The composition can be used to treat infertility in a patient with an AMN of 16 pmol/L or more, e.g.

- 5 046202 measures AMN 19 pmol/L or more, for example AMN 26 pmol/L or more, for example AMN 28 pmol/L or more, for example AMN 30 pmol/L or more, for example AMN 40 pmol/L or more.

Preferably, the composition (for example, a pharmaceutical composition) is for use in the treatment of infertility in a patient having a body weight of less than 52 kg (for example, less than 50 kg, for example, less than 45 kg) and having an AMR of 26 pmol/L or more (for example, an AMR of 28 pmol/L). l or more, for example AMN 30 pmol/L or more, for example AMN 40 pmol/L or more). In this example, treatment of infertility may include the step of determining the serum AMN level and body weight of the patient and the step of administering a dose to the patient with an AMN of 26 pmol/L or more and a body weight of less than 52 kg.

The present invention provides in a further aspect a composition (eg, a pharmaceutical composition) for use in the treatment of infertility in a patient (eg, a female patient) identified (prior to treatment) as having an AMN of 15 pmol/L or more (eg, an AMN of 16 pmol/L or more, e.g. AMN 19 pmol/L or more, e.g. AMN 26 pmol/L or more, e.g. AMN 28 pmol/L or more, e.g. AMN 40 pmol/L or more) and identified (prior to treatment) as having a body weight of less than 60 kg, wherein the composition contains a daily dose equal to or equivalent to 6-8 μg of recombinant FSH. Preferably, the composition contains a daily dose of 6 to 8 μg of recombinant FSH. More preferably, the composition contains a daily dose of 6 μg of recombinant FSH.

Treatment of infertility may include a patient identification step (prior to treatment) based on the serum AMN level and the patient's body weight. Treatment of infertility may include the step of administering a dose to a patient who is determined to have a certain serum AMN level and a certain body weight. For example, treatment of infertility may include the step of identifying a patient (pre-treatment) based on the patient's serum AMN level and body weight, and the step of dosing a patient identified (pre-treatment) as having an AMN of 15 pmol/L or more (eg AMN 16 pmol/L or more, e.g. AMN 19 pmol/L or more, e.g. AMN 26 pmol/L or more, e.g. AMN 28 pmol/L or more, e.g. AMN 40 pmol/L or more) and identified (prior to treatment ) as having a body weight of less than 60 kg [for example, a body weight of less than 55 kg, for example less than 52 kg, for example less than 50 kg, for example less than 45 kg].

The patient identification step (pre-treatment) based on the serum AMN level and the patient's body weight may occur immediately before (eg, 0 to 2 days before) the patient's first dose. The patient identification step may be based on a previously determined serum AMN level (eg, a serum AMN level determined up to twelve months prior to the first dosing of the patient). Preferably, the level of AMH in the patient's serum is determined (measured) using the ELECSYS AMH Plus immunoassay (available from Roche, Switzerland, see www.roche.com). The patient identification step may be based on the patient's body weight determined immediately before (eg, 0-2 days) the patient is first dosed. At the stage of determining the patient's body weight, scales can be used, as is well known.

The composition (eg, a pharmaceutical composition) can be used to treat infertility in a patient identified (prior to treatment) as having a body weight of less than 59 kg, for example less than 56 kg, for example less than 55 kg, for example less than 52 kg, for example less than 50 kg, for example less than 45 kg, for example less than 42 kg, for example less than 31.5 kg. The composition (eg, a pharmaceutical composition) may be used to treat infertility in a patient identified (prior to treatment) as having a body weight of 40 to 59.9 kg, for example, to treat infertility in a patient weighing 45 to 55 kg. The composition can be used for the treatment of infertility in a patient identified (prior to treatment) as having an AMR of 16 pmol/L or more, for example an AMR of 19 pmol/L or more, for example an AMR of 26 pmol/L or more, for example an AMR of 28 pmol/L or more, for example AMN 30 pmol/L or more, for example AMN 40 pmol/L or more.

Preferably, the composition (eg, a pharmaceutical composition) is for use in the treatment of infertility in a patient identified (prior to treatment) as having a body weight of less than 52 kg (eg, less than 50 kg, such as less than 45 kg) and identified (prior to treatment) as having an AMR of 26 pmol/L or more (for example, an AMR of 28 pmol/L or more, for example an AMR of 30 pmol/L or more, for example an AMR of 40 pmol/L or more). In this example, treatment for infertility may include the step of identifying a patient (prior to treatment) based on the serum AMN level and the patient's body weight, and the step of dosing a patient identified (prior to treatment) as having an AMN of 26 pmol/L or more and identified (before treatment) as having a body weight of less than 52 kg.

Preferably, the FSH is recombinant FSH (rFSH). Preferably, rFSH (eg, recombinant FSH derived from a human cell line) includes α2,3- and α2,6-sialylation. FSH (rFSH) for use in accordance with the invention may have an α2,3 sialylation representing from 1 to 99% of the total sialylation. FSH (rFSH) according to the invention may have a2,6-sialylation, representing from 1 to 99% of the total sialylation. Preferably, the a2,3-sialylation is from 80 to 95%, for example from 80 to 90%, for example from 82 to 89%, for example from

- 6 046202 up to 89% of total sialylation. Preferably, the α2,6-sialylation represents 5 to 20%, eg 10 to 20%, eg 11 to 18%, eg 11 to 15% of the total sialylation. Sialation refers to the number of sialic residues present in the carbohydrate structures of FSH. α2,3-sialylation means sialylation at position 2,3 (as is well known in the art) and α2,6-sialylation at position 2,6 (also well known in the art). Thus, α2,3-sialylation representing ...% of total sialylation refers to the % of total sialic acid residues present in the sialylated FSH at position 2,3. The term a2,6-sialylation representing ...% of total sialylation refers to the % of total sialic acid residues present in the sialylated FSH at position 2,6. rFSH may be present as a single isoform or as a mixture of isoforms.

The composition can be used to treat infertility in an Asian patient (eg, a Japanese, Chinese, Korean, Indian patient, such as a patient of the Han, Yamato or Korean ethnic group).

According to the present invention, in an additional aspect, there is provided a medicament for treating infertility in an Asian patient (eg, Japanese, Chinese, Korean, Indian patient) comprising follicle stimulating hormone (FSH), preferably recombinant FSH; wherein the drug is administered to an Asian patient (eg, Japanese, Chinese, Korean, Indian patient) identified (prior to treatment) as having a serum AMN level of 15 pmol/L or more (eg, AMN 16 pmol/L or more, e.g. AMN 19 pmol/L or more, e.g. AMN 28 pmol/L or more) and identified (prior to treatment) as having a body weight of less than 60 kg; wherein the drug is administered in a daily dose, a component, or a daily dose equivalent to 6-8 μg of recombinant FSH. Preferably, the daily dose is from 6 to 8 μg of recombinant FSH. More preferably, the daily dose is 6 μg of recombinant FSH.

Treatment of infertility may include a patient identification step (prior to treatment) based on the serum AMN level and the patient's body weight. Treatment of infertility may include the step of administering a dose to a patient who has a certain serum AMN level and a certain body weight. For example, treatment of infertility may include the step of identifying a patient (pre-treatment) based on the patient's serum AMN level and body weight, and the step of dosing a patient identified (pre-treatment) as having an AMN of 15 pmol/L or more (eg AMN 16 pmol/L or more, e.g. AMN 19 pmol/L or more, e.g. AMN 26 pmol/L or more, e.g. AMN 28 pmol/L or more, e.g. AMN 40 pmol/L or more) and identified (prior to treatment ) as having a body weight of less than 60 kg [for example, the body weight is less than 55 kg, for example less than 52 kg, for example less than 50 kg, for example less than 45 kg].

The patient identification step (pre-treatment) based on the serum AMN level and the patient's body weight may occur immediately before (eg, 0-2 days) the patient's first dose. The patient identification step may be based on a previously determined serum AMN level (eg, a serum AMN level determined twelve months prior to the patient's first dose). Preferably, the level of AMH in the patient's serum is determined (measured) using the ELECSYS AMH Plus immunoassay (available from Roche, Switzerland, see www.roche.com). The patient identification step may be based on the patient's body weight, which is determined immediately prior (eg, 0-2 days) to the first dosing of the patient. At the stage of determining the patient's body weight, scales can be used, as is well known.

As used herein, the first day of treatment, also referred to as the first day of stimulation, refers to the first day that the patient is dosed with FSH (eg, recombinant). The first day of treatment (stimulation) can occur on days 1, 2 or 3, preferably on days 2 or 3 of the patient’s menstrual cycle. In other words, the first day of treatment (stimulation) may be one, two or three days, preferably two or three days, after the patient begins menstrual bleeding, as is well known in the art.

FSH dosing begins on the first day of treatment and can continue for two to twenty days, for example continue for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11, 13, 14, 15, 16, 17, 18, 19 or 20 days. Dosing of FSH begins on the first day of treatment and may continue for seven to thirteen days, for example nine to thirteen days, for example 10 to 13 days, for example 10 to 11 days. FSH can be administered at a dose equivalent to the daily doses given above. For example, the composition may be designed to be administered at a dose of 18 μg of FSH every three days (eg, to be administered on days 1, 4, 7, etc.).

The composition (e.g., pharmaceutical composition) or drug may be administered after the subject has been pretreated with a (other) pharmaceutical composition that suppresses endogenous gonadotropin production prior to the first day of FSH treatment (e.g., after the subject has been pretreated with a steroid, GnRH agonist, GnRH antagonist and so on). As used in this document, the term pre-treatment or receiving pre-treatment

- 7 046202 treatment refers to the administration of a pharmaceutical composition that suppresses the production of endogenous gonadotropin until the first day of treatment with FSH and hCG. This is well known in the art. Thus, the composition (e.g., pharmaceutical composition) or drug may be intended for administration 12-16, e.g., 13-15, e.g., 14 days after administration (e.g., after initiation of administration, e.g., after initiation of daily administration) GnRH agonist (eg, Synarel, Lupron, Decapeptyl). The product may be intended to be administered with a GnRH agonist.

In other examples, the composition (eg, pharmaceutical composition) or drug may be intended to be administered before the administration of a GnRH antagonist (eg, ganirelix, cetrorelix), for example, for administration five or six days before the administration of the GnRH antagonist. The product may be intended for administration with a GnRH antagonist.

Preferably, the composition (eg, pharmaceutical composition) or drug is intended to be administered prior to administration of a high (ovulatory) dose of hCG (eg, 4,000 to 11,000 IU hCG, e.g., 5,000 IU hCG, 10,000 IU hCG, etc.; or 150 to 350 µg recombinant hCG, eg 250 µg recombinant hCG) to induce final follicular maturation.

The above doses can be used for the treatment of infertility in the first stimulation protocol of the patient (subject). It is understood that for further stimulation cycles, doses can be adjusted according to the actual ovarian response in the first cycle.

The inventors of the present invention have developed individualized COS protocols in which specific doses of recombinant FSH having specific characteristics are used to treat patients based on their specific AMN levels, thereby increasing the likelihood of an adequate response to stimulation (for example, in patients with a possible poor response), and /or reduced risk of OHSS (eg, in patients classified as high or excessive responders).

The level of AMN in serum can be determined (eg, measured) by any method known in the art. Serum AMN levels can be measured using the Gen-II AMN enzyme immunoassay kit (Beckman Coulter, Inc., Webster, Texas). This assay can detect AMN concentrations greater than 0.57 pmol/L, with a lower limit of quantitation of 1.1 pmol/L. Serum AMN levels can be measured using the ACCESS automated AMN assay (Beckman Coulter, Inc., Webster, Texas). Preferably, the serum AMN level is measured using the Elecsys® AMN assay from Roche Diagnostics. Other tests can also be used.

In this document, serum AMN values are generally reported in pmol/L. These can be converted to ng/mL using the formula 1 ng/mL AMN = 7.1 pmol/L AMN.

Throughout this document, the terms patient and subject are used interchangeably.

As used herein, the term infertility treatment includes treatment of infertility using controlled ovarian stimulation (COS) or methods that include a stage or step of controlled ovarian stimulation (COS), such as intrauterine insemination (IUI), in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). ). The term infertility treatment covers the treatment of infertility by ovulation induction (OI) or methods that include the step or step of ovulation induction (OI). The term infertility treatment includes treatment of infertility in a subject having tubal or unexplained infertility, including treatment of infertility in a subject having endometriosis, such as stage I or II endometriosis, and/or in a subject suffering from anovulatory infertility, such as WHO type II anovulatory infertility ( World Health Organization) and/or in a subject who has a partner with male infertility. The product (or composition) may be intended for the treatment (use in the treatment) of infertility (and/or for controlled ovarian stimulation) in a subject suffering from endometriosis, for example in a subject having stage I or II endometriosis, according to the classification system for the various stages of endometriosis proposed American Society for Reproductive Medicine (ASRM) (most severe stage IV; least severe stage I) [American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67.817 821].

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

The composition or medicament may be intended for the treatment (use in treatment) of infertility (and/or for controlled ovarian stimulation) in a subject between 18 and 42 years of age, for example 25 to 37 years. The product may be intended for the treatment (use in treatment) of infertility (and/or for controlled ovarian stimulation) in a subject having a BMI greater than 1 and a BMI less than 35 kg/m ² , for example a subject having a BMI greater than 18 and a BMI less than 25 kg/m2. ^m2 , for example, having a BMI of more than 20 and a BMI of less than 25 kg/ ^m2 .

- 8 046202

Recombinant FSH can be produced or expressed in a human cell line, such as the Per.C6 cell line, the HEK293 cell line, the HT1080 cell line, and so on. This may simplify (and make more efficient) the production process since, for example, manipulation and control of, for example, cell growth media to maintain sialylation may be less critical than with known processes. The method may also be more efficient because little basic rFSH is produced compared to the production of known rFSH products; more acidic rFSH is produced and separation/removal of basic FSH is less problematic. rFSH can be produced or expressed in a PER.C6® cell line, a PER.C6®-derived cell line, or a modified PER.C6® cell line. rFSH that is produced or expressed in a human cell line (e.g., PER.C6® cell line, HEK293 cell line, HT1080 cell line, etc.) will include some α2,6-linked sialic acids (α2,6sialylation) provided by the endogenous sialyltransferase activity of the [cell line], and will involve some α2,3-linked sialic acids (α2,3-sialylation) provided by endogenous sialyltransferase activity. The cell line can be modified using α2,3-sialyltransferase. The cell line can be modified using α2,6-sialyltransferase. Alternatively or additionally, rFSH may include α2,6-linked sialic acids (α2,6-sialylation) provided by the endogenous sialyltransferase activity of the [cell line]. As used herein, the term recombinant FSH of human origin means recombinant FSH produced or expressed by a human cell line (eg, recombinant FSH obtained by engineering a human cell line).

rFSH can be produced using α2,3- and/or α2,6-sialyltransferase. In one example, rFSH is produced using a2,3-sialyltransferase. Recombinant FSH may include α2,6-linked sialic acids (α2,6-sialylation) provided by endogenous sialyltransferase activity.

The composition may be a pharmaceutical composition. The pharmaceutical composition is intended for the treatment of infertility. Fertility treatments may include assisted reproductive technology (ART), ovulation induction, or intrauterine insemination (IUI). The pharmaceutical composition can be used, for example, for medical indications where known FSH preparations are used.

The composition or drug can be formulated in the form of well-known compositions for any route of administration of the drug, for example, oral, rectal, parenteral, transdermal (for example, by patch), intravenous, intramuscular, subcutaneous, intrasternal, intravaginal, intraperitoneal, topical (powders , ointments or drops) or as a buccal or nasal spray. A typical composition contains a pharmaceutically acceptable carrier such as an aqueous solution, non-toxic excipients including salts and preservatives, buffers and the like, as described in the fifteenth edition of Remington's Pharmaceutical Sciences (Matt Publishing Company, 1975), on pages 1405 to 1412 and 1461 - 87, and National Formulary XIV Fourteenth Edition (American Pharmaceutical Association, 1975), among others.

Examples of suitable aqueous and non-aqueous pharmaceutical carriers, diluents, solvents or carrier vehicles include water, ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. The compositions or drugs of the present invention may also contain additives such as, but not limited to, preservatives, wetting agents, emulsifying agents, surfactants and dispersing agents. Antibacterial and antifungal agents may be included to prevent microbial growth and include, for example, m-cresol, benzyl alcohol, paraben, chlorobutanol, phenol, sorbic acid and the like. If a preservative is included, benzyl alcohol, phenol and/or m-cresol are preferred; however, the preservative is in no way limited to these examples. In addition, it may be desirable to include isotonic agents such as sugars, sodium chloride and the like.

The composition or drug may further comprise a salt containing a pharmaceutically acceptable alkali metal cation selected from the group consisting of Na ⁺ or K ⁺ salts, or a combination thereof. Preferably, the salt is a Na ⁺ salt, for example NaCl or Na ₂ SO ₄

Preferably, the composition or drug contains recombinant FSH and one or more of polysorbate 20, L-methionine, phenol, disodium sulfate and sodium phosphate buffer.

In some cases, to achieve prolonged action, it is desirable to slow the absorption of FSH (and other active ingredients, if present) by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility. The rate of absorption of FSH then depends on

- 9 046202 the rate of its dissolution, which, in turn, may depend on the size of the crystals and the crystalline form. Alternatively, delayed absorption of a parenterally administered FSH combination form is achieved by dissolving or suspending the FSH combination in an oil vehicle. Injectable depot forms can be prepared by forming microcapsule matrices with FSH (and other agents if present) in biodegradable polymers such as polylactide polyglycolide. Depending on the ratio of FSH to polymer and the nature of the particular polymer used, the rate of release of FSH can be controlled. Examples of other biodegradable polymers include polyvinylpyrrolidone, poly(orthoesters), poly(anhydrides), etc. Injectable depot formulations are also prepared by entrapping FSH in liposomes or microemulsions that are compatible with body tissues.

Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injection medium immediately prior to use. Injectable preparations may be supplied in any suitable container, such as a vial, a pre-filled syringe, injection cartridges, and the like.

The composition or medicament may be formulated for single or repeated use (multiple dose). If the composition or drug is prepared for repeated use, it is preferable that a preservative be included. If a preservative is included, benzyl alcohol, phenol and/or m-cresol are preferred; however, the preservative is in no way limited to these examples. The composition or drug for single or multiple use may further comprise a salt containing a pharmaceutically acceptable alkali metal cation selected from the group consisting of Na ⁺ or K ⁺ salts, or a combination thereof. Preferably, the salt is a Na ⁺ salt, for example NaCl or Na ₂ SO ₄ .

The composition or drug may be included in a container such as a vial, a prefilled cartridge (eg, for single administration or multiple use), or an injection device such as a pen, for example, for multiple doses.

The composition or drug may be a composition (eg, an injectable composition) comprising FSH (possibly with hCG, LH, LH activity, etc.). The source of LH activity, if present, may be LH or human chorionic gonadotropin, hCG. If there is more than one active ingredient (ie FSH and, for example, hCG or LH) they may be suitable for administration separately or together. If the administration is separate, the administration may be sequential. The composition or medicament may be supplied in any suitable packaging. For example, the composition or drug may include multiple containers (eg, prefilled syringes or vials) containing either FSH or hCG, or a combination (or combination) of both FSH and hCG. hCG may be recombinant hCG or urine hCG. If the composition or drug includes multiple containers (eg, prefilled syringes or vials) containing FSH, such as recombinant FSH, each container may include the same amount of FSH. One or more containers may include varying amounts of FSH. Syringes or vials may be packaged in blister packs or other means to maintain sterility. Any composition or drug may possibly contain instructions for use of FSH formulations (and, for example, hCG, if present). The pH value and the exact concentration of the various components of the pharmaceutical composition are optimized in accordance with standard practice in this field. See Goodman and Gilman's The Pharmacological basis for therapeutics, 1st ed. In a preferred embodiment, the composition or medicament of the invention is supplied in the form of compositions for parenteral administration. General methods for preparing parenteral compositions are known in the art and are described in REMINGTON; The science and practice of pharmacy, see above, pages 780-820. Parenteral compositions may be supplied as a liquid composition or as a solid to be mixed with a sterile injection medium immediately prior to administration. In a particularly preferred embodiment, the parenteral compositions are supplied in unit dosage form for ease of administration and uniformity of dosage.

According to the present invention, in a further aspect, there is provided a method for treating infertility, comprising the step of administering a daily component dose or daily dose equivalent to 6-8 μg of recombinant FSH to a patient (eg, a female patient) with an AMN of 15 pmol/L or more ( e.g. AMN 16 pmol/L or more, e.g. AMN 19 pmol/L or more, e.g. AMN 26 pmol/L or more, e.g. AMN 28 pmol/L or more, e.g. AMN 40 pmol/L or more) and body weight less than 60 kg [for example, with a body weight of less than 55 kg, for example less than 52 kg, for example less than 50 kg, for example less than 45 kg, for example less than 42 kg, for example less than 31.5 kg]. Preferably, the daily dose is from 6 to 8 μg of recombinant FSH. More preferably, the daily dose is 6 μg of recombinant FSH.

The method may include the step of determining serum AMN levels and body weight of the patient. The method may include the step of administering a dose to a patient having a certain serum AMN level and body weight. For example, the method may include the step of determining the level of AMN in

- 10 046202 serum and body weight of the patient and the stage of dosing to the patient having an AMR of 15 pmol/L or more (for example, an AMR of 16 pmol/L or more, for example, an AMR of more than 19 pmol/L, for example, an AMR of 26 pmol/L or more, for example AMN 28 pmol/L or more, for example AMN 40 pmol/L or more) and body weight less than 60 kg (for example, body weight less than 55 kg, for example less than 52 kg, for example less than 50 kg, for example less than 45 kg, for example less than 42 kg, for example less than 31.5 kg).

According to the present invention, in a further aspect, there is provided a method of treating infertility, comprising the step of administering a daily dose of, or a daily dose equivalent to, 6-8 μg of recombinant FSH to a patient (eg, a female patient) identified (prior to treatment) as having AMN 15 pmol/L or more (eg AMN 16 pmol/L or more, e.g. AMN 19 pmol/L or more, e.g. AMN 26 pmol/L or more, e.g. AMN 28 pmol/L or more, e.g. AMN 40 pmol/L or more) and identified (prior to treatment) as having a body weight of less than 60 kg (for example, a body weight of less than 55 kg, for example less than 52 kg, for example less than 50 kg, for example less than 45 kg). Preferably, the daily dose is from 6 to 8 μg of recombinant FSH. More preferably, the daily dose is 6 μg of recombinant FSH.

The method may include the step of identifying a patient (prior to initiation of treatment) based on the serum AMN level and the patient's body weight. The method may include the step of administering a dose to a patient identified as having a certain serum AMN level and a certain body weight. For example, the method may include the step of identifying a patient (pre-treatment) based on a serum AMN level and the patient's body weight, and the step of administering a dose to a patient identified (pre-treatment) as having an AMN of 15 pmol/L or more (e.g., AMN 16 pmol/L or more, e.g. AMN 19 pmol/L or more, e.g. AMN 26 pmol/L or more, e.g. AMN 28 pmol/L or more, e.g. AMN 40 pmol/L or more) and identified (before treatment) as having a body weight of less than 60 kg [for example, a body weight of less than 55 kg, for example less than 52 kg, for example less than 50 kg, for example less than 45 kg].

The method can be used to treat infertility in an Asian patient (for example, Japanese, Chinese, Korean, Indian).

Preferably, the patient has (identified as having) a body weight of less than 52 kg (for example, less than 50 kg, for example, less than 45 kg) and has (identified as having) an AMR of 26 pmol/L or more (for example, an AMR of 28 pmol/L or more), for example AMN 30 pmol/L or more, for example AMN 40 pmol/L or more).

Preferably, the FSH is recombinant FSH (rFSH). Preferably, rFSH (eg, recombinant FSH derived from a human cell line) includes α2,3- and α2,6-sialylation. FSH (rFSH) for use in accordance with the invention may have an α2,3 sialylation representing from 1 to 99% of the total sialylation. FSH (rFSH) according to the invention may have a2,6-sialylation, representing from 1 to 99% of the total sialylation. Preferably, 80 to 95%, eg 80 to 90%, eg 82 to 89%, eg 85 to 89% of the total sialylation is a2,3-sialylation. Preferably, 5 to 20%, eg 10 to 20%, eg 11 to 18%, eg 11 to 15% of the total sialylation is α2,6 sialylation. Sialation refers to the number of sialic residues present in the carbohydrate structures of FSH. α2,3-sialylation means sialylation at position 2,3 (as is well known in the art), and α2,6-sialylation means sialylation at position 2,6 (also well known in the art). Thus, % of total sialylation may represent α2,3-sialylation refers to the % of total sialic acid residues present in FSH that are sialylated at position 2,3. The term % total sialylation, which is α2,6 sialylation, refers to the % of the total sialic acid residues present in FSH that are sialylated at position 2,6. Recombinant FSH may be present as a single isoform or as a mixture of isoforms.

According to the present invention, in one aspect, a composition is provided for use in the treatment of infertility in a patient with an AMI of 26 pmol/L or more and a body weight of less than 52 kg, where the composition contains a daily dose of recombinant FSH from 6 to 8 μg. Preferably, the patient has (identified as having) a body weight of less than 52 kg (e.g. less than 50 kg, e.g. less than 45 kg) and has (identified as having) an AMR of 26 pmol/L or more (e.g. an AMR of 28 pmol/L or more, e.g. AMN 30 pmol/L or more, for example AMN 40 pmol/L or more).

In accordance with the present invention, in another aspect, a composition is provided for use in the treatment of infertility in a patient with an AMN of 26 pmol/L or more and a body weight of less than 61 kg, wherein the composition contains a daily dose equal to or a daily dose equivalent to 6-8 μg of recombinant FSH. Preferably, the patient has (identified as having) a body weight of less than 52 kg (e.g. less than 50 kg, e.g. less than 45 kg) and has (identified as having) an AMR of 26 pmol/L or more (e.g. an AMR of 28 pmol/L or more, e.g. AMN 30 pmol/L or more, for example AMN 40 pmol/L or more).

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Detailed Description of the Invention

The present invention will now be described in more detail with reference to the following examples and FIGS. 1, which shows the body weight and AMN of all patients in the phase II clinical study in Japan discussed in the post-hoc analysis in Example 3, and shows what dose of Rekovelle® was administered according to the dosing protocol presented in Table 1. And above, less than 6 mcg (diamonds) or 6 mcg or more.

Example 1. Rekovelle.

Rekovelle® is a recombinant FSH expressed in the PER.C6® cell line constructed by the methods described in WO 2013/020996 and WO 2009/127826 A.

The marketing authorization holder for Rekovelle® is Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, 2300, Copenhagen, Denmark, and in the UK, Ferring Pharmaceuticals, Drayton Hall, Church Road, West Drayton, UB7 7PS, UK.

The active substance in Rekovelle® is follitropin delta (FE999049).

Rekovelle is highly stalylated and includes α2,3 and a2,6 stalylation, with about 85 to 90% of the total sialylation being a2,3 stalylation and about 10 to 15% of the total sialylation being a2,6 stalylation.

REKOVELLE is a clear and colorless solution for injection (injection). It is available in packs of 1 cartridge and 3 pens with needles. Each multi-dose cartridge contains 12 micrograms of follitropin delta per 0.36 milliliter solution. One milliliter of solution contains 33.3 micrograms of delta follitropin in each 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.

Example 2: Randomized, rater-blind, AMH-stratified dose-response study in Japanese patients undergoing IVF/TICSI undergoing controlled ovarian stimulation with follitropin delta.

Randomized, controlled, assessor-blinded, multicenter, parallel-group, phase 2 studies stratified by anti-Mullerian hormone (AMH) were conducted in patients undergoing IVF/ICSI in Japan to establish the dose-response relationship for FE 999049 and the number of eggs collected . Randomization was based on stratification by AMN level at screening: low AMN (5.0–14.9 pmol/L) or high AMN (15.0–44.9 pmol/L).

There were 158 patients, aged 20 to 39 years (mean age 33.7 years), who underwent COS with three dose levels of FE 999049, follitropin delta (Ferring Pharmaceuticals). Doses of FE 999049 were 6 μg/day, 9 μg/day, and 12 μg/day, and also included standard of care therapy using an approved rFSH product (FOLLISTIM, MSD, 150 IU/day) as a control. Currently, follitropin beta (FOLLISTIM) is the only drug product approved in Japan for controlled ovarian stimulation in IVF/ICSI cycles.

Patients were randomized to receive fixed doses of 6 mcg/day, 9 mcg/day, and 12 mcg/day FE 999049 (n = 117) or 150 IU follitropin beta (n = 41). Randomization was based on stratification by AMN level (low AMN, 5.0–14.9 pmol/L; high AMN, 15.0–44.9 pmol/L; Elecsys ® AMN, Roche Diagnostics). Gonadotropin was started on days 2-3 of the menstrual cycle. Ganrelix 0.25 mg/day was added from the 6th day of stimulation, and the initiation of final follicular maturation was carried out on the day when 3 or more follicles with a diameter of 17 mm or more were observed. OHSS was assessed using the Golan classification.

The daily dose was fixed throughout the stimulation period. A statistically significant dose-response relationship for FE 999049 by number of eggs collected was observed for the entire population and for each AMN randomization arm. Acceptable pregnancy rates were achieved at all doses of FE 999049.

In this study, patients were not dosed based on body weight, and no patients received a dose of FE 999049 below 6 mcg/day. In this study, patients were not identified prior to treatment by the combination of AMN and body weight.

Example 3: Retrospective analysis of a phase II study.

In many Asian countries (eg, Japan, China, South Korea, and India), many women have low body weight compared to women in the United States and Western Europe. Thus, there is a risk that administering a fixed dose suitable for European populations to Asian/Japanese patients may result in low body weight patients receiving a dose of FSH that is high per kg body weight. This, in turn, may lead to a risk of overresponse and OHSS in these patients. Traditional fixed-dose FSH protocols may be responsible for some of the high OHSS rates in Japanese studies.

The dosing protocol given in table. And above, in some way reduces this risk, since patients receive a dose based on body weight. However, very low doses of gonadotropins are potentially associated with insufficient follicular recruitment and poor ovarian response

- 12 046202 kov. Therefore, there is a risk that dosing according to the protocol in Table. This may result in patients with very low body weight and high AMN receiving a dose of FSH that may not be optimal for efficacy. Therefore, there is a need for effective dosing in low body weight (less than 60 kg) patients with high AMN to simultaneously reduce the risk of overstimulation and OHSS in these patients (who may be more predisposed to this risk because they have a high AMN and low body mass).

Overall, there were no safety concerns at the FE 999049 6 mcg dose in the Japanese phase 2 study. The safety profile was retrospectively studied in Japanese phase 2 study patients weighing less than 60 kg. As context for the observations in the 6 μg FE 999049 group, data for the control treatment group with FOLLISTIM are also shown. In table Table 1 provides safety parameters related to ovarian response.

Table 1 Comparison of safety parameters of ovarian response for subjects less than 60 kg receiving 6 mcg FE 999049 or 150 IU FOLLISTIM - overall data

FE 999049 FOLLISTIM mcg 150 IU (n equals 29) (n equals 33)

η % η % Early OHSS 4 13.8% 8 24.2% Early moderate/severe OHSS 3 10.3% 7 21.2% Triggering by GnRH agonist 1 3.0% 15-19 eggs collected 1 3.4% 5 15.2% 20 or more eggs collected 2 6.1%

Among patients weighing less than 60 kg, the total number of patients with early OHSS was 4 (13.8%) in the 6 mcg FE 999049 group and 8 (24.2%) in the 150 IU FOLLISTIM group. Early moderate/severe OHSS was observed in 3 (10.3%) patients and 7 (21.2%) patients in the 6 mcg FE 999049 and 150 IU FOLLISTIM groups, respectively. Additionally, egg yields greater than the proper response of 8-14 eggs were observed in only 1 patient (3.4%) in the 6 mcg FE 999049 group, as opposed to 7 patients (21.2%) in the 150 mcg group. IU FOLLISTIM. Excessive follicular development to the extent requiring GnRH agonist treatment was not observed in any patient in the 6 mcg FE 999049 group, but occurred in 1 patient in the 150 IU FOLLISTIM group. In summary, in patients weighing less than 60 kg, the ovarian safety response profile appeared to be better when receiving 6 mcg FE 999049 compared with 150 IU FOLLISTIM.

Table 1 covers all patients weighing less than 60 kg, regardless of the level of AMN. All patients with an AMR less than 15 pmol/L will receive 12 mcg of FE 999049. Therefore, a situation where a patient's estimated dose may be less than 6 mcg, but the patient will receive 6 mcg, only applies to patients with an AMR of 15 pmol/L or more. Data for patients in the Japanese phase 2 study who had a body weight of less than 60 kg and an AMN of 15 pmol/L or more are presented in Table 1. 2.

Table 2 Comparison of safety parameters of ovarian response for subjects less than 60 kg receiving 6 mcg FE 999049 or 150 IU FOLLISTIM - high level AMN

FE 999049 FOLLISTIM mcg 150 IU (n equals 18) (n equals 22)

η % η % Early OHSS 4 22.2% 7 31.8% Early moderate/severe OHSS 3 16.7% 6 27.3% Triggering by GnRH agonist 1 4.5% 15-19 eggs collected 1 5.6% 4 18.2% 20 or more eggs collected 2 9.1%

Among patients weighing less than 60 kg and AMN 15 pmol/L or more, the total number of patients with early OHSS was 4 (22.2%) in the 6 mcg FE 999049 group and 7 (31.8%) in the group receiving 6 mcg FE 999049.

- 13 046202 who received 150 IU FOLLISTIM. Moderate/severe OHSS was the most common severity among early OHSS cases and was reported in 3 (16.7%) patients in the 6 mcg FE 999049 group and 6 (27.3%) patients in the 150 IU group FOLLISTIM. While only 1 patient (5.6%) in the 6 mcg FE 999049 group had 15-19 eggs collected, this was the case in 4 patients (18.2%) in the 150 IU FOLLISTIM group. where an additional 2 (9.1%) patients had 20 or more eggs retrieved. GnRH agonist triggering due to excessive follicular development was not required in the 6 mcg FE 999049 group, but was required in 1 patient in the 150 IU FOLLISTIM group. In conclusion, controlled ovarian stimulation with 6 mcg FE 999049 in patients weighing less than 60 kg and with an AMN of 15 pmol/L or more 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.

Regarding the profile of adverse events in patients weighing less than 60 kg, the incidence of adverse events considered by investigators to be related to the drug used for controlled ovarian stimulation was 20.7% in the group receiving 6 mcg FE 999049, and 33 .3% in the group receiving 150 IU FOLLISTIM. Among patients weighing less than 60 kg and AMN 15 pmol/L or more, the incidence of related adverse events was 27.8% in the group receiving 6 mcg FE 999049 and 36.4% in the group receiving 150 IU FOLLISTIM.

In terms of efficacy, among patients weighing less than 60 kg, the clinical pregnancy rate per transfer cycle was 40.0% in the group receiving 6 mcg FE 999049 and 21.7% in the group receiving standard therapy. Among patients weighing less than 60 kg and AMN 15 pmol/L or more, the clinical pregnancy rate per transfer cycle was 38.5% and 20.0% in the 6 mcg FE 999049 and standard therapy groups, respectively.

Finally, Ferring identified patients in the Japanese phase 2 study who, based on AMN and body weight, would have received less than 6 mcg of FE 999049 according to the individualized FE 999049 dosing regimen (Table A above), but in this study received either 6 mcg of FE 999049 , or 150 IU FOLLISTIM according to randomization. This was only a very limited number of patients (5 patients in the 6 mcg FE 999049 group and 3 patients in the 150 IU FOLLISTIM group), but the safety data for ovarian response were consistent with those previously reported. An ovarian response of 15 or more eggs was not observed in any of the 5 patients in the 6 mcg FE 999049 group, but was observed in 2 of 3 patients (66.7%) in the 150 IU FOLLISTIM group. Excessive follicular development requiring GnRH agonist triggering was not observed in any of the 5 patients in the 6 mcg FE 999049 group, but was observed in 1 of 3 patients (33.3%) in the 150 IU FOLLISTIM group. Early OHSS was observed in 1 of 5 patients (20.0%) in the 6 mcg FE 999049 group and in 1 of 3 patients (33.3%) in the 150 IU FOLLISTIM group.

In other words, the inventors of the present invention unexpectedly discovered that, taking into account the lower body weight in the Japanese population, the minimum dose can be adjusted to 6 μg to avoid underdosing in Japanese patients with low body weight and thus maintain effectiveness in these patients, when this while avoiding side effects such as OHSS.

In addition to the safety and efficacy data of 6 μg FE 999049 in the Japanese phase 2 study supporting the appropriateness of this dose, simulations were performed using the dose-response model that was assessed in the Japanese phase 2 study. The purpose of these simulations is to estimate the expected difference in egg counts for a proposed dosing regimen where the lowest dose is 6 mcg compared to a dosing regimen where doses are allowed to be less than 6 mcg. Based on the body weight and AMN levels of all 158 randomized patients in the Japanese phase 2 study, 18 (11%) would receive a 6 mcg dose according to the proposed dosing regimen instead of the estimated dose of less than 6 mcg. All of these patients had a body weight of less than 52 kg and an AMN value greater than 26 pmol/L, as shown in FIG. 1, which presents the body weight and AMN of all patients in the study. In fig. 1, these 18 patients are indicated by diamonds (rather than squares) in the lower right corner.

In 18 patients with an estimated dose of less than 6 mcg, the average estimated dose is 5.33 mcg, and therefore the average dose under the proposed dosing regimen is 13% higher compared to the regimen where there is no minimum (average dose 6.0 mcg instead of 5. 33 mcg).

Using 6 mcg as a minimum dose is expected to have a positive effect on ovarian response. The proposed dosing regimen, where the minimum dose is 6 mcg, is expected to achieve the goal of 8-14 eggs collected in more patients for whom the estimated dose is less than 6 mcg (48.0% of patients compared to 44.8% with scheme without establishing a minimum dose), as shown in Table. 3.

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Table 3

Predicted outcome in Japanese patients with an estimated dose of less than 6 mcg FE 999049

Result of exposure FE 999049 The minimum dose is not established Minimum dose 6 mcg Difference Patients with 8-14 eggs collected 44.8% 48.0% +3.2%

Thus, in addition to the observed data from the Japanese phase 2 study, predictions based on the ovarian response model according to the proposed dosing regimen also support the appropriateness of a minimum dose of 6 mcg.

In conclusion, the proposed dosing regimen of FE 999049 using a minimum dose of 6 mcg is safe and effective and is proposed for a phase 3 study in Japan. Data from a phase 3 study in Japanese patients with a calculated dose of less than 6 mcg will be analyzed specifically for the PMDA (Pharmaceutical and Medical Devices Agency) report to confirm the effectiveness and safety of 6 mcg FE 999049 in these patients.

Example 4: Phase 3 clinical trial in Japan.

Methodology.

This will be a randomized, evaluator-blind, controlled, parallel-group, multicenter study to evaluate the efficacy and safety of FE 999049 with an individualized dosing schedule when used in Japanese patients aged 20-40 years undergoing a first cycle of controlled ovarian stimulation for IVF/ICSI. according to a protocol with a gonadotropin-releasing hormone (GnRH) antagonist. The study was designed to demonstrate that FE 999049 was non-inferior to the rFSH product approved in Japan, FOLLISTIM, in terms of the number of eggs collected.

Subjects will be assessed within 60 days prior to stimulation to determine whether they meet inclusion and exclusion criteria. On days 2-3 of the menstrual cycle, subjects will be randomized 1:1 to controlled ovarian stimulation via FE 999049 or FOLLISTIM. Randomization will be stratified by center and by AMN levels at screening (less than 15 pmol/L and 15 pmol/L or more).

Subjects randomized to receive FE 999049 will have their individual dose of FE 999049 determined based on their AMN level at screening and their body weight at the start of stimulation (see below). The daily dose of FE 999049 will be fixed throughout the stimulation period. For subjects with AMN less than 15 pmol/L, the daily dose of FE 999049 is 12 mcg regardless of body weight. For subjects with an AMN of 15 pmol/L or more, the daily dose of FE 999049 is a continuous range of 0.19 to 0.10 mcg/kg, depending on actual AMN values and body weight. This is outlined in the Table below. The minimum permissible daily dose of FE 999049 is 6 mcg and the maximum permissible daily dose of FE 999049 is 12 mcg. Subjects may receive FE 999049 for a maximum of 20 days and no delay in ovulation induction is permitted.

For subjects randomized to receive FOLLISTIM, the dosing schedule is listed on the label (see below). The initial dose of FOLLISTIM is 150 IU and is fixed for the first five days of stimulation, after which it can be adjusted to 75 IU depending on the individual response. The maximum permissible daily dose of FOLLISTIM is 375 IU. Subjects may receive FOLLISTIM for a maximum of 20 days and no delay in ovulation stimulation is allowed.

During stimulation, subjects will be monitored by transvaginal ultrasound on days 1 and 6 of stimulation and at least 24 hours thereafter. If 3 follicles of 15 mm or more are detected, visits should be carried out daily. To prevent a premature surge in luteinizing hormone (LH), administration of a GnRH antagonist will be started on day 6 of stimulation at a daily dose of 0.25 mg and continued throughout the stimulation period. Final follicular maturation will be initiated with 5000 IU of human chorionic gonadotropin from urine (hCG) per day when 3 or more follicles with a diameter of 17 mm or more are detected. In case of excessive follicular development, defined as 25 or more follicles with a diameter of 12 mm or more, the cycle should be discontinued (note: if there are 25-30 follicles with a diameter of 12 mm or more, a GnRH agonist can be administered to trigger final follicular maturation). In case of poor follicular development, as determined by the investigator who judges that 3 or more follicles with a diameter of 17 mm or more cannot be achieved by day 20, the cycle should be stopped.

Oocyte retrieval will occur 36 hours (±2 hours) after the initiation of final follicular maturation, and fertilization of the eggs can be accomplished using IVF or ICSI. Fertilization and embryo development will be assessed from the time of egg retrieval until the day of transfer. One UAV

- 15 046202 the best quality stocyst will be transferred on the 5th day after egg retrieval, and the remaining blastocysts can be cryopreserved. In subjects who have undergone final follicular maturation triggering with a GnRH agonist, transfer will not occur and blastocysts may instead be frozen at day 5. All frozen blastocysts may be used by the subject after completion of the study in accordance with the Japanese Society of Obstetrics and Gynecology (JSOG) declaration.

Vaginal progesterone tablets (LUTINUS, Ferring Pharmaceuticals) 100 mg three times daily will be provided to support the luteal phase from the day after egg retrieval until the day of the doctor's visit during pregnancy. Luteal phase support will only be provided in subjects scheduled for transfer and may be discontinued early if there is no transfer or a negative phCG test. A phCG test is performed 13-15 days post-transfer followed by transvaginal ultrasound 5-6 weeks post-transfer to assess clinical and viable pregnancy.

Blood samples will be collected during the study to evaluate the endocrine profile, as well as biochemical and hematological parameters. Hormonal parameters are determined during screening, on the 1st day of stimulation, on the 6th day of stimulation and at the end of stimulation. Biochemical and hematological parameters are assessed at screening, at the end of stimulation and at the end of the study. Local tolerability of FE 999049 following subcutaneous administration will be assessed by subjects three times daily: immediately, 30 minutes and 24 hours after injection. Assessment of injection site reactions will be made throughout the stimulation period and recorded by subjects in a diary.

If study procedures and/or evaluations occur on Sundays, holidays, or outside clinic hours, procedures and/or evaluations may be rescheduled to the next weekday (up to a maximum of the next 24 hours after the scheduled appointment) or canceled if appropriate.

Mandatory follow-up will include the collection of data on the course and outcome of pregnancy in subjects with viable pregnancies. Data will be collected on the ongoing pregnancy (10–11 weeks post-transfer) and pregnancy outcome, as well as neonatal health at birth and 4 weeks after birth. Monitoring the course of pregnancy does not include any interventions, but only data collection. Pregnancy monitoring data will be based on the subject's gynecologist/obstetrician and maternal and child health diaries. Study sites will collect data from either the subject's gynecologist/obstetrician, the subject themselves, or other sources, as appropriate. Ferring intends to submit a J-NDA (Japanese New Drug Application) after completion of the main portion of the study (i.e., prior to clinical pregnancy visit) and to include pregnancy surveillance data available at that time in the J- NDA. Pregnancy monitoring data may be presented upon completion.

Number of subjects

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

Inclusion/exclusion criteria

This study will include women who meet criteria for IVF and/or ICSI, are undergoing a first IVF/ICSI cycle, and have a diagnosis of tubal infertility, infertility associated with stage I/II endometriosis, or have partners with male infertility. Subjects will be aged 20-40 years, body mass index (BMI) 17.5-32.0 kg/m ² .

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 this study.

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

Inclusion criteria

1. Informed consent documents signed prior to the start of any study-related procedures.

2. Good physical and mental health.

3. Japanese women aged 20 to 40 years. Subjects must be at least 20 years of age (including their 20th birthday) at the time of signing informed consent documents and no more than 40 years of age (up to the day before their 41st birthday) at the time of randomization.

4. Infertile women with diagnosed tubal infertility, unexplained infertility, stage I/II endometriosis (according to the revised classification of the American Society for Reproductive Medicine (ASRM), or having partners diagnosed with male infertility, eligible for in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) using ejaculated sperm from a male partner.

5. Infertility for at least 1 year before randomization (not applicable in case of tubal or severe male infertility).

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6. The study cycle will be the first cycle of controlled ovarian stimulation for IVF/ICSI.

7. Regular menstrual cycles of 24-35 days (including 24 and 35 days), presumably ovulatory.

8. Hysterosalpingography, hysteroscopy, saline infusion sonography, or transvaginal ultrasound documenting that the uterus is consistent with expected normal function (eg, no evidence of clinically interfering uterine fibroids, defined as submucosal fibroids or intramural fibroids greater than 3 cm in diameter, no polyps, and no congenital structural abnormalities associated with a reduced likelihood of pregnancy) within 1 year before the examination. This also includes women who were diagnosed with any of the medical conditions listed above but corrected by surgery within 1 year before screening.

9. Transvaginal ultrasound documenting the presence and adequate visualization of both ovaries, with no evidence of significant abnormality (eg, no endometrioma greater than 3 cm or ovarian enlargement, which may contraindicate the use of gonadotropins), and the fallopian tubes and surrounding tissues without evidence of significant abnormality (eg, absence of tubal hydrops) within 1 year before screening. Both ovaries must be accessible for egg retrieval.

10. Early follicular phase (2-4 days of the cycle) with serum FSH levels from 1 to 15 IU/L (results obtained within 3 months before screening).

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

12. Body mass index (BMI) from 17.5 to 32.0 kg/ ^m2 (including 17.5 and 32) at screening.

13. Willingness to accept single blastocyst transfer.

Exclusion criteria

1. Known stage III-IV endometriosis (according to the revised ASRM classification).

2. One or more than one follicle larger than 10 mm (including cysts), observed during transvaginal ultrasound examination before the start of stimulation on the 1st day of stimulation (puncture of cysts is allowed before randomization).

3. Known history of recurrent miscarriage (defined as three consecutive miscarriages after ultrasound confirmation of pregnancy (excluding ectopic pregnancy) and before 24 weeks of gestation).

4. Known abnormal karyotype of the subject or her partner. In cases of severe impairment of sperm production (concentration less than 1 million/ml), a normal karyotype, including the absence of Y chromosome microdeletion, must be documented.

5. Current arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events.

6. Known porphyria.

7. Any known clinically significant systemic disease (eg, insulin-dependent diabetes).

8. Known hereditary or acquired thrombophilic disease.

9. Any known endocrine or metabolic disorders (pituitary, adrenal, pancreatic, liver or kidney) that may adversely affect participation in the study, with the exception of controlled thyroid disease.

10. Known presence of antibodies to FSH (based on information available in the subject's medical records).

11. Known tumors of the ovary, breast, uterus, adrenal glands, pituitary gland or hypothalamus, for which the use of gonadotropins is contraindicated.

12. Any biochemical, hematologic, or vital sign abnormality detected at screening that the investigator considers to be clinically significant.

13. Known moderate or severe renal or hepatic impairment.

14. Currently breastfeeding.

15. Undiagnosed vaginal bleeding.

16. Known clinically significant abnormalities in cervical cytological examination observed within 3 years before screening (except in cases where the clinical significance has disappeared).

17. Results of laboratory tests during screening, excluding stimulation with gonadotropin.

18. Gynecological examination data during screening, excluding gonadotropin stimulation.

19. Gynecological screening findings that are associated with a decreased likelihood of pregnancy, such as congenital uterine anomalies or intrauterine device retention.

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20. Pregnancy (must be confirmed by negative urinary pregnancy tests at screening and prior to randomization) or contraindication to pregnancy.

21. Currently known active inflammatory diseases of the pelvic organs.

22. Use of hormonal medications (except thyroid medications) or fertility regulators during the last menstrual cycle before screening, including dehydroepiandrosterone (DHEA), metformin, and cycle programming with oral contraceptives, progestogens, or estrogen medications.

23. Known history of chemotherapy (excluding gestational conditions) or radiation therapy.

24. Current or past alcohol or drug abuse (1 year before randomization) and/or current (last month) consumption of more than 14 units of alcohol per week.

25. Smoking habit of more than 10 cigarettes per day, currently or in the past (3 months before randomization).

26. Hypersensitivity to any drug substance or excipients in the drug products used in the study.

27. Hypersensitivity to any drug or excipients in GnRH or any GnRH analogue/derivative.

28. Previous participation in the study.

29. Current participation in another study, including follow-up period.

30. Use of any unregistered experimental drugs during the last 3 months before screening.

On days 2-3 of the menstrual cycle, subjects will be randomized 1:1 to treatment with FE 999049 or FOLLISTIM and controlled ovarian stimulation will be initiated.

Dosage schedule FE 999049.

For subjects randomized to receive FE 999049, the individual dose will be determined based on their AMN level at screening and their body weight at randomization. For subjects with AMN less than 15 pmol/L, the daily dose of FE 999049 is 12 mcg regardless of body weight. For subjects with an AMN of 15 pmol/L or more, the daily dose of FE 999049 is in a continuous range of 0.19 to 0.10 mcg/kg, depending on the actual AMN and body weight.

The daily dose of FE 999049 will be fixed throughout the stimulation period. The minimum permissible daily dose of FE 999049 is 6 mcg. The maximum permissible daily dose of FE 999049 is 12 mcg. Administration will continue until the criterion for triggering final follicular maturation is reached. Subjects can be treated with FE 999049 for a maximum of 20 days. Delaying ovulation stimulation is not allowed.

The complete dosage schedule for FE 999049 is detailed in the following table.

Treatment group Concentration AMN (pmol/l) Daily dose fixed throughout stimulation Minimum daily dose Maximum daily dose FE 999049 less than 15 12 mcg - 12 mcg 15-16 0.19 µg/kg 6 mcg 12 mcg 17 0.18 µg/kg 6 mcg 12 mcg 18 0.17 µg/kg 6 mcg 12 mcg 19-20 0.16 µg/kg 6 mcg 12 mcg 21-22 0.15 µg/kg 6 mcg 12 mcg 23-24 0.14 µg/kg 6 mcg 12 mcg 25-27 0.13 µg/kg 6 mcg 12 mcg 28-32 0.12 µg/kg 6 mcg 12 mcg 33-39 0.11 µg/kg 6 mcg 12 mcg 40 or more 0.10 µg/kg 6 mcg 12 mcg

AMN concentrations will be rounded to whole numbers.

Subjects may receive treatment for a maximum of 20 days.

The drug FE 999049 is administered once a day as a subcutaneous injection into the abdomen. The dose cannot be divided into two injections. To minimize local reactions at the injection site, it is recommended to change the injection site regularly.

The first injection of FE 999049 will be carried out in the clinic and will be carried out either by a specialist

- 18 046202 by a person conducting a study of a medicinal product, or by a subject under the supervision of a specialist conducting a study of a medicinal product. Follow-up injections can be done at home or in a clinic. The study drug examiner will provide the subject with instructions for administering FE 999049. Calculate the dose of FE 999049 and set the dose of FE 999049 in the prefilled pen syringe

The patient's serum AMN concentration will be determined from a blood sample collected at screening and analyzed in a central laboratory using the Elecsys® AMN test from Roche Diagnostics. The AMN concentration will be transferred from the central laboratory directly to the eCRF (electronic clinical record). The subject's body weight will be measured at randomization using a calibrated scale and will be performed without shoes or outer clothing. The body weight measurement will be entered into the eCRF. The eCRF is programmed with an FE 999049 administration algorithm in which the dose of FE 999049 is calculated based on the subject's AMN and body weight.

The FE 999049 Pre-Filled Injection Pen is intended for subcutaneous administration of FE 999049. It is a non-sterile, disposable, needle-equipped device with a built-in, non-replaceable 3 ml cartridge containing the liquid medicinal product FE 999049. Each cartridge contains multiple, user-adjustable doses. You can set doses from 0.33 mcg to 20.0 mcg in 0.33 mcg increments. The pre-filled FE 999049 injection pen has a dosage scale marked from 0 to 20 mcg. Each number is separated by two lines, each line representing 0.33 µg. The prefilled injection pen can be configured to deliver doses rounded to the nearest 0.33 mcg. It may be necessary to round off the estimated dose, such as for a 75.0 kg subject with an AMN level of 35 pmol/L for whom the estimated dose is 8.25 mcg (0.11 mcg/kg x 75.0 kg), which is then rounded to 8.33 mcg, that is, 8 mcg plus 1 line on the pen. The calculated dose will be provided by the eCRF as a printout where the dose will correspond to numbers and lines on the pre-filled pen; that is, any rounding will be performed automatically before the calculated dose is provided to the subject.

The study drug examiner will be instructed and trained in the proper use of the prefilled injection pen to properly instruct the subject.

5.1.2. FOLLISTIM dosage regimen.

For subjects randomized to receive FOLLISTIM, the dosing schedule is listed on the label. The initial dose of FOLLISTIM is 150 IU and is fixed for the first five days of stimulation, after which it can be adjusted to 75 IU depending on the individual response. The maximum permissible daily dose of FOLLISTIM is 375 IU. Dosing will continue until the triggering criterion for final follicular maturation is reached. Subjects may receive FOLLISTIM for a maximum of 20 days. Delaying ovulation stimulation is not allowed. The dosage schedule for FOLLISTIM is shown in detail in the following table. ____________

Treatment group Initial dose on days 1-5 of stimulation Daily dose on day 6 of stimulation and beyond Minimum daily dose Maximum daily dose FOLLISTIM 150 IU Correction of 75 IU is allowed depending on individual response 75 IU 375 IU

Subjects may receive treatment for a maximum of 20 days.

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Claims (7)

1. Use of a composition containing a daily dose of 0.18 ml of a solution of recombinant FSH (follicle-stimulating hormone) in water with a concentration of 33.3 μg FSH per 1 ml of solution for the treatment of infertility in a patient with AMH (anti-Mullerian hormone) 26 pmol/ l or more and body weight less than 60 kg. 2. Use according to claim 1, wherein the treatment of infertility includes determining the level of AMN in the serum and the body weight of the patient. 3. Use according to claim 1, wherein the infertility treatment includes the step of identifying the patient based on the serum AMN level and the patient's body weight. 4. Use according to any one of claims 1 to 3 for the treatment of a patient having or identified as having a body weight of less than 59, 56, 55, 52, 50 or less than 45 kg. 5. Use according to any one of claims 1 to 4 for the treatment of a patient having or identified as having an AMR of 28 pmol/L or more, an AMR of 30 pmol/L or more, or an AMR of 40 pmol/L or more. 6. Use according to any one of claims 1 to 5, wherein the recombinant FSH includes α2,3- and α2,6-sialylation. 7. A method of treating infertility, comprising the step of administering a daily dose of 0.18 ml of a solution of recombinant FSH in water with a concentration of 33.3 μg of FSH per 1 ml of solution to a patient identified as having an AMN of 26 pmol/L or more and a body weight of less 60 kg.