Compositions and Methods for the Treatment of Male Infertility

Abstract

Methods, uses and compositions comprising rFSH comprising α2,3- and α2,6-sialylation for use in the treatment of infertility in male patients are described.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical and a method for treating male infertility in male patients.

Background Art

[0002] Approximately 15% of couples worldwide suffer from infertility, and male infertility is estimated to account for about 50% of the cases. (Agarwal, et al., Reprod Biol Endocrinol 13, 37 (2015)). However, in up to 40% of male infertility cases, the cause of infertility cannot be identified; many of these cases lead to a diagnosis of idiopathic infertility. (Sabanegh et al., Male infertility in CAMPBELL-WALSH UROLOGY 10th ed. (Campbell et al., ed.) (Saunders Elsevier, 2012) 616-647). Idiopathic male infertility (also known as idiopathic oligospermia, asthenospermia, teratozoospermia) generally refers to an unexplained decrease in sperm quality.

[0003] FSH has been used for many years in the treatment of female infertility to promote ovulation to enable pregnancy after natural conception or intrauterine insemination, and to induce multiple follicular development to obtain sufficient oocytes for assisted reproductive technology (ART). Approved recombinant FSH (rFSH) products for ovarian stimulation include follitropin alpha (GONAL-F®, Merck Serono / EMD Serono) and follitropin beta (PUREGON® / FOLLISTIM®, MSD / Schering-Plough), which are derived from the Chinese hamster ovary (CHO) cell line. The applicants have developed rFSH derived from a human cell line (follitropin delta, also known as FE 999049), which is the subject of International Patent Application No. PCT / GB2009 / 000978 published as WO 2009 / 127826A. The European Commission (EC) granted marketing authorization for REKOVELLE® (follitropin delta) in December 2016 for use in controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technology (ART), such as in vitro fertilization (IVF) cycles or intracytoplasmic sperm injection (ICSI) cycles. REKOVELLE® is the first rFSH derived from a human cell line (the PER.C6® cell line). The REKOVELLE® (follitropin delta) product is manufactured by the method disclosed in International Patent Application No. PCT / GB2009 / 000978.

[0004] However, there is a need for improved treatment of male infertility, particularly idiopathic infertility, to improve the chances of natural pregnancy in female partners. There is also a need for improved treatment of male factor infertility, testosterone deficiency in male patients, and idiopathic oligospermia. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0005] The pharmaceuticals and methods described herein rely on the therapeutic value of rFSH, including α2,3-sialylation and α2,6-sialylation, in the treatment of infertile men, particularly men with idiopathic infertility, due to the important role of FSH in spermatogenesis. Accordingly, the use of rFSH, including α2,3-sialylation and α2,6-sialylation, to increase sperm production in male infertility patients is disclosed herein as an alternative treatment to the current standard technique of intracytoplasmic sperm injection (ICSI).

[0006] A past meta-analysis of controlled clinical trials of FSH treatment in men with idiopathic infertility reported improved pregnancy rates, both spontaneously and after ART, when men were treated with recombinant (GONAL-F®) or urine-derived FSH (Santi et al., Endocr Connect. 2015;4:R46-58). However, the strength of the authors' conclusions was limited by trial heterogeneity, a high risk of bias, and the lack of precise criteria for selecting the population most likely to respond to treatment, highlighting the need for further research in this area, including clinical trials to define who responds and who does not respond to FSH treatment.

[0007] A more recent meta-analysis evaluating the effect of FSH treatment on sperm parameters concluded that high FSH doses (700 - 1050 IU / week) improved sperm concentration, total sperm count, and progressive motility, while lower FSH doses (up to 262.5 IU / week) increased only sperm motility, and intermediate FSH doses (350 - 525 IU / week) improved sperm concentration with only a tendency for increased sperm count and motility (Canarella et al., Asian J Androl. 2020;22:309 - 16). The reported analysis did not confirm different efficacy between urine-derived FSH and recombinant FSH.

[0008] The results of a dose-ranging study in 354 men concluded that men with idiopathic azoospermia treated with the injectable FSH product urofollitropin (Livzon Pharmaceutical Group Co., Ltd., Zhuhai, China) had significantly increased sperm counts when treated at at least 200 IU every other day, and those results were first observed at the beginning of the third month of treatment (Ding et al., Clin Endocrinol. 2015;83:866-71). Improvements in both sperm morphology and progressive motility were reported at the beginning of the fifth month of treatment, and it was reported that administration of 300 IU every other day for 5 months could substantially improve the natural pregnancy rate as well as the ART pregnancy rate. The authors refer to FSH as "recombinant FSH" and "rFSH," but the specific FSH product actually used in the study (injectable urofollitropin) is thought to be a purified urine-derived FSH rather than a recombinant product.

[0009] In view of this background, the inventors believe that treatment of men by daily administration of 11-13 μg of rFSH (e.g., 12 μg of FE 999049) containing α2,3-sialylation and α2,6-sialylation would be effective in the treatment of idiopathic infertility to improve the likelihood of natural pregnancy observed in female partners as compared to placebo. The inventors also believe that this dosing regimen would be effective in the treatment of male factor infertility, testosterone deficiency in male patients, and idiopathic oligospermia. The treatment may also be effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective in reducing sperm / semen DNA fragmentation in the semen of treated male patients. The treatment may also be effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of treated subjects as compared to men treated with placebo (non-effective treatment). The treatment may also be effective in shortening the time to natural pregnancy in the female partners of treated subjects as compared to men treated with placebo (when evaluable by, for example, one or more of elapsed time and number of menstrual cycles).

[0010] This dosing regimen provides a higher dose of FSH than previously used (e.g., more than the alternate-day dosing regimen of 300 IU of FSH reported in Ding) and includes more frequent dosing (i.e., daily dosing). Thus, the dosing regimens described herein result in increased exposure to FSH. While FSH has been shown to act in a dose-dependent manner in other situations, e.g., in the treatment of female infertility, the effects of such high daily dosing in males have not been previously studied. For example, while the pituitary releases FSH pulsatively, the effects of daily FSH dosing, which results in a relatively stable serum concentration of FSH in males, have not been reported.

[0011] In women, 150 IU / day of follitropin alpha (GONAL-F®) is equivalent to 10 μg / day of FE 999049 (Arce et al., RBMO. 2020;41(4):616-22). Thus, the inventors believe that, for example, the daily administration of 12 μg of FE 999049 described herein provides an exposure level that is 20% higher than the previously evaluated dose of 300 IU every other day, i.e., the dosing regimens described herein will provide an exposure equivalent to approximately 180 IU / day.

[0012] The inventors also believe that the daily dosing described herein will result in less variability in serum FSH concentration (i.e., more consistent exposure) than alternate-day treatment for two reasons: first, rFSH containing α2,3-sialylation and α2,6-sialylation, such as the human cell line-derived FSH product FE99049, has a lower clearance rate than CHO cell-derived products; second, daily dosing is expected to eliminate variability compared to, for example, dosing with two doses every other day. However, as described above, the pituitary releases FSH pulsatively and the effects of more stable FSH dosing in males have not been reported.

[0013] On the one hand, since FSH interacts only via specific FSH receptors (FSHR) within testicular Sertoli cells, supraphysiological FSH levels in men are thought to be safe and well tolerated (Simoni et al., Andrology 2020;8(3):535-44). Furthermore, to date, no evidence of FSHR downregulation in response to FSH stimulation has been reported, and the direct role of FSH in human bone turnover or metabolic function has not been confirmed.

[0014] Based on the above, a proof-of-concept (PoC) clinical trial is described hereinafter in this specification. The clinical trial evaluated the treatment of men with idiopathic infertility using daily administration of 11 - 13 μg of FE 999049 (e.g., 12 μg of FE 999049) over 6 months, compared to placebo, with respect to the improvement in the likelihood of natural pregnancy observed in female partners. Without wishing to be bound by theory, for the reasons including those outlined above, the inventors believe that the dosing regimen described herein using rFSH comprising α2,3-sialylation and α2,6-sialylation will be effective in improving the likelihood of natural pregnancy observed in female partners compared to placebo. For example, the inventors believe that the results of the clinical trial will demonstrate that daily administration of 11 - 13 μg of FE 999049 (e.g., 12 μg of FE 999049) provides a significantly higher FSH exposure level than that provided by daily administration of conventional (e.g., CHO cell-derived) rFSH. The inventors also believe that the dosing regimen described herein for rFSH comprising α2,3-sialylation and α2,6-sialylation, such as FE 999049, will result in less variation in serum FSH levels than treatment with 300 IU of FSH every other day (e.g., the dosing regimen reported in Ding 2015, supra). Thus, while Ding reported the effectiveness of his every-other-day regimen of 300 IU of FSH, the inventors believe that the dosing regimen described herein for rFSH comprising α2,3-sialylation and α2,6-sialylation (e.g., FE 999049) can be proven to be more effective. Furthermore, the inventors believe that daily administration of 11 - 13 μg of rFSH comprising α2,3-sialylation and α2,6-sialylation (e.g., 12 μg of FE 999049) will be safe and well-tolerated in male patients.

[0015] Accordingly, the inventors believe that the dosing regimens described herein can improve the likelihood of natural pregnancy observed in the female partners of treated male patients as compared to placebo. The inventors also believe that this dosing regimen will be effective in the treatment of male factor infertility, testosterone deficiency in male patients, and idiopathic oligospermia. The treatment may also be effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or in reducing semen DNA fragmentation of the sperm / semen of the treated male patient. The treatment may also be effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of treated subjects as compared to males treated with placebo. The treatment may also be effective in shortening the time to natural pregnancy in the female partners of treated subjects as compared to males treated with placebo (as may be evaluated by, for example, one or more of elapsed time and number of menstrual cycles).

[0016] Most studies of FSH treatment to improve sperm parameters have a treatment period of at least 3 months. See, e.g., Ding, supra. This is because a complete spermatogenic cycle is estimated to take 60-70 days. See, e.g., Heller, Science, 140:184-86 (1963). Also, the time for transport within the ductal system is estimated to take an additional 20-30 days. See, e.g., Shaw’s Textbook of Gynaecology, p. 201 (Padubidri and Daftary, eds.) (15th ed., 2011). However, evidence is emerging that these periods can be shorter. Accordingly, the inventors believe that the treatments described herein may exhibit a therapeutic effect in a shorter period, such as 30 days or 1 month (e.g., a medical month of 28 days). Thus, in some embodiments, the treatments described herein have a treatment period of 28 days, 30 days, 1 month, or a longer treatment period, as further described below.

[0017] According to some aspects, there is provided a composition comprising rFSH for use in the treatment of idiopathic infertility in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg). The infertility can be at least one sperm-related infertility selected from azoospermia, oligospermia, asthenospermia, teratospermia, oligospermatism, spermatocytopenia, and morphological abnormalities. In some aspects, the rFSH comprises α2,3-sialylation and α2,6-sialylation, and 5 to 20% of the total sialylation is α2,6-sialylation. In some aspects, the rFSH is produced or expressed in a human cell line, such as the PERC6® cell line, for example, the PERC6® cell line modified with α2,3-sialyltransferase.

[0018] In some embodiments, administration to a patient at a daily dose of 11 - 13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11 - 13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11 - 13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11 - 13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11 - 13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11 - 13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11 - 13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11 - 13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11 - 13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11 - 13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11 - 13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11 - 13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11 - 13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including a treatment period of at least 1 year).

[0019] In some embodiments, a patient has one or more of the following characteristics before treatment, e.g., at the start of treatment or within about 90 days of the start of treatment. In some embodiments, a patient has a body mass index (BMI) ≤ 35 kg / m 2has. In some embodiments, the patient has a semen volume ≧ 1.4 mL. In some embodiments, the patient has a baseline total sperm count of 5 million to 39 million. In some embodiments, the patient has a sperm concentration of less than 5 million sperm / mL. In some embodiments, the patient has a sperm concentration of 3 million sperm / mL or less, such as 2 million sperm / mL or less, such as 1 million sperm / mL or less, such as 500,000 sperm / mL or less. In some embodiments, the patient has a total motile sperm count of 5 million to 16 million. In some embodiments, the patient has ≧ 15% sperm with normal morphology (oval head, intact midpiece, and single, uncoiled tail and the ability to swim well and straight). In some embodiments, the patient has a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of testosterone of ≧ 300 ng / dL (equal to ≧ 10.4 nmol / L). In some embodiments, the patient has not received FSH treatment that has not led to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormone preparation within 3 months prior to screening.

[0020] According to some embodiments, the treatment is effective in improving the likelihood of natural pregnancy observed in the female partners of treated male patients as compared to placebo. According to some embodiments, the treatment is effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective in reducing semen DNA fragmentation of the sperm / semen of the treated male patient. According to some embodiments, the treatment is effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of treated subjects as compared to males treated with placebo. According to some embodiments, the treatment is effective in shortening the time to natural pregnancy in the female partners of treated subjects as compared to males treated with placebo (as may be evaluated by, for example, one or more of elapsed time and number of menstrual cycles).

[0021] According to some embodiments, there is provided a composition comprising rFSH for use in the treatment of male patient infertility, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg). The infertility can be at least one sperm-related infertility selected from azoospermia, oligospermia, asthenospermia, teratospermia, hypospermatogenesis, spermatocytopenia, and morphological abnormalities. In some embodiments, the rFSH comprises α2,3-sialylation and α2,6-sialylation, and 5-20% of the total sialylation is α2,6-sialylation. In some embodiments, the rFSH is produced or expressed in a human cell line, such as the PERC6® cell line, such as the PERC6® cell line modified with α2,3-sialyltransferase.

[0022] In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including a treatment period of at least 1 year).

[0023] In some embodiments, the patient has one or more of the following characteristics before treatment, e.g., at the start of treatment or within about 90 days of the start of treatment. In some embodiments, the patient has a body mass index (BMI) ≤ 35 kg / m 2has. In some embodiments, the patient has a semen volume ≧ 1.4 mL. In some embodiments, the patient has a baseline total sperm count of 5 million to 39 million. In some embodiments, the patient has a sperm concentration of less than 5 million sperm / mL. In some embodiments, the patient has a sperm concentration of 3 million or less sperm / mL, such as 2 million or less sperm / mL, such as 1 million or less sperm / mL, such as 500,000 or less sperm / mL. In some embodiments, the patient has a total motile sperm count of 5 million to 16 million. In some embodiments, the patient has ≧ 15% sperm with normal morphology (oval head, intact midpiece and single, uncoiled tail and the ability to swim well and straight). In some embodiments, the patient has a baseline serum hormone concentration of follicle stimulating hormone (FSH) of 1.5 - 8.0 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of testosterone of ≧ 300 ng / dL (equal to ≧ 10.4 nmol / L). In some embodiments, the patient has not received FSH treatment that has not led to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormone preparation within 3 months prior to screening.

[0024] According to some aspects, the treatment is effective in improving the likelihood of natural pregnancy observed in the female partners of male patients treated, as compared to a placebo. According to some aspects, the treatment is effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective in reducing semen DNA fragmentation of the sperm / semen of the treated male patient. According to some aspects, the treatment is effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of the treated subjects, as compared to males treated with a placebo. According to some aspects, the treatment is effective in shortening the time to natural pregnancy in the female partners of the treated subjects, as compared to males treated with a placebo (when evaluable, for example, by one or more of elapsed time and number of menstrual cycles).

[0025] According to some aspects, there is provided a composition comprising rFSH for use in the treatment of male factor infertility in a patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to a patient at a daily dose of 11 to 13 μg (for example, 12 μg). The infertility can be at least one sperm-related infertility selected from azoospermia, oligospermia, asthenozoospermia, teratozoospermia, hypospermatogenesis, spermatocytopenia, and morphological abnormalities. In some aspects, the rFSH comprises α2,3-sialylation and α2,6-sialylation, and 5 to 20% of the total sialylation is α2,6-sialylation. In some aspects, the rFSH is produced or expressed in a human cell line, for example, the PERC6® cell line, for example, the PERC6® cell line modified with α2,3-sialyltransferase.

[0026] In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including a treatment period of at least 1 year).

[0027] In some embodiments, the patient has one or more of the following characteristics before treatment, e.g., at the start of treatment or within about 90 days of the start of treatment. In some embodiments, the patient has a body mass index (BMI) ≤ 35 kg / m 2has. In some embodiments, the patient has a semen volume ≥ 1.4 mL. In some embodiments, the patient has a baseline total sperm count of 5 million to 39 million. In some embodiments, the patient has a sperm concentration of less than 5 million sperm / mL. In some embodiments, the patient has a sperm concentration of 3 million or less sperm / mL, such as 2 million or less sperm / mL, such as 1 million or less sperm / mL, such as 500,000 or less sperm / mL. In some embodiments, the patient has a total motile sperm count of 5 million to 16 million. In some embodiments, the patient has ≥ 15% sperm with normal morphology (oval head, intact midpiece and single, uncoiled tail and the ability to swim well and straight). In some embodiments, the patient has a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of testosterone of ≥ 300 ng / dL (equivalent to ≥ 10.4 nmol / L). In some embodiments, the patient has not received FSH treatment that has not led to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormone preparation within 3 months prior to screening.

[0028] According to some embodiments, the treatment is effective in improving the likelihood of natural pregnancy observed in female partners of treated male patients as compared to placebo. According to some embodiments, the treatment is effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective in reducing semen DNA fragmentation of the sperm / semen of the treated male patient. According to some embodiments, the treatment is effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in female partners of treated subjects as compared to males treated with placebo. According to some embodiments, the treatment is effective in shortening the time to natural pregnancy in female partners of treated subjects as compared to males treated with placebo (when evaluable, for example, by one or more of elapsed time and number of menstrual cycles).

[0029] According to some embodiments, there is provided a composition comprising rFSH for use in the treatment of testosterone deficiency in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg). In some embodiments, the rFSH comprises α2,3-sialylation and α2,6-sialylation, and 5 to 20% of the total sialylation is α2,6-sialylation. In some embodiments, the rFSH is produced or expressed in a human cell line, such as the PERC6® cell line, such as the PERC6® cell line modified with α2,3-sialyltransferase.

[0030] In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including at least a 1-year treatment period).

[0031] In some embodiments, a patient has one or more of the following characteristics before treatment, e.g., at the start of treatment or within about 90 days of the start of treatment. In some embodiments, a patient has a body mass index (BMI) ≤ 35 kg / m 2has. In some embodiments, the patient has a semen volume ≥ 1.4 mL. In some embodiments, the patient has a baseline total sperm count of 5 million to 39 million. In some embodiments, the patient has a sperm concentration of less than 5 million sperm / mL. In some embodiments, the patient has a sperm concentration of 3 million or less sperm / mL, such as 2 million or less sperm / mL, such as 1 million or less sperm / mL, such as 500,000 or less sperm / mL. In some embodiments, the patient has a total motile sperm count of 5 million to 16 million. In some embodiments, the patient has ≥ 15% sperm with normal morphology (oval head, intact midpiece, and single, uncoiled tail and the ability to swim well and straight). In some embodiments, the patient has a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 to 8.0 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of testosterone of ≥ 300 ng / dL (equal to ≥ 10.4 nmol / L). In some embodiments, the patient has not received FSH treatment that has not led to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormone preparation within 3 months prior to screening.

[0032] According to some embodiments, the treatment is effective to improve the likelihood of natural pregnancy observed in the female partners of treated male patients as compared to placebo. According to some embodiments, the treatment is effective to improve one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective to reduce semen DNA fragmentation of the sperm / semen of the treated male patient. According to some embodiments, the treatment is effective to improve the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of treated subjects as compared to males treated with placebo. According to some embodiments, the treatment is effective to shorten the time to natural pregnancy in the female partners of treated subjects as compared to males treated with placebo (as may be evaluated by, for example, one or more of elapsed time and number of menstrual cycles).

[0033] According to some embodiments, there is provided a composition comprising rFSH for use in the treatment of idiopathic oligospermia in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg). In some embodiments, the rFSH comprises α2,3-sialylation and α2,6-sialylation, and 5 to 20% of the total sialylation is α2,6-sialylation. In some embodiments, the rFSH is produced or expressed in a human cell line, such as the PERC6® cell line, such as the PERC6® cell line modified with α2,3-sialyltransferase.

[0034] In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including a treatment period of at least 1 year).

[0035] In some embodiments, the patient has one or more of the following characteristics before treatment, e.g., at the start of treatment or within about 90 days of the start of treatment. In some embodiments, the patient has a body mass index (BMI) ≤ 35 kg / m 2has. In some embodiments, the patient has a semen volume ≧ 1.4 mL. In some embodiments, the patient has a baseline total sperm count of 5 million to 39 million. In some embodiments, the patient has a sperm concentration of less than 5 million sperm / mL. In some embodiments, the patient has a sperm concentration of 3 million or less sperm / mL, such as 2 million or less sperm / mL, such as 1 million or less sperm / mL, such as 500,000 or less sperm / mL. In some embodiments, the patient has a total motile sperm count of 5 million to 16 million. In some embodiments, the patient has ≧ 15% sperm with normal morphology (oval head, intact midpiece, and single, uncoiled tail and the ability to swim well and straight). In some embodiments, the patient has a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of testosterone of ≧ 300 ng / dL (equal to ≧ 10.4 nmol / L). In some embodiments, the patient has not received FSH treatment that has not led to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormone preparation within 3 months prior to screening.

[0036] According to some embodiments, the treatment is effective to improve the likelihood of natural pregnancy observed in female partners of male patients treated, as compared to placebo. According to some embodiments, the treatment is effective to improve one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective to reduce semen DNA fragmentation of sperm / semen of the treated male patient. According to some embodiments, the treatment is effective to improve the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in female partners of treated subjects, as compared to males treated with placebo. According to some embodiments, the treatment is effective to shorten the time to natural pregnancy in female partners of treated subjects, as compared to males treated with placebo (as may be evaluated by, for example, one or more of elapsed time and number of menstrual cycles).

[0037] According to some embodiments, a method of treating infertility in a male patient, including idiopathic infertility and male factor infertility, comprising administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11 to 13 μg (e.g., 12 μg) / day, is provided. The infertility may be one or more sperm-related infertility conditions selected from azoospermia, oligospermia, asthenozoospermia, teratozoospermia, hypospermatogenesis, spermatocytopenia, and morphological abnormalities. In some embodiments, the rFSH comprises α2,3-sialylation and α2,6-sialylation, and 5 to 20% of the total sialylation is α2,6-sialylation. In some embodiments, the rFSH is produced or expressed in a human cell line, such as the PERC6® cell line, such as the PERC6® cell line modified with α2,3-sialyltransferase.

[0038] In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including a treatment period of at least 1 year).

[0039] In some embodiments, the patient has one or more of the following characteristics before treatment, e.g., at the start of treatment or within about 90 days of the start of treatment. In some embodiments, the patient has a body mass index (BMI) ≤ 35 kg / m 2has. In addition to or instead of this, in some embodiments, the patient has a semen volume ≧ 1.4 mL. In addition to or instead of this, in some embodiments, the patient has a baseline total sperm count of 5 million to 39 million. In addition to or instead of this, in some embodiments, the patient has a sperm concentration of less than 5 million sperm / mL. In addition to or instead of this, in some embodiments, the patient has a sperm concentration of 3 million or less sperm / mL, for example, 2 million or less sperm / mL, for example, 1 million or less sperm / mL, for example, 500,000 or less sperm / mL. In addition to or instead of this, in some embodiments, the patient has a total motile sperm count of 5 million to 16 million. In addition to or instead of this, in some embodiments, the patient has ≧ 15% sperm with normal morphology (oval head, intact midpiece and single, uncoiled tail and the ability to swim well and straight). In addition to or instead of this, in some embodiments, the patient has a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 to 8.0 IU / L. In addition to or instead of this, in some embodiments, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. In addition to or instead of this, in some embodiments, the patient has a baseline serum hormone concentration of testosterone of ≧ 300 ng / dL (equivalent to ≧ 10.4 nmol / L). In some embodiments, the patient has not received FSH treatment that does not lead to pregnancy in the partner. In addition to or instead of this, in some embodiments, the patient has not received administration of a hormone preparation within 3 months prior to screening.

[0040] According to some embodiments, the treatment is effective to improve the likelihood of natural pregnancy observed in female partners of treated male patients as compared to placebo. According to some embodiments, the treatment is effective to improve one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective to reduce semen DNA fragmentation of sperm / semen of treated male patients. According to some embodiments, the treatment is effective to improve the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in female partners of treated subjects as compared to male subjects treated with placebo. According to some embodiments, the treatment is effective to shorten the time to natural pregnancy in female partners of treated subjects as compared to male subjects treated with placebo (as may be evaluated, for example, by one or more of elapsed time and number of menstrual cycles).

[0041] According to some embodiments, there is provided a method for treating testosterone deficiency in a male patient, comprising administering to the patient recombinant follicle stimulating hormone (rFSH) comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11 to 13 μg (e.g., 12 μg) per day. In some embodiments, the rFSH comprises α2,3-sialylation and α2,6-sialylation, and 5 to 20% of the total sialylation is α2,6-sialylation. In some embodiments, the rFSH is produced or expressed in a human cell line, such as the PERC6® cell line, such as the PERC6® cell line modified with α2,3-sialyltransferase.

[0042] In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including a treatment period of at least 1 year).

[0043] In some embodiments, the patient has one or more of the following characteristics before treatment, e.g., at the start of treatment or within about 90 days of the start of treatment. In some embodiments, the patient has a body mass index (BMI) ≤ 35 kg / m 2has. In some embodiments, the patient has a semen volume ≧ 1.4 mL. In some embodiments, the patient has a baseline total sperm count of 5 million to 39 million. In some embodiments, the patient has a sperm concentration of less than 5 million sperm / mL. In some embodiments, the patient has a sperm concentration of 3 million or less sperm / mL, such as 2 million or less sperm / mL, such as 1 million or less sperm / mL, such as 500,000 or less sperm / mL. In some embodiments, the patient has a total motile sperm count of 5 million to 16 million. In some embodiments, the patient has ≧ 15% sperm with normal morphology (oval head, intact midpiece, and single, uncoiled tail and the ability to swim well and straight). In some embodiments, the patient has a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of testosterone of ≧ 300 ng / dL (equal to ≧ 10.4 nmol / L). In some embodiments, the patient has not received FSH treatment that has not led to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormone preparation within 3 months prior to screening.

[0044] According to some embodiments, the treatment is effective in improving the likelihood of natural pregnancy observed in the female partners of treated male patients as compared to placebo. According to some embodiments, the treatment is effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective in reducing semen DNA fragmentation of the sperm / semen of the treated male patient. According to some embodiments, the treatment is effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of treated subjects as compared to male subjects treated with placebo. According to some embodiments, the treatment is effective in shortening the time to natural pregnancy in the female partners of treated subjects as compared to male subjects treated with placebo (as may be evaluated by, for example, one or more of elapsed time and number of menstrual cycles).

[0045] According to some embodiments, there is provided a method for treating idiopathic oligospermia in a male patient, comprising administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11 to 13 μg (e.g., 12 μg) / day. In some embodiments, the rFSH comprises α2,3-sialylation and α2,6-sialylation, and 5 to 20% of the total sialylation is α2,6-sialylation. In some embodiments, the rFSH is produced or expressed in a human cell line, such as the PERC6® cell line, such as the PERC6® cell line modified with α2,3-sialyltransferase.

[0046] In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including a treatment period of at least 1 year).

[0047] In some embodiments, a patient has one or more of the following characteristics before treatment, e.g., at the start of treatment or within about 90 days of the start of treatment. In some embodiments, a patient has a body mass index (BMI) ≤ 35 kg / m 2has. In some embodiments, the patient has a semen volume ≧ 1.4 mL. In some embodiments, the patient has a baseline total sperm count of 5 million to 39 million. In some embodiments, the patient has a sperm concentration of less than 5 million sperm / mL. In some embodiments, the patient has a sperm concentration of 3 million or less sperm / mL, such as 2 million or less sperm / mL, such as 1 million or less sperm / mL, such as 500,000 or less sperm / mL. In some embodiments, the patient has a total motile sperm count of 5 million to 16 million. In some embodiments, the patient has ≧ 15% sperm with normal morphology (oval head, intact midpiece, and single, uncoiled tail, and the ability to swim well and straight). In some embodiments, the patient has a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 to 8.0 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L. In some embodiments, the patient has a baseline serum hormone concentration of testosterone of ≧ 300 ng / dL (equal to ≧ 10.4 nmol / L). In some embodiments, the patient has not received FSH treatment that has not led to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormone preparation within 3 months prior to screening.

[0048] According to some embodiments, the treatment is effective in improving the likelihood of natural pregnancy observed in the female partners of treated male patients as compared to placebo. According to some embodiments, the treatment is effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective in reducing semen DNA fragmentation of the sperm / semen of treated male patients. According to some embodiments, the treatment is effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of treated subjects as compared to males treated with placebo. According to some embodiments, the treatment is effective in shortening the time to natural pregnancy in the female partners of treated subjects as compared to males treated with placebo (as may be evaluated by, for example, one or more of elapsed time and number of menstrual cycles).

[0049] Accordingly, there is provided a composition comprising rFSH for use in the treatment of idiopathic infertility in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg). Further, there is provided a composition comprising rFSH for use in the treatment of infertility in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg). Further, there is provided a composition comprising rFSH for use in the treatment of male factor infertility in a patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg). Further, there is provided a composition comprising rFSH for use in the treatment of testosterone deficiency in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg). Further, there is provided a composition comprising rFSH for use in the treatment of idiopathic oligospermia in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg). Further, there is provided a method of treating infertility in male patients, including male factor infertility and / or idiopathic infertility, comprising administering to the patient an rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11 to 13 μg / day, optionally at a dose of 12 μg / day. Further, there is provided a method of treating testosterone deficiency in male patients, comprising administering to the patient an rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11 to 13 μg / day, optionally at a dose of 12 μg / day.Furthermore, there is provided a method for treating idiopathic oligospermia in male patients, which comprises administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11 to 13 μg / day, optionally at a dose of 12 μg / day.

[0050] According to any of the above, infertility can be at least one sperm-related infertility selected from azoospermia, oligospermia, asthenospermia, teratozoospermia, oligospermatism, spermatocytopenia, and morphological abnormalities.

[0051] According to any of the above, 5 to 20% of the total sialylation may be α2,6-sialylation, and / or the rFSH can be produced or expressed in the PERC6® cell line.

[0052] According to any of the above, administration to the patient at a daily dose of 11 to 13 μg (e.g., 12 μg) can be over a treatment period selected from (i) at least 28 days; (ii) from 28 days to 6 months; (iii) at least 30 days; (iv) from 30 days to 6 months; (v) 28 days; (vi) 30 days; (vii) 6 weeks; (viii) 8 weeks; (ix) 2 months; (x) 10 weeks; (xi) 12 weeks; (xii) 3 months; (xiii) 14 weeks; (xiv) 16 weeks; (xv) 4 months; (xvi) 18 weeks; (xvii) 20 weeks; (xviii) 5 months; (xix) 22 weeks; (xx) 24 weeks; and (xxi) 6 months.

[0053] According to any of the above, the patient may have, for example, one or more or all of the following characteristics before treatment: body mass index (BMI) ≤ 35 kg / m 2; Seminal volume ≥ 1.4 mL; Baseline total sperm count of 5 million - 39 million; Sperm concentration < 5 million sperm / mL; Sperm concentration of ≤ 3 million sperm / mL, e.g., ≤ 2 million sperm / mL, e.g., ≤ 1 million sperm / mL, e.g., ≤ 500,000 sperm / mL; Total motile sperm count of 5 million - 16 million; ≥ 15% of sperm having normal morphology (oval head, intact midpiece, and single, uncoiled tail, and the ability to swim well and straight); Baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L; Baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L; Baseline serum hormone concentration of testosterone ≥ 300 ng / dL (equivalent to ≥ 10.4 nmol / L).

[0054] According to any of the above, the treatment may be effective in providing an improved likelihood of natural pregnancy in the female partner of the treated male patient. In addition to or instead of this, according to any of the above, the treatment may be effective in improving one or more or all of seminal volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or in reducing semen DNA fragmentation of the sperm / semen of the treated male patient. In addition to or instead of this, according to any of the above, the treatment may be effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partner of the treated subject compared to a male treated with a placebo. In addition to or instead of this, according to any of the above, the treatment may be effective in shortening the time to natural pregnancy in the female partner of the treated subject compared to a male treated with a placebo.

Mode for Carrying Out the Invention

[0055] The proof-of-concept (PoC) test described below demonstrates the effectiveness of the therapeutic agents and methods described herein. The inventors believe that men with idiopathic infertility, after being treated with daily administration of 11-13 μg of FE 999049 (e.g., 12 μg of FE 999049), will have an improved likelihood of natural pregnancy observed in their female partners as compared to men treated with placebo. The treatment may also be effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective in reducing semen DNA fragmentation of the sperm / semen of the treated male patient. The treatment may also be effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of the treated subjects as compared to men treated with placebo. The treatment may also be effective in shortening the time to natural pregnancy in the female partners of the treated subjects as compared to men treated with placebo (e.g., as may be evaluated by one or more of elapsed time and number of menstrual cycles).

[0056] As described above, the therapeutic effect can be observed before the end of the 6-month test treatment period. Furthermore, since the therapeutic effect on the patient can persist over a certain period after the treatment is interrupted, the test will follow up the results for, for example, 3 months after the end of the 6-month test treatment period.

[0057] Accordingly, a treatment and dosing regimen is provided herein for use in treating male patients having infertility, including idiopathic infertility and male factor infertility, and further for treating male testosterone deficiency and idiopathic oligospermia.

[0058] Definitions The technical and scientific terms used in this specification have the meanings commonly understood by those skilled in the art of assisted reproductive technology to which the present invention pertains, unless otherwise defined. In this specification, various methodologies known to those skilled in the art are referenced. Any suitable materials and / or methods known to those skilled in the art may be used in practicing the present invention based on the guidance provided herein. However, specific materials and methods are described. The materials, reagents, etc. referenced in the following description and examples are available from commercial sources unless otherwise noted.

[0059] It is to be understood that all definitions and terms defined in this specification have the same meaning and purpose in any of the aspects and embodiments of the present invention, unless explicitly stated otherwise.

[0060] As used in this specification, the singular forms "a", "an", and "the" denote both the singular and plural forms unless explicitly stated otherwise to denote only the singular form.

[0061] As used in this specification, the term "about" means that the modified number or range, as understood by those skilled in the art in the context in which the number or range is used, is not limited to the exact number or range specified, but includes the range before and after the recited number or range. Unless otherwise clear from the context or the convention in the art, "about" means plus or minus 10% of the particular term.

[0062] As used in this specification, "natural pregnancy" is defined as a viable pregnancy (confirmation of fetal heart tones by ultrasound and at least one intrauterine gestational sac).

[0063] As used in this specification, "continuing pregnancy" refers to a pregnancy with a viable fetus and detectable fetal heart tones at 10 - 11 weeks of gestation (e.g., 8 - 9 weeks after blastocyst / embryo transfer).

[0064] As used herein, "clinical pregnancy" refers to pregnancy at 5 - 6 weeks of gestation (e.g., 3 - 4 weeks after blastocyst / embryo transfer) and a detectable fetal heart sound.

[0065] In the treatments, methods, and uses described herein, administration of rFSH may be initiated on "day 1" of the treatment and may continue for 6 months or longer; for example, the treatment may continue for 1, 2, 3, 4, 5, or 6 months as described in more detail below.

[0066] As used herein, the term "spermatogenesis" refers to the production or generation of mature sperm.

[0067] As used herein, the term "azoospermia" refers to a condition in which no measurable sperm are present in the semen. As used herein, the term "oligospermia" refers to a condition in which a low sperm concentration, e.g., less than 15 million sperm per mL of semen, is present in the semen. As used herein, the term "asthenospermia" refers to a condition in which sperm have low motility, e.g., less than 40% motility. As used herein, the term "teratospermia" refers to a condition in which sperm have a large number of abnormal morphologies, where normal morphology is defined as an oval head, an intact midpiece, and a single, uncoiled tail, as well as the ability to swim well and straight. As used herein, the term "hypospermatogenesis" refers to a condition in which a male has a small volume of semen, e.g., less than 2 mL or less than 1.5 mL. As used herein, the term "oligocytospermia" refers to a decrease in the number of sperm from normal values.

[0068] In this specification, the terms "patient", "subject", "male", and "man" are used synonymously.

[0069] In some embodiments, the patient has a BMI as follows before treatment, for example, at the start of treatment or within about 90 days of the start of treatment. The subject can have a BMI > 15 and BMI < 40 kg / m2, for example, a BMI > 17.5 and BMI < 38 kg / m2, for example, a BMI > 18 and BMI < 25 kg / m2, for example, a BMI > 20 and BMI < 25 kg / m2. Thus, the products or methods described herein can be used for the treatment of infertility in patients having a BMI > 15 and BMI < 40 kg / m2, for example, subjects having a BMI > 17.5 and BMI < 38 kg / m2, for example, subjects having a BMI > 18 and BMI < 25 kg / m2, for example, subjects having a BMI > 20 and BMI < 25 kg / m2. Thus, the products or methods described herein can be used for the treatment of infertility in patients having a BMI > 17.5 and BMI < 32 kg / m2. The BMI can be measured by methods well known in the art for identifying patients for treatment.

[0070] In some embodiments, the patient has one or more of the following characteristics before treatment, for example, at the start of treatment or within about 90 days of the start of treatment. The patient has a body mass index (BMI) ≤ 35 kg / m 2may have. The patient may have a semen volume ≥ 1.4 mL. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of 3 million or less sperm / mL, for example, 2 million or less sperm / mL, for example, 1 million or less sperm / mL, for example, 500,000 or less sperm / mL. The patient may have a total motile sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥ 15% sperm with normal morphology (oval head, intact midpiece, and single, uncoiled tail and the ability to swim well and straight). The patient may have a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone ≥ 300 ng / dL (equivalent to ≥ 10.4 nmol / L).

[0071] The selection criteria are designed to identify the patients who are most likely to benefit from the treatments described herein. For example, the FSH, LH, and testosterone parameters may include patients with gonadotropin values on the normal lower side. The FSH, LH, and testosterone thresholds may exclude patients with hypogonadotropic hypogonadism for whom single FSH treatment is not helpful. On the other hand, the upper limits of the FSH and LH parameters may exclude patients with values that are excessively high from the normal high values of gonadotropins, patients with idiopathic infertility who may have etiologies other than gonadotropins, and patients in whom the therapeutic effect of FSH (if any) may be difficult to detect.

[0072] Thus, at the time of treatment, including at the start of treatment (including within about 90 days of the start of treatment), the patient may have one or more or all of the following characteristics: body mass index (BMI) ≤ 35 kg / m 2; Semen volume ≥ 1.4 mL; Baseline total sperm count of 5 million - 39 million; Sperm concentration of less than 5 million sperm / mL, e.g., less than 4 million sperm / mL; Sperm concentration of 3 million or less sperm / mL, e.g., 2 million or less sperm / mL, e.g., 1 million or less sperm / mL, e.g., 500,000 or less sperm / mL; Total motile sperm count of 5 million - 16 million, e.g., 5 million - 10 million, e.g., 6 million - 8 million; ≥ 15% of sperm having normal morphology (oval head, intact midpiece, and single, uncoiled tail, and the ability to swim well and straight (e.g., progressive motility / forward motility rate)); Baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L; Baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L; Baseline serum hormone concentration of testosterone ≥ 300 ng / dL (equivalent to ≥ 10.4 nmol / L).

[0073] The above parameters can be evaluated by methods known in the art, such as those compliant with World Health Organisation (WHO) standards. See, for example, Boitrelle et al., Life (2021) 11(12):1368. The evaluation of semen and sperm parameters can optionally be performed by a manual semen examination in the laboratory, including computer-assisted sperm analysis. In addition or alternatively, the evaluation of sperm parameters can include the use of a sperm test device such as the ExSeed® device (ExSeed Health, Denmark), or other sperm test devices, e.g., as outlined in Onofre, et al., Facts Views Vis ObGyn (2021) 13(1):79-93). Parameters regarding semen and sperm characteristics can be evaluated and confirmed in one or more samples taken at the same time or at different time points, e.g., at the time of initial screening for treatment and then at a time closer to the start of treatment, e.g., in one sample taken at the time of initial screening for treatment and in two consecutive samples taken within about 90 days of the start of treatment (e.g., more than 2 weeks before the start of treatment but within about 90 days of the start of treatment).

[0074] In some embodiments, the patient has not received FSH treatment that does not lead to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormonal preparation within 3 months prior to screening.

[0075] According to all embodiments described herein, recombinant human follicle stimulating hormone (rFSH) comprising α2,3- and α2,6-sialylation can be recombinant FSH derived from a human cell line, as described in more detail below. In all embodiments, recombinant FSH comprising α2,3- and α2,6-sialylation can be that sold under the trademark REKOVELLE® (hollitropin delta) (Ferring B.V.). In all embodiments, recombinant FSH can be administered by injection, such as subcutaneous injection.

[0076] Treatment In the proof-of-concept (PoC) study described below, the inventors will show that men with idiopathic infertility have an improved likelihood of natural pregnancy in their female partners after being treated with daily administration of 11 - 13 μg of FE 999049 (e.g., 12 μg of FE 999049), compared to men treated with placebo.

[0077] Treatment can also be effective to improve one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or can be effective to reduce semen DNA fragmentation of sperm / semen in treated male patients. For example, treatment can be effective to increase the total sperm count or total motile sperm count to 50% or more of baseline.

[0078] Treatment may also be effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of treated subjects as compared to men treated with placebo. Treatment may also be effective in shortening the time to natural pregnancy in the female partners of treated subjects as compared to men treated with placebo (when assessable, for example, by one or more of elapsed time and number of menstrual cycles).

[0079] As described above, treatment effects may be observed from 28 or 30 days to 6 months after treatment. Further, the treatment effect on patients may persist over a period of time after treatment is discontinued, for example, for 3 months or longer after the end of treatment.

[0080] The inventors believe that the results of the study will demonstrate that daily administration of 11 - 13 μg of FE 999049 (for example, 12 μg of FE 999049) provides a significantly higher FSH exposure level (1.7-fold and 1.6-fold higher, respectively, as evaluated by AUC and C max when compared to daily administration of conventional (CHO cell-derived) rFSH due to a lower clearance rate of FE 999049 (0.58 L / h for FE 999049 compared to 0.99 L / h for follitropin alpha) (see, for example, Olssen et al., J. Clin. Pharmacol. (2014) 54(11) 1299 - 1307). The inventors also believe that daily administration of FE 999049 will result in less variability in serum FSH levels (i.e., more consistent exposure) than treatment with 300 IU of FSH every other day (reported in Ding 2015, supra). Further, the inventors believe that daily administration of 11 - 13 μg of FE 999049 (for example, 12 μg of FE 999049) will be safe and well-tolerated in male patients.

[0081] Accordingly, the inventors believe that the dosing regimens described herein will improve the likelihood of natural pregnancy observed in female partners of treated male patients compared to patients treated with placebo (non-effective treatment). The treatment may also be effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective in reducing semen DNA fragmentation of sperm / semen of treated male patients. The treatment may also be effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in female partners of treated subjects compared to male subjects treated with placebo. The treatment may also be effective in shortening the time to natural pregnancy in female partners of treated subjects compared to male subjects treated with placebo (as may be evaluated by, for example, one or more of elapsed time and number of menstrual cycles).

[0082] Therapeutic composition In a first aspect, there is provided a composition (e.g., a pharmaceutical composition) comprising rFSH for use in the treatment of idiopathic infertility in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation (e.g., follitropin delta), and the rFSH is for administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg).

[0083] Infertility can be at least one sperm-related infertility selected from azoospermia, oligospermia, asthenozoospermia, teratozoospermia, hypospermatogenesis, spermatocytopenia, and morphological abnormalities.

[0084] rFSH may contain α2,3-sialylation and α2,6-sialylation, with 5 to 20% of total sialylation being α2,6-sialylation. rFSH may contain α2,3-sialylation and α2,6-sialylation, with 80 to 90% of total sialylation being α2,3-sialylation and 10 to 20% of total sialylation being α2,6-sialylation (e.g., follitropin delta available from Ferring B.V.). rFSH can be rFSH produced or expressed in a human cell line, such as the PERC6® cell line, such as the PERC6® cell line modified with α2,3-sialyltransferase. The PER.C6® cell line was deposited with the European Collection of Authenticated Cell Cultures under ECACC deposit number 96022940 as of February 29, 1996.

[0085] As described above, in some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including a treatment period of at least 1 year). It will be understood that administration of rFSH to a patient at a daily dose of 11-13 μg (e.g., 12 μg) may be required for a longer period of up to 18 months, for example, to achieve spermatogenesis.On the one hand, since the therapeutic effect on the patient can persist for a certain period after the treatment is interrupted, a shorter treatment period can be effective.

[0086] The patient may have a body mass index (BMI) ≤ 35 kg / m 2 The patient may have a semen volume ≥ 1.4 mL. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of 3 million or less sperm / mL, for example, 2 million or less sperm / mL, for example, 1 million or less sperm / mL, for example, 500,000 or less sperm / mL. The patient may have a total motile sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥ 15% sperm with normal morphology (oval head, intact midpiece, and single, uncoiled tail, and the ability to swim well and straight). The patient may have a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone ≥ 300 ng / dL (equivalent to ≥ 10.4 nmol / L). In some embodiments, the patient has not received FSH treatment that does not lead to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormone preparation within 3 months prior to screening.

[0087] According to some aspects, the treatment is effective in improving the likelihood of natural pregnancy observed in female partners of treated male patients as compared to placebo. According to some aspects, the treatment is effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective in reducing semen DNA fragmentation of sperm / semen of treated male patients. According to some aspects, the treatment is effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in female partners of treated subjects as compared to male subjects treated with placebo. According to some aspects, the treatment is effective in shortening the time to natural pregnancy in female partners of treated subjects as compared to male subjects treated with placebo (when evaluable, for example, by one or more of elapsed time and number of menstrual cycles).

[0088] In a second aspect, there is provided a composition (e.g., a pharmaceutical composition) comprising rFSH for use in the treatment of male patient infertility, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation (e.g., follitropin delta), and the rFSH is for administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg).

[0089] Infertility can be at least one sperm-related infertility selected from azoospermia, oligospermia, asthenospermia, teratospermia, hypospermia, spermatocytopenia, and morphological abnormalities.

[0090] rFSH may include α2,3-sialylation and α2,6-sialylation, and 5 to 20% of the total sialylation is α2,6-sialylation. rFSH may include α2,3-sialylation and α2,6-sialylation, 80 to 90% of the total sialylation is α2,3-sialylation, and 10 to 20% of the total sialylation is α2,6-sialylation (e.g., follitropin delta available from Ferring B.V.). rFSH can be rFSH produced or expressed in a human cell line, such as the PERC6® cell line, such as the PERC6® cell line modified with α2,3-sialyltransferase.

[0091] In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including a treatment period of at least 1 year). It will be understood that administration of rFSH to a patient at a daily dose of 11-13 μg (e.g., 12 μg) may be required for a longer period of up to 18 months, for example, to achieve spermatogenesis.On the one hand, since the therapeutic effect on the patient can persist for a certain period after the treatment is interrupted, a shorter treatment period may be effective.

[0092] The patient may have a body mass index (BMI) ≤ 35 kg / m 2 The patient may have a semen volume ≥ 1.4 mL. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of 3 million or less sperm / mL, for example, 2 million or less sperm / mL, for example, 1 million or less sperm / mL, for example, 500,000 or less sperm / mL. The patient may have a total motile sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥ 15% sperm with normal morphology (elliptical head, intact midpiece, and single, uncoiled tail and the ability to swim well and straight). The patient may have a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone ≥ 300 ng / dL (equivalent to ≥ 10.4 nmol / L). In some embodiments, the patient has not received FSH treatment that does not lead to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormone preparation within 3 months prior to screening.

[0093] According to some embodiments, the treatment is effective in improving the likelihood of natural pregnancy observed in the female partners of treated male patients as compared to placebo. According to some embodiments, the treatment is effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective in reducing semen DNA fragmentation of the sperm / semen of the treated male patient. According to some embodiments, the treatment is effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of treated subjects as compared to males treated with placebo. According to some embodiments, the treatment is effective in shortening the time to natural pregnancy in the female partners of treated subjects as compared to males treated with placebo (when evaluable, for example, by one or more of elapsed time and number of menstrual cycles).

[0094] In a further embodiment, there is provided a composition (e.g., a pharmaceutical composition) comprising rFSH for use in the treatment of male factor infertility in a patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation (e.g., follitropin delta), and the rFSH is for administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg).

[0095] Infertility can be at least one sperm-related infertility selected from azoospermia, oligospermia, asthenospermia, teratospermia, hypospermatogenesis, spermatocytopenia, and morphological abnormalities.

[0096] rFSH may contain α2,3-sialylation and α2,6-sialylation, and 5 to 20% of the total sialylation is α2,6-sialylation. rFSH may contain α2,3-sialylation and α2,6-sialylation, 80 to 90% of the total sialylation is α2,3-sialylation, and 10 to 20% of the total sialylation is α2,6-sialylation (e.g., follitropin delta available from Ferring B.V.). rFSH can be rFSH produced or expressed in a human cell line, such as the PERC6® cell line, for example, the PERC6® cell line modified with α2,3-sialyltransferase. The PER.C6® cell line was deposited with the European Collection of Authenticated Cell Cultures under the ECACC deposit number 96022940 as of February 29, 1996.

[0097] In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including a treatment period of at least 1 year). It will be understood that administration of rFSH to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg) may be required for a longer period of up to 18 months, for example, to achieve spermatogenesis.On the one hand, since the therapeutic effect on the patient can persist for a certain period after the treatment is interrupted, a shorter treatment period may be effective.

[0098] The patient may have a body mass index (BMI) ≤ 35 kg / m 2 The patient may have a semen volume ≥ 1.4 mL. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of 3 million or less sperm / mL, for example, 2 million or less sperm / mL, for example, 1 million or less sperm / mL, for example, 500,000 or less sperm / mL. The patient may have a total motile sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥ 15% sperm with normal morphology (oval head, intact midpiece, and single, uncoiled tail, and the ability to swim well and straight). The patient may have a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone ≥ 300 ng / dL (equivalent to ≥ 10.4 nmol / L). As used herein, a "baseline" value refers to the value before the treatment described herein. In some embodiments, the patient has not received FSH treatment that does not lead to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormone preparation within 3 months prior to screening.

[0099] According to some embodiments, the treatment is effective to improve the likelihood of natural pregnancy observed in the female partners of treated male patients as compared to placebo. According to some embodiments, the treatment is effective to improve one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective to reduce semen DNA fragmentation of sperm / semen of treated male patients. According to some embodiments, the treatment is effective to improve the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of treated subjects as compared to male subjects treated with placebo. According to some embodiments, the treatment is effective to shorten the time to natural pregnancy in the female partners of treated subjects as compared to male subjects treated with placebo (as may be evaluated by, for example, one or more of elapsed time and number of menstrual cycles).

[0100] In a further aspect, there is provided a composition (e.g., a pharmaceutical composition) comprising rFSH for use in the treatment of testosterone deficiency in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation (e.g., follitropin delta), and the rFSH is for administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg).

[0101] rFSH may include α2,3-sialylation and α2,6-sialylation, and 5 to 20% of the total sialylation is α2,6-sialylation. rFSH may include α2,3-sialylation and α2,6-sialylation, 80 to 90% of the total sialylation is α2,3-sialylation, and 10 to 20% of the total sialylation is α2,6-sialylation (e.g., follitropin delta available from Ferring B.V.). rFSH can be rFSH produced or expressed in a human cell line, such as the PERC6® cell line, for example, the PERC6® cell line modified with α2,3-sialyltransferase. The PER.C6® cell line was deposited with the European Collection of Authenticated Cell Cultures under the ECACC deposit number 96022940 as of February 29, 1996.

[0102] In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including a treatment period of at least 1 year). It will be understood that administration of rFSH to a patient at a daily dose of 11-13 μg (e.g., 12 μg) may be required for a longer period of up to 18 months, for example, to achieve spermatogenesis.On the one hand, since the therapeutic effect on the patient can persist for a certain period after the treatment is interrupted, a shorter treatment period may be effective.

[0103] The patient may have a body mass index (BMI) ≤ 35 kg / m 2 The patient may have a semen volume ≥ 1.4 mL. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of 3 million or less sperm / mL, for example, 2 million or less sperm / mL, for example, 1 million or less sperm / mL, for example, 500,000 or less sperm / mL. The patient may have a total motile sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥ 15% of sperm with normal morphology (oval head, intact midpiece and single, uncoiled tail and the ability to swim well and straight). The patient may have a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone of ≥ 300 ng / dL (equivalent to ≥ 10.4 nmol / L). In some embodiments, the patient has not received FSH treatment that does not lead to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormone preparation within 3 months prior to screening.

[0104] According to some aspects, the treatment is effective in improving the likelihood of natural pregnancy observed in female partners of treated male patients as compared to placebo. According to some aspects, the treatment is effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective in reducing semen DNA fragmentation of the sperm / semen of the treated male patient. According to some aspects, the treatment is effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in female partners of treated subjects as compared to males treated with placebo. According to some aspects, the treatment is effective in shortening the time to natural pregnancy in female partners of treated subjects as compared to males treated with placebo (when evaluable, for example, by one or more of elapsed time and number of menstrual cycles).

[0105] In a further aspect, there is provided a composition (e.g., a pharmaceutical composition) comprising rFSH for use in the treatment of idiopathic oligospermia in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation (e.g., follitropin delta), and the rFSH is for administration to a patient at a daily dose of 11 to 13 μg (e.g., 12 μg).

[0106] rFSH may contain α2,3-sialylation and α2,6-sialylation, with 5 to 20% of the total sialylation being α2,6-sialylation. rFSH may contain α2,3-sialylation and α2,6-sialylation, with 80 to 90% of the total sialylation being α2,3-sialylation and 10 to 20% of the total sialylation being α2,6-sialylation (e.g., follitropin delta available from Ferring B.V.). rFSH can be rFSH produced or expressed in a human cell line, such as the PERC6® cell line, such as the PERC6® cell line modified with α2,3-sialyltransferase. The PER.C6® cell line was deposited with the European Collection of Authenticated Cell Cultures under ECACC deposit number 96022940 as of February 29, 1996.

[0107] In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including a treatment period of at least 1 year). It will be understood that administration of rFSH to a patient at a daily dose of 11-13 μg (e.g., 12 μg) may be required for a longer period of up to 18 months, for example, to achieve spermatogenesis.On the one hand, since the therapeutic effect on the patient can persist for a certain period after the treatment is interrupted, a shorter treatment period may be effective.

[0108] The patient may have a body mass index (BMI) ≤ 35 kg / m 2 The patient may have a semen volume ≥ 1.4 mL. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of 3 million or less sperm / mL, for example, 2 million or less sperm / mL, for example, 1 million or less sperm / mL, for example, 500,000 or less sperm / mL. The patient may have a total motile sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥ 15% sperm with normal morphology (oval head, intact midpiece, and single, uncoiled tail, and the ability to swim well and straight). The patient may have a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone ≥ 300 ng / dL (equivalent to ≥ 10.4 nmol / L). In some embodiments, the patient has not received FSH treatment that does not lead to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormone preparation within 3 months prior to screening.

[0109] According to some embodiments, the treatment is effective in improving the likelihood of natural pregnancy observed in female partners of treated male patients as compared to placebo. According to some embodiments, the treatment is effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective in reducing semen DNA fragmentation of sperm / semen of treated male patients. According to some embodiments, the treatment is effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in female partners of treated subjects as compared to males treated with placebo. According to some embodiments, the treatment is effective in shortening the time to natural pregnancy in female partners of treated subjects as compared to males treated with placebo (e.g., as may be evaluated by one or more of elapsed time and number of menstrual cycles).

[0110] Method of treatment In a further aspect, there is provided a method of treating infertility in a male patient, comprising administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11-13 μg (e.g., 12 μg) / day. As described above, the rFSH can be administered by injection, such as subcutaneous injection.

[0111] The treatment of infertility can be the treatment of idiopathic infertility. The treatment of infertility can be the treatment of male factor infertility. The infertility can be one or more sperm-related infertility conditions selected from azoospermia, oligospermia, asthenospermia, teratozoospermia, hypospermatogenesis, spermatocytopenia, and morphological abnormalities.

[0112] In a further aspect, there is provided a method for treating male testosterone deficiency, comprising administering to a male patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11-13 μg (e.g., 12 μg) / day. As described above, the rFSH can be administered by injection, such as subcutaneous injection.

[0113] In a further aspect, there is provided a method for treating idiopathic oligospermia in a male patient, the method comprising administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11 to 13 μg (e.g., 12 μg) / day. As described above, the rFSH can be administered by injection, e.g., subcutaneous injection.

[0114] In any of these methods of treatment, the rFSH may comprise α2,3-sialylation and α2,6-sialylation, with 5 to 20% of the total sialylation being α2,6-sialylation. The rFSH may comprise α2,3-sialylation and α2,6-sialylation, with 80 to 90% of the total sialylation being α2,3-sialylation and 10 to 20% of the total sialylation being α2,6-sialylation (e.g., follitropin delta available from Ferring B.V.). The rFSH can be rFSH produced or expressed in a human cell line, e.g., the PERC6® cell line, e.g., the PERC6® cell line modified with α2,3-sialyltransferase. The PER.C6® cell line was deposited with the European Collection of Authenticated Cell Cultures under ECACC deposit number 96022940 as of February 29, 1996.

[0115] In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 28 days (e.g., a medical month). In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period of at least 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 28 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period from 30 days to 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) is for a treatment period selected from 28 days, 30 days, 6 weeks, 8 weeks, 2 months, 10 weeks, 12 weeks, 3 months, 14 weeks, 16 weeks, 4 months, 18 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, and 6 months, or a longer period. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 28 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 30 days. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 2 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 3 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 4 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 5 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for 6 months. In some embodiments, administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg) lasts for a treatment period of at least 6 months (including a treatment period of at least 1 year). It will be understood that administration of rFSH to a patient at a daily dose of 11-13 μg (e.g., 12 μg) may be required for a longer period of up to 18 months, for example, to achieve spermatogenesis.On the one hand, since the therapeutic effect on the patient can persist for a certain period after the treatment is interrupted, a shorter treatment period may be effective.

[0116] In some embodiments, the patient has one or more of the following characteristics before treatment, for example, at the start of treatment or within about 90 days of the start of treatment. The patient may have a body mass index (BMI) ≤ 35 kg / m 2 The patient may have a semen volume ≥ 1.4 mL. The patient may have a baseline total sperm count of 5 million to 39 million. The patient may have a sperm concentration of less than 5 million sperm / mL, for example, less than 4 million sperm / mL. The patient may have a sperm concentration of 3 million or less sperm / mL, for example, 2 million or less sperm / mL, for example, 1 million or less sperm / mL, for example, 500,000 or less sperm / mL. The patient may have a total motile sperm count of 5 million to 16 million, for example, 5 million to 10 million, for example, 6 million to 8 million. The patient may have ≥ 15% sperm with normal morphology (oval head, intact midpiece and single, uncoiled tail and the ability to swim well and straight). The patient may have a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L. The patient may have a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L. The patient may have a baseline serum hormone concentration of testosterone ≥ 300 ng / dL (equal to ≥ 10.4 nmol / L). In some embodiments, the patient has not received FSH treatment that does not lead to pregnancy in the partner. In addition or alternatively, in some embodiments, the patient has not received administration of a hormone preparation within 3 months before screening.

[0117] According to some aspects, the treatment is effective in improving the likelihood of natural pregnancy observed in female partners of treated male patients as compared to placebo. According to some aspects, the treatment is effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or may be effective in reducing semen DNA fragmentation of sperm / semen of treated male patients. According to some aspects, the treatment is effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in female partners of treated subjects as compared to males treated with placebo. According to some aspects, the treatment is effective in shortening the time to natural pregnancy in female partners of treated subjects as compared to males treated with placebo (as may be evaluated by, for example, one or more of elapsed time and number of menstrual cycles).

[0118] Recombinant FSH and rFSH compositions The methods and compositions described herein use recombinant FSH (rFSH) including α2,3-sialylation and α2,6-sialylation. FSH comprises a 92 amino acid alpha subunit common to other glycoprotein hormones, LH and chorionic gonadotropin (CG), and a 111 amino acid beta subunit unique to FSH that confers the biological specificity of the hormone. Each subunit is post-translationally modified by the addition of complex carbohydrate residues. Both subunits have two sites for N-linked glycan attachment, amino acids 52 and 78 of the alpha subunit, and amino acid residues 7 and 24 of the beta subunit. FSH is glycosylated in this way up to about 30% by mass.

[0119] The glycosylation of a given rFSH product reflects the range of glycosyltransferases present in the host cell line. Commercially available rFSH products derived from modified CHO cells have a more limited range of glycan modifications than those seen in native human products. Examples of decreased glycan heterogeneity found in CHO cell-derived rFSH include the absence of bisecting GlcNAc, as well as decreased levels of core fucosylation and sialyl-lactosamine elongation. Furthermore, CHO cells can add sialic acid only using the α2,3 linkage; rFSH derived from CHO cells contains only α2,3-linked sialic acid and no α2,6-linked sialic acid. Thus, CHO cell-derived rFSH differs from naturally produced human FSH (e.g., human pituitary / serum / urinary FSH), which contains glycans having a mixture of α2,3-linked and α2,6-linked sialic acid with α2,3-linked sialic acid being predominant.

[0120] As described above, the Applicants developed rFSH derived from a human cell line which is the subject of International Patent Application No. PCT / GB2009 / 000978 (published as International Publication No. WO 2009 / 127826 A) and which has also been approved by the EC as REVOKELLE® (also known as follitropin delta, FE 999049). By modifying a human cell line to express both rFSH and α2,3 sialyltransferase, a recombinant FSH was produced in which both α2,3-linked sialic acid and α2,6-linked sialic acid were mixed. The amino acid sequence of the human cell line-derived recombinant FSH (e.g., FE 999049 / follitropin delta), which is the subject of International Patent Application No. PCT / GB2009 / 000978 published as International Publication No. WO 2009 / 127826 A, is the same as the native human FSH sequence, but FE 999049 has a different glycosylation pattern. The recombinantly expressed product is highly acidic and has a mixture of both α2,3-linked sialic acid and α2,6-linked sialic acid, the latter being provided by the endogenous sialyltransferase activity. It has been found that the sialic acid linkage type, α2,3- or α2,6-, can have a dramatic effect on the biological clearance of FSH. Thus, REVOKELLE® (e.g., FE 999049) may be more biologically appropriate (and more biologically active) compared to recombinant products derived from CHO cells which have only α2,3-linked sialic acid and a reduced sialic acid content.

[0121] Thus, recombinant FSH comprising α2,3-sialylation and α2,6-sialylation used in accordance with the methods and compositions described herein can be produced or expressed in human cell lines such as the PER.C6® cell line. As described above, the PER.C6® cell line was deposited with the European Collection of Authenticated Cell Cultures under ECACC deposit number 96022940 as of February 29, 1996. Recombinant FSH can be produced or expressed in the PER.C6® cell line, a PER.C6®-derived cell line, or a modified PER.C6® cell line. Recombinant FSH produced or expressed in the PER.C6® cell line will contain some α2,6-linked sialic acid (α2,6-sialylation) resulting from the endogenous 2,6-sialyltransferase activity of the cell line and will likely contain some α2,3-linked sialic acid (α2,3-sialylation) resulting from the endogenous 2,3-sialyltransferase activity. The cell line can be modified using α2,3-sialyltransferase (e.g., to increase the amount of α2,3-sialylation in the product rFSH). The cell line can be modified using α2,6-sialyltransferase (e.g., to increase the amount of α2,6-sialylation in the product rFSH). Alternatively or in addition, recombinant FSH can contain α2,6-linked sialic acid (α2,6-sialylation) resulting from the endogenous sialyltransferase activity of the cell line.

[0122] The recombinant FSH used in the methods and compositions described herein may include α2,3- and α2,6-sialylation. 1% to 99% of the total sialylation of the recombinant FSH for use according to the invention may be α2,3-sialylation. 1% to 99% of the total sialylation of the recombinant FSH for use according to the invention may be α2,6-sialylation. The recombinant FSH may have 1% to 50% of the total sialylation being α2,6-sialylation and 50% to 99% of the total sialylation being 2,3-sialylation. For example, 80% to 95%, such as 80% to 90%, such as 82% to 89%, such as 85% to 89% of the total sialylation may be α2,3-sialylation. For example, 5% to 20%, such as 10% to 20%, such as 11% to 18%, such as 11% to 15% of the total sialylation may be α2,6-sialylation. In one example, the recombinant FSH has 5% to 20% of the total sialylation being α2,6-sialylation and 80% to 95% of the total sialylation being 2,3-sialylation. In another example, the recombinant FSH has 50% to 80% of the total sialylation being α2,6-sialylation and 20% to 50% of the total sialylation being 2,3-sialylation.

[0123] As used herein, "sialylation" means the amount of sialic acid residues present in the recombinant FSH carbohydrate structure. Consistent with use in the art, α2,3-sialylation means sialylation at the 2,3 position and α2,6 sialylation means sialylation at the 2,6 position. Thus, "% of total sialylation that may be α2,3 sialylation" refers to the % of the total number of sialic acid residues present in FSH sialylated at the 2,3 position. The term "% of total sialylation that is α2,6-sialylation" refers to the % of the total number of sialic acid residues present in FSH sialylated at the 2,6 position.

[0124] In all embodiments, the rFSH may exist as a single isoform or as a mixture of isoforms. The composition may be a pharmaceutical composition. The pharmaceutical composition is for the treatment of infertility.

[0125] The recombinant FSH, composition, or pharmaceutical composition can be formulated into well-known compositions for any route of drug administration, typically formulated for subcutaneous injection and administered by subcutaneous injection. Typical compositions include pharmaceutically acceptable carriers, such as aqueous solutions, non-toxic excipients, such as salts and preservatives, buffers, etc., as described in particular in pages 1405 - 1412 and 1461 - 87 of Remington’s Pharmaceutical Sciences fifteenth edition (Matt Publishing Company, 1975), and national formulary XIV fourteenth edition (American Pharmaceutical Association, 1975). For example, the recombinant FSH, composition or pharmaceutical composition can be formulated for injection, such as subcutaneous injection.

[0126] Examples of suitable aqueous and non-aqueous pharmaceutical carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.

[0127] The compositions of the present invention may also include 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 the growth of microorganisms, for example, m-cresol, benzyl alcohol, parabens, chlorobutanol, phenol, sorbic acid, etc. When a preservative is included, benzyl alcohol, phenol and / or m-cresol are preferred, but the preservative is by no means limited to these examples. Furthermore, it may be desirable to include isotonic agents such as sugars, sodium chloride, amino acids, etc.

[0128] The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine operations in the art. See GOODMAN and GILMAN’s THE PHARMACOLOGICAL BASIS FOR THERAPEUTICES, 7th ed. In typical embodiments, the recombinant FSH, composition or agent is provided as a parenteral composition, for example by subcutaneous injection. General methods of preparing parenteral formulations, including those for administration by subcutaneous injection, are known in the art and are described in REMINGTON; THE SCIENCE AND PRACTICE OF PHARMACY, supra, at pages 780-820. The composition can be provided as a liquid formulation or as a solid that is mixed with a sterile injection medium immediately prior to administration. The composition can be provided in unit dosage form for ease of administration and uniformity of dosage. th See, e.g., for example, the recombinant FSH, composition or agent may include one or more of polysorbate 20, L-methionine, phenol, and arginine hydrochloride. Such compositions can be formulated for injection, such as by subcutaneous injection. For example, the composition or agent may be the REKOVELLE® formulation (rFSH with α2,3- and α2,6-sialylation, with excipients phenol, polysorbate 20, L-methionine, sodium sulfate decahydrate, disodium phosphate dodecahydrate, phosphoric acid [for concentration, pH adjustment], sodium hydroxide [for pH adjustment] and water for injection).

[0129] For example, the composition or agent may include one or more of polysorbate 20, L-methionine, phenol, and arginine hydrochloride. Such compositions can be formulated for injection, such as by subcutaneous injection. For example, the composition or agent may be the REKOVELLE® formulation (rFSH with α2,3- and α2,6-sialylation, with excipients phenol, polysorbate 20, L-methionine, sodium sulfate decahydrate, disodium phosphate dodecahydrate, phosphoric acid [for concentration, pH adjustment], sodium hydroxide [for pH adjustment] and water for injection).

[0130] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or another sterile injection medium immediately prior to use. Injectable formulations can be provided in any suitable container, such as vials, prefilled syringes, injection cartridges, and the like.

[0131] The recombinant FSH, composition or agent can be formulated for single use or multiple uses (multiple administrations). When the recombinant FSH, composition or agent is formulated for multiple uses, usually one or more preservatives are included. When a preservative is included, benzyl alcohol, phenol or m-cresol is preferred; however, the preservative is by no means limited to these examples. The composition or agent formulated for single use or multiple uses may further contain an amino acid or a combination of amino acids. Typically, the amino acid is arginine, and is added, for example, as arginine or more typically as arginine hydrochloride.

[0132] The recombinant FSH, composition or agent can be contained in a container such as a vial, a prefilled cartridge (for example, for single administration or multiple uses), or an injection device such as a "pen" for multiple administrations. The recombinant FSH, composition, or agent can be provided in a container (for example, an administration "pen") designed to deliver one or more doses described herein, for example, one or more predetermined doses of 11 to 13 μg (for example, 12 μg) of rFSH. For example, a prefilled cartridge or pen may contain one or more predetermined doses of 11 to 13 μg (for example, 12 μg) of rFSH.

[0133] The recombinant FSH, composition or pharmaceutical composition can be a formulation containing rFSH (for example, an injectable formulation).

[0134] The recombinant FSH, composition or agent can be supplied in any suitable package. For example, the composition or agent may include several containers (for example, prefilled syringes or vials) containing rFSH. The syringe or vial can be packaged in a blister package or other means of maintaining sterility. Any composition or agent may optionally include instructions for using the FSH formulation.

[0135] In a further aspect, there is provided the use of recombinant follicle stimulating hormone (FSH) comprising α2,3- and α2,6-sialylation in the manufacture of a medicament for use as described herein.

[0136] Further aspects will be described in the following examples, which are not limiting in any way.

Example

[0137] The following example uses REKOVELLE® (chorionic gonadotropin delta), a recombinant FSH containing α2,3- and α2,6-sialylation expressed in a PER.C6® cell line modified by the methods disclosed in International Publication No. WO 2013 / 020996 pamphlet and International Publication No. WO 2009 / 127826A pamphlet.

[0138] The marketing authorization holder of REKOVELLE® is Ferring Pharmaceuticals A / S of Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark, and REKOVELLE® is available in the UK from Ferring Pharmaceuticals of Drayton Hall, Church Road, West Drayton, UB7 7PS, UK.

[0139] The active substance in REKOVELLE® is chorionic gonadotropin delta (FE999049). REKOVELLE® is highly sialylated, containing α2,3-sialylation and α2,6-sialylation, with approximately 85 - 90% of total sialylation being α2,3-sialylation and approximately 10 - 15% of total sialylation being α2,6-sialylation.

[0140] REKOVELLE® is a colorless, clear solution for injection (injectable). Each 1 mL of the solution contains 33.3 micrograms of chorionic gonadotropin delta in each 1 mL of the solution. Other components are phenol, polysorbate 20, L-methionine, sodium sulfate decahydrate, disodium phosphate dodecahydrate, concentrated phosphoric acid, sodium hydroxide, and water for injection.

[0141] Example 1: A trial (ADAM) to compare the efficacy and safety of follitropin delta compared to placebo (ineffective treatment) in the treatment of men with idiopathic infertility (a decrease in semen quality that cannot be explained). Introduction The ADAM trial examines whether men with idiopathic infertility, after being treated with daily administration of 12 μg of recombinant follicle-stimulating hormone (rFSH) for 6 months, have an improved likelihood of natural pregnancy in their female partners compared to men treated with placebo (ineffective treatment). Since the therapeutic effect on patients can persist over a certain period after treatment is interrupted, the trial will follow up the results for 3 months after the end of the 6-month test treatment, i.e., after the end of treatment. As described above, the therapeutic effect can be observed over shorter periods such as 30 days or 1 month. The treatment may also be effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or in reducing semen DNA fragmentation of sperm / semen in treated male patients. The treatment may also be effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of treated subjects compared to men treated with placebo (ineffective treatment). The treatment may also be effective in shortening the time to natural pregnancy in the female partners of treated subjects compared to men treated with placebo (when evaluated by one or more of, for example, elapsed time and number of menstrual cycles). The treatment may also be effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partners of treated subjects compared to men treated with placebo. The treatment may also be effective in shortening the time to natural pregnancy in the female partners of treated subjects compared to men treated with placebo (when evaluated by one or more of, for example, elapsed time and number of menstrual cycles).

[0142] Methods This is a randomized, double-blind, placebo-controlled, multi-site trial to evaluate the efficacy and safety of FE 999049 in men with idiopathic infertility. Patients are expected to be enrolled at approximately 25 sites in approximately 7 countries in Europe and North America. All participants will provide written informed consent prior to receiving any study-related procedures.

[0143] Study participants It is planned to enroll 400 men aged 18 to 50 years (inclusive of end values) with a history of infertility for 12 to 60 months with their current partner (at the time of consent signature). Their current partners must be premenopausal women aged 18 to 35 years who are not contraindicated for pregnancy, have regular menstrual cycles of 21 to 35 days, and have no history or current condition of pelvic inflammatory disease, endometriosis stage II-IV by definitive or empirical diagnosis, or tubal ligation.

[0144] Additional selection criteria for male subjects are body mass index (BMI) ≤ 35 kg / m 2 , total sperm count at screening of 5 million to 39 million (confirmed by two consecutive samples taken more than 2 weeks before randomization), total motile sperm count at screening of 5 million to 16 million (confirmed by two consecutive samples taken more than 2 weeks before randomization), semen volume at screening ≥ 1.4 mL (confirmed by two consecutive samples taken more than 2 weeks before randomization), serum follicle-stimulating hormone (FSH) value at screening of 1.5 to 8.0 IU / L, serum luteinizing hormone (LH) value at screening of 1.2 to 7.5 IU / L, and serum total testosterone value at screening ≥ 300 ng / dL (equal to ≥ 10.4 nmol / L). Exclusion criteria include past FSH treatment not leading to pregnancy and administration of hormonal preparations within 3 months before screening. The first male will be enrolled in August 2022, and 400 will be randomized at multiple sites in the United States and European countries.

[0145] Study procedures Within 90 days before randomization, screen the subjects to determine whether they comply with the inclusion criteria and exclusion criteria. Approximately 200 participants will receive a once-daily subcutaneous injection of 12 μg of FE 999049, and approximately 200 participants will be randomized to receive placebo treatment (Table 1).

[0146]

Table 1

[0147] All randomized subjects will continue treatment for 6 months, followed by an additional 3 months of follow-up. The 6-month period was chosen as the treatment period to ensure subject exposure to FE 999049 during at least two complete spermatogenic cycles and to allow for a thorough evaluation of the therapeutic potential of FE 999049. Subjects will remain in the study for 9 months regardless of whether natural pregnancy is established at an earlier time point. Subjects will also remain in the study if the couple experiences a pregnancy loss.

[0148] In addition to the pregnancy outcome of the partner, changes in semen parameters (e.g., semen volume, sperm concentration, total sperm count, sperm motility, sperm morphology, and DNA fragmentation) and other male patient parameters (e.g., changes in serum hormone concentrations (e.g., FSH, LH, inhibin B, testosterone, estradiol) and changes in free testosterone concentration) will be measured and analyzed. Semen and sperm parameters are evaluated by testing methods known in the art, such as those compliant with World Health Organisation (WHO) standards. See, for example, Boitrelle et al., Life (2021). Additionally, subjects may evaluate their own sperm parameters using a sperm testing device such as the ExSeed (registered trademark) device (ExSeed Health, Denmark), or other sperm testing devices, such as those outlined in Onofre, et al., Facts Views Vis ObGyn (2021) 13(1):79-93.

[0149] All cases of natural pregnancy in female partners that occur within 9 months from the date of randomization of male subjects are followed throughout the pregnancy to collect information on pregnancy loss and live birth. Additionally, data on minor / major congenital anomalies of the neonate are collected at birth, 4 weeks after birth, and 1 year after birth.

[0150] Test Results The primary endpoint of the trial is natural pregnancy observed in female partners within 9 months after the start of treatment of male subjects, where natural pregnancy is defined as a viable pregnancy (confirmation of fetal heart tones by ultrasound and at least one intrauterine gestational sac). Secondary objectives are the changes in positive urinary βhCG in female partners, time to natural pregnancy, semen parameters (e.g., semen volume, sperm concentration, total sperm count, sperm motility, sperm morphology, and semen DNA fragmentation), changes in serum hormone concentrations (e.g., FSH, LH, inhibin B, testosterone, estradiol), and changes in free testosterone concentration, which objectively measure the effect of FE 999049 treatment in male subjects. Safety is evaluated by assessing blood samples for anti-FSH antibody and identifying immune-related adverse events.

[0151] Results The ADAM trial will be the first trial to use FE 999049 (follitropin delta) for the treatment of idiopathic infertility in male patients. The inventors believe that a daily dose of 12 μg of FE 999049, which is an rFSH containing α2,3-sialylation and α2,6-sialylation, will be safe and well-tolerated in the patient population described herein. Furthermore, the inventors believe that a high daily dose of 12 μg of FE 999049 (rFSH containing α2,3-sialylation and α2,6-sialylation) will result in a significantly higher (e.g., as measured by AUC and C max when measured) and more consistent FSH exposure than that observed with daily administration of conventional (e.g., urine or CHO cell-derived) FSH.

[0152] Increased FSH dosages, as compared to past trials (see, e.g., Ding and Cannarella described on page 2 above), are expected to yield better signs of the greatest possible therapeutic effect on natural pregnancy rates and semen parameters. The study population was carefully defined to include men who received a diagnosis of unexplained infertility, including asthenozoospermia, consistent with the possible benefits from FSH treatment. The primary endpoint was a natural ongoing pregnancy observed in the female partner within 9 months of randomization of male subjects, and secondary endpoints included changes in semen parameters. A Bayesian framework was used to determine the existence of a single target treatment effect, defined such that effectiveness above this target was aimed for. The trial aimed to demonstrate at least a 10% improvement in the natural pregnancy rate when comparing the FE 999049 and placebo treatment groups. The proof-of-concept conclusion will be based on the primary endpoint demonstrating evidence of statistical significance and clinical relevance using Bayesian decision criteria.

[0153] The inventors believe that the therapeutic compositions and methods described herein will result in a 10% improvement in the natural pregnancy rate when comparing the FE 999049 treatment group to the placebo treatment group; such an improvement is considered clinically significant. Accordingly, the inventors believe that the dosing regimens described herein will improve the likelihood of natural pregnancy observed in the female partners of treated subjects as compared to placebo (non-effective treatment).

[0154] The products, products for use, uses and methods (recombinant FSH, recombinant FSH products, pharmaceutical compositions, uses and methods) defined by the following numbered paragraphs are disclosed above herein:

[0155] 1. A composition comprising rFSH for use in the treatment of idiopathic infertility in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and wherein the rFSH is for administration to patients at a daily dose of 11 to 13 μg (e.g., 12 μg).

[0156] 2. A composition comprising rFSH for use in the treatment of infertility in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to patients at a daily dose of 11 to 13 μg (for example, 12 μg).

[0157] 3. A composition comprising rFSH for use in the treatment of male factor infertility in patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to patients at a daily dose of 11 to 13 μg (for example, 12 μg).

[0158] 4. A composition for use according to paragraph 1, 2 or 3, wherein the infertility can be at least one sperm-related infertility selected from azoospermia, oligospermia, asthenozoospermia, teratozoospermia, oligospermia, spermatocytopenia and morphological abnormalities.

[0159] 5. A composition for use according to any of the above paragraphs, wherein 5 to 20% of the total sialylation is α2,6-sialylation and / or the rFSH is produced or expressed in the PERC6® cell line.

[0160] 6. A composition for use according to any of the above paragraphs, wherein administration to patients at a daily dose of 11 to 13 μg (for example, 12 μg) is over a treatment period selected from (i) at least 28 days; (ii) from 28 days to 6 months; (iii) at least 30 days; (iv) from 30 days to 6 months; (v) 28 days; (vi) 30 days; (vii) 6 weeks; (viii) 8 weeks; (ix) 2 months; (x) 10 weeks; (xi) 12 weeks; (xii) 3 months; (xiii) 14 weeks; (xiv) 16 weeks; (xv) 4 months; (xvi) 18 weeks; (xvii) 20 weeks; (xviii) 5 months; (xix) 22 weeks; (xx) 24 weeks; and (xxi) 6 months.

[0161] 7. A composition for use according to any of the above paragraphs, wherein the patient has a body mass index (BMI) ≤ 35 kg / m 2 and has.

[0162] 8. A composition for use as described in any of the above paragraphs, wherein the patient has a semen volume ≧ 1.4 mL.

[0163] 9. A composition for use as described in any of the above paragraphs, wherein the patient has a baseline total sperm count of 5 million to 39 million.

[0164] 10. A composition for use as described in any of the above paragraphs, wherein the patient has a sperm concentration of less than 5 million sperm / mL.

[0165] 11. A composition for use as described in any of the above paragraphs, wherein the patient has a sperm concentration of 3 million or less sperm / mL, such as 2 million or less sperm / mL, such as 1 million or less sperm / mL, such as 500,000 or less sperm / mL.

[0166] 12. A composition for use as described in any of the above paragraphs, wherein the patient has a total motile sperm count of 5 million to 16 million.

[0167] 13. A composition for use as described in any of the above paragraphs, wherein the patient has ≧ 15% sperm with normal morphology (elliptical head, intact midpiece, and a single, uncoiled tail, as well as the ability to swim well and straight).

[0168] 14. A composition for use as described in any of the above paragraphs, wherein the patient has a baseline serum hormone concentration of follicle-stimulating hormone (FSH) of 1.5 - 8.0 IU / L.

[0169] 15. A composition for use as described in any of the above paragraphs, wherein the patient has a baseline serum hormone concentration of luteinizing hormone (LH) of 1.2 - 7.5 IU / L.

[0170] 16. A composition for use as described in any of the above paragraphs, wherein the patient has a baseline serum hormone concentration of testosterone of ≧ 300 ng / dL (equivalent to ≧ 10.4 nmol / L).

[0171] 17. A composition comprising rFSH for use in the treatment of testosterone deficiency in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg).

[0172] 18. A composition comprising rFSH for use in the treatment of idiopathic oligospermia in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the rFSH is for administration to a patient at a daily dose of 11-13 μg (e.g., 12 μg).

[0173] 19. A method for treating infertility in male patients, comprising administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11-13 μg / day, optionally at a dose of 12 μg / day.

[0174] 20. The method according to paragraph 19, wherein the infertility is male factor infertility.

[0175] 21. The method according to paragraph 19, wherein the infertility is idiopathic infertility.

[0176] 22. The infertility can be at least one sperm-related infertility selected from azoospermia, oligospermia, asthenospermia, teratospermia, oligospermia, spermatocytopenia, and morphological abnormalities. The method according to paragraph 19.

[0177] 23. A method for treating testosterone deficiency in male patients, comprising administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11-13 μg / day, optionally at a dose of 12 μg / day.

[0178] 24. A method for treating idiopathic oligospermia in male patients, comprising administering to the patient rFSH comprising α2,3-sialylation and α2,6-sialylation, wherein the rFSH is administered at a dose of 11 to 13 μg / day, optionally at a dose of 12 μg / day.

[0179] 25. The method according to any one of paragraphs 19 to 24, wherein 5 to 20% of the total sialylation of rFSH is α2,6-sialylation.

[0180] 26. The method according to any one of paragraphs 19 to 25, wherein the rFSH is produced or expressed in the PERC6® cell line.

[0181] 27. The method according to any one of paragraphs 19 to 26, comprising administering to the patient rFSH at a daily dose of 11 to 13 μg over a treatment period selected from (i) at least 28 days; (ii) from 28 days to 6 months; (iii) at least 30 days; (iv) from 30 days to 6 months; (v) 28 days; (vi) 30 days; (vii) 6 weeks; (viii) 8 weeks; (ix) 2 months; (x) 10 weeks; (xi) 12 weeks; (xii) 3 months; (xiii) 14 weeks; (xiv) 16 weeks; (xv) 4 months; (xvi) 18 weeks; (xvii) 20 weeks; (xviii) 5 months; (xix) 22 weeks; (xx) 24 weeks; and (xxi) 6 months.

[0182] 28. The patient has the following characteristics before treatment: Body mass index (BMI) ≤ 35 kg / m 2 ; Seminal volume ≥ 1.4 mL; Total sperm count of 5 million to 39 million; Sperm concentration of less than 5 million sperm / mL; Sperm concentration of 3 million or less sperm / mL; Total motile sperm count of 5 million to 16 million; ≥ 15% of sperm with normal morphology; Serum concentration of follicle-stimulating hormone (FSH) of 1.5 to 8.0 IU / L; Serum concentration of luteinizing hormone (LH) of 1.2 to 7.5 IU / L; A serum concentration of testosterone of ≧300 ng / dL (≧10.4 nmol / L) The method according to any one of paragraphs 19 to 27, having one or more or all of the above.

[0183] 29. The method according to any one of paragraphs 19 to 28, wherein the patient has a sperm concentration selected from less than 5 million sperm / mL, less than 4 million sperm / mL, less than 3 million sperm / mL, less than 2 million sperm / mL, less than 1 million sperm / mL, and less than 0.5 million sperm / mL.

[0184] 30. The method according to any one of paragraphs 19 to 29, wherein the method is effective in providing an improved likelihood of natural pregnancy in the female partner of the treated male patient.

[0185] 31. The method according to any one of paragraphs 19 to 30, wherein the method is effective in improving one or more or all of semen volume, sperm concentration, total sperm count, sperm motility, and sperm morphology, or in reducing semen DNA fragmentation of sperm / semen of the treated male patient.

[0186] 32. The method according to any one of paragraphs 19 to 31, wherein the method is effective in improving the likelihood of a positive β-human chorionic gonadotropin (βhCG) urine test in the female partner of the treated subject as compared to a male treated with a placebo.

[0187] 33. The method according to any one of paragraphs 19 to 32, wherein the method is effective in shortening the time to natural pregnancy in the female partner of the treated subject as compared to a male treated with a placebo.

Claims

1. A composition comprising rFSH for use in the treatment of idiopathic infertility in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the composition is for administration to the patient at a daily dose of 12 to 13 μg (e.g., 12 μg).

2. A composition comprising rFSH for use in the treatment of infertility in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the composition is for administration to the patient at a daily dose of 12 to 13 μg (e.g., 12 μg).

3. A composition comprising rFSH for use in the treatment of male factor infertility in a patient, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the composition is for administration to the patient at a daily dose of 12 to 13 μg (e.g., 12 μg).

4. The composition according to any one of claims 1 to 3, wherein the infertility may be at least one sperm-related infertility selected from azoospermia, oligospermia, asthenospermia, teratospermia, oligospermia, polyspermia, and morphological abnormalities.

5. The composition according to any one of claims 1 to 3, wherein 5 to 20% of the total sialylation is α2,6-sialylation, and / or the rFSH is produced or expressed in the PERC6® cell line.

6. The composition according to any one of claims 1 to 3, wherein the administration to the patient at a daily dose of 12 to 13 μg (e.g., 12 μg) is for a treatment period selected from (i) at least 28 days; (ii) from 28 days to 6 months; (iii) at least 30 days; (iv) from 30 days to 6 months; (v) 28 days; (vi) 30 days; (vii) 6 weeks; (viiii) 8 weeks; (ix) 2 months; (x) 10 weeks; (xi) 12 weeks; (xi) 3 months; (xiiii) 14 weeks; (xiv) 16 weeks; (xv) 4 months; (xvi) 18 weeks; (xvii) 20 weeks; (xviiii) 5 months; (xix) 22 weeks, (xx) 24 weeks, and (xxi) 6 months.

7. The aforementioned patient had a body mass index (BMI) of ≤ 35 kg / m². ２ A composition according to any one of claims 1 to 3, having the following characteristics.

8. The composition according to any one of claims 1 to 3, wherein the patient has a semen volume of ≥ 1.4 mL.

9. The composition according to any one of claims 1 to 3, wherein the patient has a baseline total sperm count of 5 million to 39 million.

10. The composition according to any one of claims 1 to 3, wherein the patient has a sperm concentration of less than 5 million sperm / mL.

11. The composition according to any one of claims 1 to 3, wherein the patient has a sperm concentration of 3 million or less sperm / mL, for example, 2 million or less sperm / mL, for example, 1 million or less sperm / mL, for example, 500,000 or less sperm / mL.

12. The composition according to any one of claims 1 to 3, wherein the patient has a total motile sperm count of 5 million to 16 million.

13. The composition according to any one of claims 1 to 3, wherein the patient has ≥15% sperm having normal morphology (oval head, intact center and uncoiled single tail and ability to swim well and straight), and / or the patient has a baseline serum hormone concentration of 1.5 to 8.0 IU / L of follicle-stimulating hormone (FSH), and / or the patient has a baseline serum hormone concentration of 1.2 to 7.5 IU / L of luteinizing hormone (LH), and / or the patient has a baseline serum hormone concentration of ≥300 ng / dL (equal to ≥10.4 nmol / L) of testosterone.

14. A composition comprising rFSH for use in the treatment of testosterone deficiency in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the composition is for administration to the patient at a daily dose of 11 to 13 μg (e.g., 12 μg).

15. A composition comprising rFSH for use in the treatment of idiopathic oligospermia in male patients, wherein the rFSH comprises α2,3-sialylation and α2,6-sialylation, and the composition is for administration to the patient at a daily dose of 12 to 13 μg (e.g., 12 μg).