Compositions and methods for controlled ovarian stimulation

Abstract

Products and pharmaceutical compositions comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation).

Description

[0001] Compositions and Methods for Controlled Ovarian Stimulation

[0002] The present invention relates to products, compositions and methods for the treatment of infertility.

[0003] Background

[0004] Assisted reproductive technologies (ART) such as in vitro fertilisation (IVF) and microinsemination (or intracytoplasmic sperm injection, ICSI) are well known. ART generally requires a step of controlled ovarian stimulation (COS), in which a cohort of follicles is stimulated to maturity. Standard COS regimens include administration of gonadotrophins, such as follicle stimulating hormone (FSH), alone or in combination with luteinising hormone (LH) activity, to stimulate multiple follicular development. Usually COS requires administration of a GnRH agonist or GnRH antagonist prior to and / or during stimulation to prevent a premature LH surge which may induce ovulation before planned oocyte retrieval. The pharmaceutical compositions generally used for COS include recombinant follicle stimulating hormone (rFSH) including REKOVELLE® and GONAL-F®, urinary derived FSH, recombinant FSH + LH preparations, urinary derived menotrophin [human menopausal gonadotrophin (hMG)] and highly purified human menopausal gonadotrophin (HP-hMG).

[0005] In case of a too high ovarian response, COS can be associated with a risk of ovarian hyperstimulation syndrome (OHSS), which can become life threatening in severe cases. The ability to predict the ovarian response potential of women to COS may allow the development of personalised or individualised COS protocols. Such individualised protocols could, for example, reduce the risk of OHSS in women predicted to have an excessive ovarian response to COS, and / or improve the chance of pregnancy in women classed as poor responders. Levels of AMH are directly correlated with the ovarian response to gonadotrophins during COS. Thus, high levels of AMH are a good predictor of excessive ovarian response, and an indicator of risk of OHSS, whereas low levels of AMH predict a poor ovarian response to COS.

[0006] As indicated above, standard COS protocols require daily FSH administration to induce multiple follicular growth to obtain sufficient oocytes for IVF / ICSI . FSH is a natural hormone that is secreted by the anterior pituitary gland. In healthy women FSH induces monthly the growth of a single dominant follicle that ovulates during each natural cycle. FSH purified from the urine of post-menopausal women has been used for many years in infertility treatment, both to promote ovulation in natural reproduction and to induce multiple follicular growth to obtain sufficient oocytes for ART.

[0007] Until recently, the only approved rFSH products for ovarian stimulation, such as follitropin alfa (GONAL-F®, Merck Serono I EMD Serono) and follitropin beta (PUREGON® / FOLLISTIM®, MSD / Schering-Plough), were derived from a Chinese Hamster Ovary (CHO) cell line. The present applicants have developed a human cell line-derived rFSH which is the subject of International Patent Application No. PCT / GB2009 / 000978, published as W02009 / 127826A. On 13 December 2016, the European Commission (EC) granted marketing authorisation for REKOVELLE® (follitropin delta, also known as FE 999049), a human cell line-derived recombinant follicle stimulating hormone (human rFSH), for use in controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART), such as an in vitro fertilisation (IVF) cycle. REKOVELLE® is the first rFSH to be derived from a human cell line. The REKOVELLE® (follitropin delta) product is produced by the methods disclosed in International Patent Application No. PCT / GB2009 / 000978.

[0008] As explained above, COS protocols may also use FSH and LH activity, and the latter may be in the form of human chorionic gonadotropin (hCG). Human chorionic gonadotropin (hCG) is a natural glycoprotein produced by the trophoblast cells that form the human placenta. During a normal pregnancy; hCG secreted by the trophoblasts / placenta maintains the corpus luteum after LH secretion decreases, supporting continued secretion of oestrogen and progesterone to ensure embryo implantation and development of the early pregnancy. During the normal menstrual cycle, LH supports FSH in the development and maturation of the dominant follicle, and since hCG also stimulates the LH / CG receptor, it can substitute for LH in this role.

[0009] HCG extracted from the urine of pregnant women [CHORAGON® (Ferring)] has been used for many years in infertility treatment for triggering ovulation. The production of hCG extracted from urine involves the collection and processing of large amounts of urine. A recombinant version of hCG, OVITRELLE® (Merck Serono), is also available and expressed in CHO cells. These products are used for triggering ovulation and are not approved for use during COS.

[0010] The present applicants have developed FE999032, a human cell line-derived recombinant hCG which is the subject of International Patent Application No. PCT / GB2010 / 001854, published as WO2011 / 042688A. Recombinant hCG was made by engineering a human cell line to express both rhCG and a2,3 sialyltransferase. The expressed product FE99302 is highly acidic and carries a mix of both a2,3- and a2,6-linked sialic acids; the latter provided by the endogenous sialyl transferase activity. Recombinant hCG with a mixture of both a2,3 and a2,6-linked sialic acid has two advantages over rhCG expressed in conventional CHO cells: first the material is more highly sialylated due to the combined activities of the two sialyltransferases; and secondly the material more closely resembles the natural hCG. A phase I trial showed that single subcutaneous administration of 4-256 pg FE 999302, and repeated administration of 8 pg / day and 16 pg / day FE 999302, were safe and well tolerated and did not cause any safety concerns. FE 999302 demonstrated different pharmacokinetics (AUG) to a CHO cell derived hCG product.

[0011] The efficacy and safety of daily doses of FE 999302 (CG beta) as add-on treatment to the daily doses of recombinant follicle-stimulating hormone (rFSH) follitropin delta (REKOVELLE, Ferring) was investigated in the phase 2 trial 000289 (RAINBOW), which included women undergoing controlled ovarian stimulation with an individualised dose of follitropin delta in a long gonadotropin-releasing hormone (GnRH) agonist protocol. Since the therapeutic window of CG beta was unknown, the trial was designed to investigate the efficacy and safety of a broad range of CG beta doses to enable the selection of the optimal CG beta dose or a range of doses for further development. All tested CG beta doses were well-tolerated and no safety concerns were identified. However, regardless of the CG beta dose, a reduction in the number of intermediate follicles available at end-of stimulation was observed impacting all down-stream parameters, including the number of good-quality blastocysts and pregnancy rates.

[0012] There remains a need for COS protocols which provide adequate response to stimulation and / or decreased risk of OHSS.

[0013] SUMMARY

[0014] The present applicants have developed products and compositions including rFSH and rhCG which provide effective and safe dosing of FSH and hCG. hCG dosing every other day

[0015] In accordance with some aspects of the invention, there is provided a product (e.g. a pharmaceutical product) comprising recombinant follicle stimulating hormone (rFSH) and recombinant human chorionic gonadotropin (rhCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered daily (e.g. starting on day 1 of treatment); and the recombinant hCG is to be administered every other (e.g. starting on day 1 of treatment). The product may be for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female (e.g. human) patient. The product may be for use wherein the recombinant FSH is to be administered daily from day 1 of treatment (stimulation); and the recombinant hCG is to be administered every other day starting from day 1 of treatment (stimulation). The product may be for use wherein the recombinant FSH is to be administered at a dose of 9 to 18 pg, e.g. 9 to 12 pg, e.g. 10 pg or 15 pg per day starting from day 1 of treatment (stimulation). The product may be for use wherein the recombinant hCG is to be administered at a dose of 0.1 to 1 pg hCG, e.g. 0.1 to 0.5 pg hCG, e.g. 0.25 pg hCG every other day starting from day 1 of treatment (stimulation). The product may be for use wherein the recombinant FSH includes a2,6-sialylation and a2,3- sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6-sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation or optionally wherein 50 % to 99% of the total sialylation is a2, 6-sialyation, and 1 % to 50% of the total sialylation is a 2,3-sialyation. The product may be for use wherein the recombinant hCG includes a2,6-sialylation and a2,3- sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. The product may be for use wherein a GnRH antagonist is administered starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation). The GnRH antagonist may be administered (e.g. daily) starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation) until the end of treatment. The GnRH antagonist may be ganirelix acetate administered (e.g. daily, e.g. at a daily dose of 0.25 mg) starting from day 5 to 7 (e.g. starting from day 6) of treatment (stimulation) until the end of treatment.

[0016] In accordance with some aspects of the invention, there is provided a product (e.g. a pharmaceutical product) comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 9 to 12, e.g. 10 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.25 pg hCG every other day starting from day 1 of treatment.

[0017] The product may be for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female (e.g. human) patient. The product may be for use wherein the recombinant FSH includes a2,6-sialylation and a2,3-sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6-sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation or optionally wherein 50 % to 99% of the total sialylation is a2, 6-sialyation, and 1% to 50% of the total sialylation is a 2,3-sialyation. The product may be for use wherein the recombinant hCG includes a2,6-sialylation and a2,3-sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. The product may be for use wherein a GnRH antagonist is administered starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation). The GnRH antagonist may be administered (e.g. daily) starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation) until the end of treatment. The GnRH antagonist may be ganirelix acetate administered (e.g. daily, e.g. at a daily dose of 0.25 mg) starting from day 5 to 7 (e.g. starting from day 6) of treatment (stimulation) until the end of treatment.

[0018] It will be appreciated that products according to these aspects of the invention may comprise separate (e.g. injectable) formulations of rFSH and of rhCG. In other words, in products according to these aspects of the invention, the rFSH and hCG will generally be formulated separately (e.g. each as injectable formulations as described herein), so the rFSH can be injected every day and the rhCG injected every other day. However, it will be appreciated that other arrangements are possible, for example the products according to these aspects of the invention may comprise a combined rFSH and hCG formulation [e.g. for administration every other day starting from day 1 of treatment] and a separate rFSH formulation [e.g. for administration every other day starting from day 2 of treatment].

[0019] Nonclinical data in the rat indicate that very low doses of FE 999302 can augment the FSH treatment. The applicants therefore proposed a clinical trial using a dose of 0.25 pg rhCG (FE 999302 ) every second day, alongside a daily dose of 10 pg rFSH (Rekovelle). The dose of 0.25 pg rhCG is well below the lowest dose (1 pg daily) tested in the RAINBOW trial, and well below known doses of rhCG used alongside rFSH.

[0020] In further aspects, there is provided a method of treating infertility (e.g. by controlled ovarian stimulation) in a female patient comprising administering recombinant follicle stimulating hormone (rFSH) daily (e.g. starting on day 1 of treatment / stimulation) and administering recombinant hCG (rhCG) every other day (e.g. starting on day 1 of treatment / stimulation). The method may comprise administering rFSH daily from day 1 of treatment (stimulation) and administering rhCG every other day starting from day 1 of treatment (stimulation). The rFSH may be administered at a dose of 9 to 18 pg, e.g. 9 to 12 pg, e.g. 10 pg or 15 pg FSH per day starting from day 1 of treatment (stimulation). The rhCG may be administered at a dose of 0.1 to 1 pg hCG, e.g. 0.1 to 0.5 pg hCG, e.g. 0.25 pg hCG every other day starting from day 1 of treatment (stimulation). The rFSH may include a2,6-sialylation and a2,3-sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6-sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation or optionally wherein 50 % to 99% of the total sialylation is a2, 6- sialyation, and 1 % to 50% of the total sialylation is a 2,3-sialyation. The rhCG may include a2,6-sialylation and a2,3-sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. The method may further comprise administration of a GnRH antagonist starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation). The GnRH antagonist may be administered (e.g. daily) starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation) until the end of treatment. The GnRH antagonist may be ganirelix acetate administered (e.g. daily, e.g. at a daily dose of 0.25 mg) starting from day 5 to 7 (e.g. starting from day 6) of treatment (stimulation) until the end of treatment.

[0021] In further aspects, there is provided a method of treating infertility (e.g. by controlled ovarian stimulation) in a female patient comprising administering recombinant follicle stimulating hormone (FSH) at a dose of 9 to 12 pg, e.g. 10 pg FSH per day starting from day 1 of treatment and administering recombinant human chorionic gonadotropin (hCG) at a dose of 0.25 pg hCG every other day starting from day 1 of treatment. The rFSH may include a2,6-sialylation and a2,3-sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6-sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation or optionally wherein 50 % to 99% of the total sialylation is a2, 6-sialyation, and 1% to 50% of the total sialylation is a 2,3-sialyation. The rhCG may include a2,6-sialylation and a2,3-sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. The method may further comprise administration of a GnRH antagonist starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation). The GnRH antagonist may be administered (e.g. daily) starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation) until the end of treatment. The GnRH antagonist may be ganirelix acetate administered (e.g. daily, e.g. at a daily dose of 0.25 mg) starting from day 5 to 7 (e.g. starting from day 6) of treatment (stimulation) until the end of treatment.

[0022] In a further aspect there is provided the use of recombinant follicle stimulating hormone (FSH) and recombinant hCG (rhCG) in the manufacture of a product or medicament for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered daily (e.g. starting on day 1 of treatment); and the recombinant hCG is to be administered every other day (e.g. starting on day 1 of treatment). The product or medicament may be for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female (e.g. human) patient. The product or medicament may be for use as described herein.

[0023] In a further aspect there is provided the use of recombinant follicle stimulating hormone (FSH) and recombinant hCG (rhCG) in the manufacture of a product or medicament for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 9 to 12 pg, e.g. 10 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.25 pg hCG every other day starting from day 1 of treatment. The product or medicament may be for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female (e.g. human) patient. The product or medicament may be for use as described herein. hCG dosing every day

[0024] The applicants have also devised COS protocols wherein a very low daily dose of, for example, 0.25 pg or 1 pg rhCG (FE 999302), is administered every day alongside a daily dose of 10 pg or 15 pg rFSH (Rekovelle).

[0025] Thus, in aspects of the invention, there is provided a composition (e.g. pharmaceutical composition) comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 9 to 12 pg, e.g. 10 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.15 pg to 1 .1 pg hCG per day, for example 0.25 pg or 1 pg hCG per day starting from day 1 of treatment. In other aspects of the invention, there is provided a composition (e.g. pharmaceutical composition) comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 12 to 18 pg, e.g. 15 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.15 pg to 1 pg hCG per day, for example 0.15 pg to 0.35 pg hCG per day, for example 0.25 pg hCG per day starting from day 1 of treatment. The product may be for use wherein the recombinant FSH includes a2,6- sialylation and a2,3-sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6- sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation or optionally wherein 50 % to 99% of the total sialylation is a2, 6-sialyation, and 1 % to 50% of the total sialylation is a 2,3- sialyation. The product may be for use wherein the recombinant hCG includes a2,6-sialylation and a2,3-sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. The product may be for use wherein a GnRH antagonist is administered starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation). The GnRH antagonist may be administered (e.g. daily) starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation) until the end of treatment. The GnRH antagonist may be ganirelix acetate administered (e.g. daily, e.g. at a daily dose of 0.25 mg) starting from day 5 to 7 (e.g. starting from day 6) of treatment (stimulation) until the end of treatment. In further aspects, there is provided a method of treating infertility (e.g. by controlled ovarian stimulation) in a female patient comprising administering recombinant follicle stimulating hormone (FSH) at a dose of 9 to 12 pg, e.g. 10 pg FSH per day starting from day 1 of treatment and administering recombinant human chorionic gonadotropin (hCG) at a dose of of 0.15 pg to 1 .1 pg hCG per day, for example 0.25 pg or 1 pg hCG per day starting from day 1 of treatment. In still further aspects, there is provided a method of treating infertility (e.g. by controlled ovarian stimulation) in a female patient comprising administering recombinant follicle stimulating hormone (FSH) at a dose of 12 to 18 pg, e.g. 15 pg FSH per day starting from day 1 of treatment and administering recombinant human chorionic gonadotropin (hCG) at a dose of 0.15 pg to 1 pg hCG per day, for example 0.15 pg to 0.35 pg hCG per day, for example 0.25 pg hCG per day starting from day 1 of treatment. The rFSH may include a2,6-sialylation and a2,3- sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6-sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation or optionally wherein 50 % to 99% of the total sialylation is a2, 6-sialyation, and 1 % to 50% of the total sialylation is a 2,3-sialyation. The rhCG may include a2,6-sialylation and a2,3-sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. The method may further comprise administration of a GnRH antagonist starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation). The GnRH antagonist may be administered (e.g. daily) starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation) until the end of treatment. The GnRH antagonist may be ganirelix acetate administered (e.g. daily, e.g. at a daily dose of 0.25 mg) starting from day 5 to 7 (e.g. starting from day 6) of treatment (stimulation) until the end of treatment.

[0026] In further aspects, there is provided the use of recombinant follicle stimulating hormone (FSH) and recombinant hCG (rhCG) in the manufacture of a medicament for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 9 to 12 pg, e.g. 10 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.15 pg to 1 .1 pg hCG per day, for example 0.25 pg or 1 pg hCG per day starting from day 1 of treatment. The medicament may be for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female (e.g. human) patient. The product or medicament may be for use as described herein.

[0027] In further aspects there is provided the use of recombinant follicle stimulating hormone (FSH) and recombinant hCG (rhCG) in the manufacture of a medicament for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 15 to 18 pg, e.g. 15 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.15 pg to 1 pg hCG per day, for example 0.15 pg to 0.35 pg hCG per day, for example 0.25 pg hCG per day starting from day 1 of treatment. The medicament may be for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female (e.g. human) patient. The product or medicament may be for use as described herein.

[0028] Detailed Description

[0029] The present applicants have now developed a dosing protocol with the aim of preventing the reduction of the number of follicles (e.g. sub-ordinate follicles) and promoting a beneficial effect on follicular development and / or other downstream parameters influencing pregnancy rates, while maintaining safety. The applicants have devised COS protocols wherein a low dose of, for example, 0.25 pg rhCG (FE 999302) is administered every other day, alongside a daily dose of 10 pg rFSH (Rekovelle).

[0030] The applicants have also devised COS protocols wherein a very low dose of, for example, 0.25 pg or 1 pg rhCG (FE 999302) every day, is administered alongside a daily dose of 10 pg or 15 pg rFSH (Rekovelle).

[0031] With regard to efficacy, the outcome variable defining ART success now goes beyond the initial fresh transfer of the embryos / blastocyst. Cryopreservation of surplus embryos for potential use after the fresh cycle now is standard practice in ART treatment, and serves to improve chances of pregnancy from a single stimulation cycle. The percentage of transfer cycles involving cryopreserved embryos has steadily increased over recent years. In the clinical trial described below, the pregnancy outcomes from the first transfer are measured, allowing assessment of the potential clinical efficiency of one stimulation cycle with transfer.

[0032] With regard to safety, implementation of a gonadotropin-releasing hormone (GnRH) agonist trigger improves patient safety by reducing the risk of early ovarian hyperstimulation syndrome (OHSS). However, the GnRH agonist trigger impairs the efficacy of a fresh transfer by lowering the pregnancy rate, but it does not compromise the efficacy in terms of pregnancy rate in cryopreserved transfer cycles. Implementation of GnRH agonist triggering in patients with excessive response to reduce the risk of OHSS, as well as implementation of mandatory single blastocyst transfer to maximize the incidence of singletons and reduce the risk of multiple gestation, address the most common safety concerns. Therefore, provided herein are dosing regimens constructed to prevent the reduction of the number of sub-ordinate follicles and promote a beneficial effect on follicular development and / or other downstream parameters influencing pregnancy rates, while maintaining safety.

[0033] Definitions

[0034] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art of assisted reproductive technology to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies known to those of ordinary skill in the art. Any suitable materials and / or methods known to those of ordinary skill in the art can be utilized in carrying out the present invention. However, specific materials and methods are described. Materials, reagents and the like to which reference is made in the following description and examples are obtainable from commercial sources, unless otherwise noted.

[0035] It is to be understood, that any definitions and terms herein defined is meant to have the same meaning and purpose in any of the aspects and embodiments of the invention unless explicitly otherwise stated not to.

[0036] As used herein, the singular forms “a,” “an,” and “the” designate both the singular and the plural, unless expressly stated to designate the singular only.

[0037] As used herein, the term “about” means that the number or range is not limited to the exact number or range set forth, but encompass ranges around the recited number or range as will be understood by persons of ordinary skill in the art depending on the context in which the number or range is used. Unless otherwise apparent from the context or convention in the art, “about” mean up to plus or minus 10% of the particular term.

[0038] Herein the terms “patient” and “subject” are used interchangeably.

[0039] A subject may have normal serum FSH level of 1 to 16 IU / L, for example 1 to 15 IU / L, for example 1 to 12 IU / L in the early follicular phase. Thus a product, composition or medicament as described herein may be for (use in) the treatment of infertility (and / or for controlled ovarian stimulation) in a subject having normal serum FSH level of 1 to 16 IU / L, for example 1 to 15 IU / L, for example 1 to 12 IU / L in the early follicular phase. It is preferred that the subject has a early follicular phase serum FSH level of 1 to 15 IU / L. A subject may have a BMI >1 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 >18 and BMI < 32 kg / m2, for example a BMI >20 and BMI<25 kg / m2. Thus a product, composition or medicament as described herein may be for (use in) the treatment of infertility (and / or for controlled ovarian stimulation) in a subject having BMI >1 and BMI < 40 kg / m2, for example a subject having BMI >17.5 and BMI < 38 kg / m2, for example a subject having BMI >18 and BMI < 32 kg / m2, for example a subject having BMI >18 and BMI < 25 kg / m2, for example a subject having BMI >20 and BMI < 25 kg / m2. It is preferred that the subject has a BMI of 18 - 32 kg / m2. The composition may be for use in the treatment of a patient having serum AMH level of 5 to 50 pmol / L for example 15 to 35 pmol / L. The treatment of infertility may include a step of identifying the patient (prior to treatment) based on the serum AMH level. The treatment of infertility may include a step of administering the defined doses of FSH and hCG to the patient identified as having the defined serum AMH level. For example, the treatment of infertility may include a step of identifying the patient (prior to treatment) based on the serum AMH level of the patient, and a step of administering the dose to the patient identified (prior to treatment) as having AMH level of 15 to 35 pmol / L. The step of identifying the patient (prior to treatment) based on the serum AMH level of the patient may take place up to 90 days before (e.g. 0 to 90 days before) the dose of rFSH and rhCG is first administered to the patient. The step of identifying the patient (prior to treatment) based on the serum AMH level of the patient may take place just before (e.g. 0 to 2 days before) the dose of rFSH and rhCG is first administered to the patient. The step of identifying the patient may be based on a serum AMH level determined previously (e.g. a serum AMH level determined up to twelve months before the dose is first administered to the patient). Preferably the serum AMH level of the patient is determined (measured) by the ELECSYS® AMH Plus immunoassay (available from Roche, of Switzerland, see

[0040] Herein the term “treatment of infertility” includes treatment of infertility by controlled ovarian stimulation (COS) or methods which include a step or stage of controlled ovarian stimulation (COS), for example in vitro fertilisation (IVF), or intracytoplasmic sperm injection (ICSI). The term “treatment of infertility” includes treatment of infertility in a subject having tubal or unexplained infertility, including treatment of infertility in a subject having endometriosis, for example stage I or stage II endometriosis, and / or in a subject with a partner with male factor infertility. The composition may be for (use in) the treatment of infertility (and / or for controlled ovarian stimulation) in a subject having endometriosis, for example in a subject having stage I or stage II endometriosis, as defined by The American Society for Reproductive Medicine (ASRM) classification system for the various stages of endometriosis, (stage IV most severe; stage I least severe) [American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67,817 821 .].

[0041] Herein the term “GnRH agonist” means gonadotropin-releasing hormone agonist. GnRH agonists are a class of medications that act as agonists of the gonadotropin-releasing hormone receptor (GnRH receptor), the biological target of gonadotropin-releasing hormone.

[0042] Herein the term “GnRH antagonist” means gonadotropin-releasing hormone antagonist. GnRH antagonists are a class of medications that antagonize the gonadotropin-releasing hormone receptor (GnRH receptor) and thus the action of gonadotropin-releasing hormone (GnRH).

[0043] The term “follicle” herein means an ovarian follicle which is a fluid-filled sac that contains an immature egg, or oocyte.

[0044] A blastocyst forms in the early development of a human (or other mammal). In humans, blastocyst formation begins about 5 days after fertilization. The use of blastocysts in (IVF) generally involves retrieval (harvesting) from the woman a number of oocytes resulting from a controlled ovarian stimulation cycle; fertilization (insemination of) one or more oocytes and culturing the fertilized egg (oocyte) for five days to form a blastocyst (i.e. allowing the fertilized oocyte to develop to the blastocyst stage); and transferring the blastocyst into the uterus.

[0045] In accordance with all aspects described herein, it is preferred that the treatment of infertility described herein, is or includes, a step of COS. The cause of infertility could be the woman’s partner suffering from male infertility, although it will be appreciated that according to the present invention it is the woman (female human) who is treated by COS.

[0046] A treatment of infertility as described herein may be for, and may be effective for, development of multiple follicles and pregnancy after fresh and / or cryopreserved embryo transfer in ovulatory women undergoing assisted reproductive technology (ART).

[0047] A treatment of infertility as described herein may be for, and may be effective for, promoting good quality blastocysts (e.g., category 3BB or higher blastocysts, e.g., treatment of infertility to increase the number of category 3BB or higher blastocysts on day 5 after oocyte retrieval) and / or to improve embryo implantation. The treatment of infertility may be treatment of infertility to increase the number of category 3BB or higher blastocysts on day 5 after oocyte retrieval (e.g., as compared to treatment with GONAL-F®). The treatment of infertility may be treatment of infertility to increase the number of fertilised (2PN) oocytes (e.g., as compared to treatment with GONAL-F®). The above classification is with reference to embryo scoring based on the classification system by Gardner & Schoolcraft. [Gardner DK, Schoolcraft WB. In vitro culture of human blastocysts. In: Towards reproductive certainty (Eds. Jansen R & Mortimer D). The plenary proceedings of the 11th world congress on in vitro fertilization and human reproductive genetics. The Parthenon Publishing Group. 1999: 378-88].

[0048] As used herein, “day one of treatment”, also referred to as “day one of stimulation”, refers to the first day that the dose of (e.g., recombinant) FSH and (e.g., recombinant) hCG is administered to the patient. Day one of treatment (stimulation) may take place on day 1 , 2 or 3, for example on day 2 or day 3, of the patient’s menstrual cycle. In other words, day one of treatment (stimulation) may be one, two or three days, for example two or three days, after the patient commences menstrual bleeding, consistent with usage of this term in clinical practice with GnRH antagonist or GnRH agonist protocols. The term “during treatment” means on a day or on days that FSH is being administered to the patient.

[0049] In the treatments described herein, the administration of recombinant FSH starts on day one of treatment and may continue for two to twenty days, for example continue for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 days. The dose administered on day 1 is referred to herein as the “starting dose”. The administration of recombinant FSH starts on day one of treatment and may continue for four to twenty days, for example seven to thirteen days, for example nine to thirteen days, for example 10 to 13 days, for example 10 to 11 days. The dose may be the same every day.

[0050] In some of the treatments described herein (see “hCG dosing every other day” below), the recombinant hCG is administered every other day starting from day 1 of treatment. The hCG may be administered every other day starting from day 1 of treatment and may continue for 3 days (that is dosing on days 1 and 3) , 5 days (that is dosing on days 1 , 3 and 5), 7 days, 9 days, 11 days, 13 days, 15 days, 17 days or 19 days (that is dosing on days 1 , 3, 5, 7, 9, 11 , 13, 15, 17 and 19). The hCG may be administered every other day starting from day 1 until the end of treatment (for example may be administered on each of day 1 , day 3, day 5, day 7, day 9, day 11 , day 13, day 15, day 17, day 19). The dose administered on day 1 is referred to herein as the “starting dose”.

[0051] In other treatments described herein (see “hCG dosing every day” below), the administration of recombinant hCG starts on day one of treatment and may continue for two to twenty days, for example continue for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 days. The dose administered on day 1 is referred to herein as the “starting dose”. The administration of recombinant hCG starts on day one of treatment and may continue for four to twenty days, for example seven to thirteen days, for example nine to thirteen days, for example 10 to 13 days, for example 10 to 11 days. The dose may be the same every day. hCG dosing every other day

[0052] In accordance with some aspects of the invention, there is provided a product (e.g. a pharmaceutical product) comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered daily (e.g. starting on day 1 of treatment / stimulation); and the recombinant hCG is to be administered every other day (e.g. starting on day 1 of treatment / stimulation). The product may be for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female (e.g. human) patient. The product may be for use wherein the recombinant FSH is to be administered daily from day 1 of treatment (stimulation); and the recombinant hCG is to be administered every other day starting from day 1 of treatment (stimulation). The product may be for use wherein the recombinant FSH is to be administered at a dose of 9 to 18 pg, e.g. 9 to 12 pg, e.g. 10 pg or 15 pg FSH per day starting from day 1 of treatment (stimulation). The product may be for use wherein the recombinant hCG is to be administered at a dose of 0.1 to 1 pg hCG, e.g. 0.1 to 0.5 pg hCG, e.g. 0.25 pg hCG every other day starting from day 1 of treatment (stimulation). The product may be for use wherein the recombinant FSH includes a2,6-sialylation and a2,3- sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6-sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation or optionally wherein 50 % to 99% of the total sialylation is a2, 6-sialyation, and 1 % to 50% of the total sialylation is a 2,3-sialyation. The product may be for use wherein the recombinant hCG includes a2,6-sialylation and a2,3- sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. The product may be for use wherein a GnRH antagonist is administered starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation). The GnRH antagonist may be administered (e.g. daily) starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation) until the end of treatment. The GnRH antagonist may be ganirelix acetate administered (e.g. daily, e.g. at a daily dose of 0.25 mg) starting from day 5 to 7 (e.g. starting from day 6) of treatment (stimulation) until the end of treatment.

[0053] In accordance with some aspects of the invention, there is provided a product (e.g. a pharmaceutical product) comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 9 to 12 pg, e.g. 10 pg FSH per day starting from day 1 of treatment / stimulation; and the recombinant hCG is to be administered at a dose of 0.25 pg hCG every other day starting from day 1 of treatment / stimulation. The product may be for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female (e.g. human) patient. The product may be for use wherein the recombinant FSH includes a2,6-sialylation and a2,3-sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6-sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation or optionally wherein 50 % to 99% of the total sialylation is a2, 6-sialyation, and 1 % to 50% of the total sialylation is a 2,3-sialyation. The product may be for use wherein the recombinant hCG includes a2,6-sialylation and a2,3-sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. The product may be for use wherein a GnRH antagonist is administered starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation). The GnRH antagonist may be administered (e.g. daily) starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation) until the end of treatment. The GnRH antagonist may be ganirelix acetate administered (e.g. daily, e.g. at a daily dose of 0.25 mg) starting from day 5 to 7 (e.g. starting from day 6) of treatment (stimulation) until the end of treatment.

[0054] It will be appreciated that products according to these aspects of the invention may comprise separate (e.g. injectable) formulations of rFSH and of rhCG. In other words, in products according to these aspects of the invention, the rFSH and hCG will generally be formulated separately (e.g. as injectable formulations as described herein), so the rFSH can be injected every day and the rhCG injected every other day. However, it will be appreciated that other arrangements are possible, for example the products according to these aspects of the invention may comprise a combined rFSH and hCG formulation [e.g. for administration every other day starting from day 1 of treatment] and a separate rFSH formulation [e.g. for administration every other day starting from day 2 of treatment].

[0055] Nonclinical rat data indicate that very low doses of FE 999302 can augment the FSH treatment. The applicants therefore proposed a clinical trial using a dose of 0.25 pg rhCG (FE 999302 ) every second day, alongside a daily dose of 10 pg rFSH (Rekovelle). The dose of 0.25 pg rhCG is well below the lowest dose (1 pg daily) tested in the RAINBOW trial, and well below known doses of rhCG used alongside rFSH.

[0056] In a further aspect there is provided a method of treating infertility (e.g. by controlled ovarian stimulation) in a female patient comprising administering recombinant follicle stimulating hormone (rFSH) daily (e.g. starting on day 1 of treatment / stimulation) and administering recombinant hCG (rhCG) every other day (e.g. starting on day 1 of treatment / stimulation). The method may comprise administering rFSH daily from day 1 of treatment (stimulation) and administering rhCG every other day starting from day 1 of treatment (stimulation). The rFSH may be administered at a dose of 9 to 18 pg, e.g. 9 to 12 pg, e.g. 10 pg or 15 pg FSH per day starting from day 1 of treatment (stimulation). The rhCG may be administered at a dose of 0.1 to 1 pg hCG, e.g. 0.1 to 0.5 pg hCG, e.g. 0.25 pg hCG every other day starting from day 1 of treatment (stimulation). The rFSH may include a2,6-sialylation and a2,3-sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6-sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation. The rhCG may include a2,6-sialylation and a2,3-sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. The method may further comprise administration of a GnRH antagonist starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation). The GnRH antagonist may be administered (e.g. daily) starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation) until the end of treatment. The GnRH antagonist may be ganirelix acetate administered (e.g. daily, e.g. at a daily dose of 0.25 mg) starting from day 5 to 7 (e.g. starting from day 6) of treatment (stimulation) until the end of treatment.

[0057] In a further aspect, there is provided a method of treating infertility (e.g. by controlled ovarian stimulation) in a female patient comprising administering recombinant follicle stimulating hormone (FSH) at a dose of 9 to 12 pg, e.g. 10 pg FSH per day starting from day 1 of treatment and administering recombinant human chorionic gonadotropin (hCG) at a dose of 0.25 pg hCG every other day starting from day 1 of treatment. The rFSH may include a2,6-sialylation and a2,3-sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6-sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation or optionally wherein 50 % to 99% of the total sialylation is a2, 6-sialyation, and 1% to 50% of the total sialylation is a 2,3-sialyation. The rhCG may include a2,6-sialylation and a2,3-sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. The method may further comprise administration of a GnRH antagonist starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation). The GnRH antagonist may be administered (e.g. daily) starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation) until the end of treatment. The GnRH antagonist may be ganirelix acetate administered (e.g. daily, e.g. at a daily dose of 0.25 mg) starting from day 5 to 7 (e.g. starting from day 6) of treatment (stimulation) until the end of treatment. In a further aspect there is provided the use of recombinant follicle stimulating hormone (FSH) and recombinant hCG (rhCG) in the manufacture of a product or medicament for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered daily (e.g. starting on day 1 of treatment); and the recombinant hCG is to be administered every other day (e.g. starting on day 1 of treatment). The product or medicament may be for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female (e.g. human) patient. The product or medicament may be for use as described herein.

[0058] In a further aspect there is provided the use of recombinant follicle stimulating hormone (FSH) and recombinant hCG (rhCG) in the manufacture of a product or medicament for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 9 to 12 pg, e.g. 10 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.25 pg hCG every other day starting from day 1 of treatment. The product or medicament may be for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female (e.g. human) patient. The product or medicament may be for use as described herein.

[0059] Further aspects - hCG dosing every day

[0060] The applicants have also devised COS protocols wherein a very low dose of, for example, 0.25 pg or 1 pg rhCG (FE 999302) every day, is administered alongside a daily dose of 10 pg or 15 pg rFSH (Rekovelle).

[0061] Thus, in aspects of the invention, there is provided a composition (e.g. pharmaceutical composition) comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 9 to 12 pg, e.g. 10 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.15 pg to 1 .1 pg hCG per day, for example 0.25 pg or 1 pg hCG per day starting from day 1 of treatment. In other aspects of the invention, there is provided a composition (e.g. pharmaceutical composition) comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 12 to 18 pg, e.g. 15 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.15 pg to 1 pg hCG per day, for example 0.15 pg to 0.35 pg hCG per day, for example 0.25 pg hCG per day starting from day 1 of treatment. The product may be for use wherein the recombinant FSH includes a2,6- sialylation and a2,3-sialylation , optionally wherein 1 % to 50% of the total sialylation is a2, 6- sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation or optionally wherein 50 % to 99% of the total sialylation is a2, 6-sialyation, and 1 % to 50% of the total sialylation is a 2,3- sialyation. The product may be for use wherein the recombinant hCG includes a2,6-sialylation and a2,3-sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. The product may be for use wherein a GnRH antagonist is administered starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation). The GnRH antagonist may be administered (e.g. daily) starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation) until the end of treatment. The GnRH antagonist may be ganirelix acetate administered (e.g. daily, e.g. at a daily dose of 0.25 mg) starting from day 5 to 7 (e.g. starting from day 6) of treatment (stimulation) until the end of treatment.

[0062] In a further aspect, there is provided a method of treating infertility (e.g. by controlled ovarian stimulation) in a female patient comprising administering recombinant follicle stimulating hormone (FSH) at a dose of 9 to 12 pg, e.g. 10 pg FSH per day starting from day 1 of treatment and administering recombinant human chorionic gonadotropin (hCG) at a dose of 0.15 pg to 1 .1 pg hCG per day, for example 0.25 pg or 1 pg hCG per day starting from day 1 of treatment. In a still further aspect, there is provided a method of treating infertility (e.g. by controlled ovarian stimulation) in a female patient comprising administering recombinant follicle stimulating hormone (FSH) at a dose of 12 to 18 pg, e.g. 15 pg FSH per day starting from day 1 of treatment and administering recombinant human chorionic gonadotropin (hCG) at a dose of 0.15 pg to 1 pg hCG per day, for example 0.15 pg to 0.35 pg hCG per day, for example 0.25 pg hCG per day starting from day 1 of treatment. The rFSH may include a2,6-sialylation and a2,3- sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6-sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation or optionally wherein 50 % to 99% of the total sialylation is a2, 6-sialyation, and 1 % to 50% of the total sialylation is a 2,3-sialyation. The rhCG may include a2,6-sialylation and a2,3-sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. The method may further comprise administration of a GnRH antagonist starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation). The GnRH antagonist may be administered (e.g. daily) starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation) until the end of treatment. The GnRH antagonist may be ganirelix acetate administered (e.g. daily, e.g. at a daily dose of 0.25 mg) starting from day 5 to 7 (e.g. starting from day 6) of treatment (stimulation) until the end of treatment. In a further aspect there is provided the use of recombinant follicle stimulating hormone (FSH) and recombinant hCG (rhCG) in the manufacture of a medicament for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 9 to 12 pg, e.g. 10 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.15 pg to 1 .1 pg hCG per day, for example 0.25 pg or 1 pg hCG per day starting from day 1 of treatment. The medicament may be for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female (e.g. human) patient. The product or medicament may be for use as described herein.

[0063] In a further aspect there is provided the use of recombinant follicle stimulating hormone (FSH) and recombinant hCG (rhCG) in the manufacture of a medicament for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 15 to 18 pg, e.g. 15 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.15 pg to 1 pg hCG per day, for example 0.15 pg to 0.35 pg hCG per day, for example 0.25 pg hCG per day starting from day 1 of treatment. The medicament may be for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female (e.g. human) patient. The product or medicament may be for use as described herein.

[0064] General

[0065] In accordance with all aspects described herein, the recombinant FSH may be human cell line- derived recombinant FSH as described in more detail below (see “Recombinant FSH and rFSH products, compositions and methods”). In all aspects, the recombinant FSH may be that sold under the trademark REKOVELLE® (follitropin delta) (Ferring B.V.). In all aspects, the recombinant FSH may be administered by injection, e.g., subcutaneous injection.

[0066] In accordance with all aspects described herein, the recombinant hCG may be human cell line- derived recombinant FSH as described in more detail below (see “Recombinant hCG and rhCG methods, roducts and compositions”). In all aspects, the recombinant hCG may be FE999032. In all aspects, the recombinant hCG may be administered by injection, e.g., subcutaneous injection.

[0067] In accordance with all aspects described herein, the product, composition (e.g., pharmaceutical composition) or medicament of the invention may be administered, or may be for administration, prior to administration of a GnRH antagonist (e.g., GANIRELIX®, CETRORELIX®), for example for administration five or six or seven days prior to administration of a GnRH antagonist (i.e., for administration such that day 1 of stimulation is 5 or 6 or 7 days prior to administration of a GnRH antagonist). Additionally or alternatively, the product, composition (e.g., pharmaceutical composition) or medicament of the invention for use described herein may be for administration with a GnRH antagonist.

[0068] Alternatively, the product, composition (e.g., pharmaceutical composition) or medicament of the invention may be administered after pre-treatment of the patient with a (different) pharmaceutical composition, herein termed “composition A”, which suppresses endogenous gonadotropin production prior to day one of the treatment with rFSH. In other words, the composition (e.g., pharmaceutical composition) or medicament may be administered after the subject has been (pre-) treated with composition A, wherein composition A is a steroid, a GnRH agonist, a GnRH antagonist, etc. Herein, the term “pre-treated” or “pre-treatment” refers to administration of the pharmaceutical composition which suppresses endogenous gonadotropin production prior to day one of the treatment with rFSH (i.e., prior to day 1 of treatment), consistent with usage of this term in clinical practice with long GnRH agonist protocols.

[0069] Thus, the product, composition (e.g., pharmaceutical composition) or medicament for use described herein may be for administration 12 to 16, e.g., 13 to 15, e.g., 14 days, after administration of (e.g., after initiation of administration of, e.g., after initiation of daily administration of) a GnRH agonist (e.g., SYNAREL®, LUPRON®, DECAPEPTYL®). Additionally or alternatively, the product, composition (e.g., pharmaceutical composition) or medicament for use described herein may be for administration with a GnRH agonist.

[0070] Typically, in accordance with all aspects described herein, the product, composition (e.g., pharmaceutical composition) or medicament of the invention is administered, or is for administration, prior to administration of a high (ovulatory) dose of human chorionic gonadotropin (hCG) (for example 4,000 to 11 ,000 IU hCG, e.g., 5,000 IU hCG, 10,000 IU hCG, etc.; or 150 to 500 pg recombinant hCG, for example 250 pg recombinant hCG); to induce final follicular maturation. Thus, in some embodiments, the uses and methods described herein further comprise administration of a high (ovulatory) dose of human chorionic gonadotropin (hCG).

[0071] In accordance with all aspects described herein, the treatment of infertility described herein may further comprise: retrieving (e.g., harvesting) oocyte(s); fertilizing (e.g., inseminating) the oocytes (s); and allowing the fertilized oocytes to develop to the blastocyst stage. The fertilization (e.g., insemination) may be in vitro fertilization, optionally intra-cytoplasmic sperm injection (ICSI).

[0072] In accordance with all aspects described herein, the treatment of infertility described herein may further comprise assessing the quality of blastocysts obtained after fertilization of the harvested oocytes [e.g., to identify one or more good quality (i.e. grade 3BB or above) blastocysts]. Assessment of blastocyst quality may take place on day 5 after oocyte retrieval and may study three parameters: blastocyst expansion and hatching status (grade 1 -6), blastocyst inner cell mass grading (grade A-D) and trophectoderm grading (grade A-D), as is well known in the art. Blastocysts can be given a numerical score by using the system of Gardner & Schoolcraft, as is well known in the art, with the addition of D-categories for inner cell mass and trophectoderm.

[0073] In accordance with all aspects described herein, the treatment of infertility described herein may further comprise transfer of one or more blastocyst(s) identified by assessment of quality of the blastocysts (e.g., fresh blastocyst transfer). In specific embodiments, a single blastocyst is transferred.

[0074] In accordance with all aspects described herein, the treatment of infertility described herein may further comprise freezing one or more blastocysts identified by assessment of quality of the blastocysts (for later transfer).

[0075] Thus, In accordance with all aspects described herein, the treatment of infertility described herein may further comprise — in addition to optional administration of a GnRH agonist or antagonist, administration of recombinant FSH and recombinant hCG, and administration of an ovulatory dose of hCG, retrieving (e.g., harvesting) oocyte(s); fertilizing (e.g., inseminating) the oocyte(s) — allowing the fertilized oocytes to develop to the blastocyst stage and cryopreserving one or more blastocysts (e.g., blastocysts identified by assessment of quality of the blastocysts, e.g., for later transfer).

[0076] The treatment of infertility described herein may be for, and may be effective for, optimising efficacy (i.e., maximising the patient’s chance of successful pregnancy following fresh or subsequent cryopreserved cycle) and / or reducing OHSS risk (i.e. reducing the risk of OHSS by e.g., monitoring and / or control of over-response to treatment). Recombinant FSH and rFSH and methods

[0077] The following describes the recombinant FSH which may be used in the methods, products and compositions according to aspects of the invention.

[0078] As noted above, the products, methods and compositions described herein use recombinant FSH (rFSH). FSH comprises a 92 amino acid alpha sub-unit, also common to the 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 [Pierce JG, and Parsons TF (1981 ) Glycoprotein hormones: structure and function Annu Rev Biochem. 50, 465- 495]. Each sub-unit is post translationally modified by the addition of complex carbohydrate residues. Both subunits carry 2 sites for N-linked glycan attachment, the alpha sub-unit at amino acids 52 and 78 and the beta sub-unit at amino acid residues 7 and 24 (Rathnam and Saxena, 1975, Saxena and Rathnam, 1976). FSH is thus glycosylated to about 30% by mass (Dias and Van Roey. 2001 . Fox et al. 2001 ).

[0079] The glycosylation of rFSH products reflects the range of glycosyl-transferases present in the host cell line. Commercially available rFSH products derived from engineered CHO cells have a more limited range of glycan modifications than those found on the natural products. Examples of the reduced glycan heterogeneity found in CHO cell derived rFSH include a lack of bisecting glucosamine and a reduced content of core fucosylation and acetyl lactosamine extensions. In addition, CHO cells are only able to add sialic acid using the a2,3 linkage (Kagawa et al, 1988, Takeuchi et al, 1988); CHO cell-derived rFSH only includes a2,3-linked sialic acid and does not include a2,6-linked sialic acid. Thus, CHO cell-derived rFSH is different from naturally produced FSH (e.g., human pituitary / serum / urinary FSH) which contains glycans with a mixture of a2,3 and a2,6-linked sialic acid, with a predominance of the former.

[0080] As noted above, the present applicants have developed a human cell line-derived rFSH which is the subject of International Patent Application No. PCT / GB2009 / 000978, published as W02009 / 127826A, and also approved by the EC as REVOKELLE® (follitropin delta, also known as FE 999049). Recombinant FSH with a mixture of both a2,3 and a2,6-linked sialic acid was made by engineering a human (PER.C6®) cell line to express both rFSH and a2,3 sialyltransferase. The amino acid sequence of the human cell line-derived recombinant FSH which is the subject of International Patent Application No. PCT / GB2009 / 000978, published as W02009 / 127826A (e.g., FE 999049), is the native human FSH sequence, but the product has a different glycosylation pattern. The PER.C6® cell line has been generally commercially available for many years. Further, the Per.C6 cell was deposited under the accession number 96022940 with the European Collection of Cell Cultures ECACC, UK. The European patent application which refers to the deposited biological material is EP 1 445 3322 A1 filed by Crucell Holland B.V. on June 14, 1996. The cell line was available by request under Rule 33 EPC at the present filing date, as well as commercially available. The expressed product is highly acidic and carries a mix of both a2,3- and a2,6-linked sialic acids; the latter provided by the endogenous sialyl transferase activity. It was found that the type of sialic acid linkage, a2,3- or a2,6-, can have a dramatic influence on biological clearance of FSH. Thus REVOKELLE® (e.g., FE 999049) may be more biologically appropriate compared to CHO cell-derived recombinant products that have only a2,3 linked sialic acid (Kagawa et al, 1988, Takeuchi etal, 1988, Svensson etal., 1990) and have decreased sialic acid content (Ulloa-Aguirre et al. 1995., Andersen et al. 2004).

[0081] Thus, the recombinant FSH used in accordance with the methods and compositions described herein may be produced or expressed in a human cell line, such as a PER. C6® cell line. The recombinant FSH may be produced or expressed in a PER. C6® cell line, a PER. C6® derived cell line or a modified PER.C6® cell line. Recombinant FSH which is produced or expressed in a PER. C6® cell line will include some a2,6-linked sialic acids (a2,6 sialylation) provided by endogenous sialyl transferase activity (of the cell line) and will include some a2,3-linked sialic acids (a2,3 sialylation) provided by endogenous sialyl transferase activity. The cell line may be modified using a2,3-sialyltransferase. The cell line may be modified using a2,6- sialyltransferase. Alternatively or additionally, the recombinant FSH may include a2,6-linked sialic acids (a2,6 sialylation) provided by endogenous sialyl transferase activity (of the cell line). Herein, the term “human-derived recombinant FSH” means recombinant FSH which is produced or expressed in a human cell line (e.g., recombinant FSH made by engineering a human cell line).

[0082] The recombinant FSH used in the products, methods and compositions described herein may include a2,3- and a2,6- sialylation. The recombinant FSH for use according to the invention may have 1 % to 99% of the total sialylation being a2,3-sialylation. The recombinant FSH for use according to the invention may have 1 % to 99% of the total sialylation being a2,6- sialylation. The recombinant FSH may have 1 % to 50% of the total sialylation as a2, 6- sialyation, and 50% to 99% of the total sialylation as 2,3-sialyation. For example, 80% to 95%, for example 80% to 90%, for example 82% to 89%, for example 85% to 89% of the total sialylation may be a2,3-sialylation. For example, 5% to 20%, for example 10% to 20%, for example 11 % to 18%, for example 11 % to 15%, of the total sialylation may be a2,6- sialylation In an example, the recombinant FSH has 5% to 20% of the total sialylation as a2, 6-sialyation, and 80% to 95% of the total sialylation as 2,3-sialyation. In another example, the recombinant FSH has 50% to 80% of the total sialylation as a2, 6-sialyation, and 20% to 50% of the total sialylation as 2,3-sialyation.

[0083] Herein, by “sialylation”, it is meant the amount of sialic residues present on the recombinant FSH carbohydrate structures. Consistent with usage in the art, a2,3-sialylation means sialylation at the 2,3 position and a2,6 sialylation means sialylation at the 2,6 position. Thus “% of the total sialylation may be a 2,3 sialylation” refers to the % of the total number of sialic acid residues present in the FSH (or hCG) which are sialylated in the 2,3 position. The term “% of the total sialylation being a2,6-sialylation” refers to the % of the total number of sialic acid residues present in the FSH (or hCG) which are sialylated in the 2,6 position.

[0084] In all aspects, the rFSH may be present as a single isoform or as a mixture of isoforms.

[0085] Recombinant hCG and rhCG methods, products and compositions

[0086] The following describes the recombinant hCG which may be used in the Methods, Products and Compositions according to aspects of the invention.

[0087] As noted above, the products, methods and compositions described herein use recombinant hCG (rhCG). HCG comprises a 92 amino acid alpha sub-unit, also common to the other glycoprotein hormones LH and FSH, and a 145 amino acid beta sub-unit unique to hCG, which dictates the hormone specificity. Each sub-unit is post translationally modified by the addition of complex carbohydrate residues. The alpha sub-unit contains 2-N-linked glycosylation sites at amino acids 52 and 78 and the beta sub-unit contains 2-N-linked glycosylation sites at amino acids 13 and 30 and four O-linked glycosylation sites at amino acids 121 , 127, 132 and 138.

[0088] HCG extracted from the urine of pregnant women [CHORAGON® (Ferring)] has been used for many years in infertility treatment. The production of hCG extracted from urine involves the collection and processing of large amounts of urine. A recombinant version of hCG, OVITRELLE® (Merck Serono), is also available and expressed in CHO cells. Ovitrelle does not include tetrasialylated structures.

[0089] The present applicants have developed a human cell line derived recombinant hCG which is the subject of International Patent Application No. PCT / GB2010 / 001854, published as WO2011 / 042688A. Recombinant hCG with a mixture of both a2,3 and a2,6-linked sialic acid was made by engineering a human cell line to express both rhCG and a2,3 sialyltransferase. The expressed product is highly acidic and carries a mix of both a2,3- and a2,6-linked sialic acids; the latter provided by the endogenous sialyl transferase activity. Recombinant hCG with a mixture of both a2,3 and a2,6-linked sialic acid has two advantages over rhCG expressed in conventional CHO cells: first the material is more highly sialylated due to the combined activities of the two sialyltransferases; and secondly the material more closely resembles the natural hCG.

[0090] FE 999302 is a human cell line derived recombinant hCG produced by the method described in International Patent Application No. PCT / GB2010 / 001854. FE 999302 is being developed by Ferring Pharmaceuticals and intended for treatment of infertility given as daily administrations. FE 999302 is produced in the same human cell line as FE999049 (follitropin delta, REKOVELLE®). This is a human derived cell line, PER.C6®, differentiating it from OVITRELLE®, a recombinant hCG produced from CHO cells. The PER. C6® cell line has been generally commercially available for many years. Further, the Per.C6 cell was deposited under the accession number 96022940 with the European Collection of Cell Cultures ECACC, UK. The European patent application which refers to the deposited biological material is EP 1 445 3322 A1 filed by Crucell Holland B.V. on June 14, 1996. The cell line was available by request under Rule 33 EPC at the present filing date, as well as commercially available.

[0091] The recombinant hCG used in the products, methods and compositions described herein may include a2,3- and a2,6- sialylation. The recombinant hCG may include a2,6-sialylation and a2,3-sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. In some preferred aspects of the invention the recombinant hCG includes a2,6-sialylation and a2,3-sialylation, and includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures. The recombinant hCG may include a2,6-sialylation and a2,3- sialylation, and include mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures, wherein between 0.5% and 1 .5%, for example 0.7% to 1 %, for example 0.8% of the glycan structures are tetra (4S) sialylated glycan structures. The presence of even a small amount of tetra (4S) sialylated glycan structures is indicative of very high sialylation overall. The levels of includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures on the hCG may be measured by WAX analysis, for example by the method set out in Example 8D of PCT / GB2010 / 001854, published as WO2011 / 042688A.

[0092] In all aspects, the rhCG may be present as a single isoform or as a mixture of isoforms.

[0093] The doses of FE 999302 administered are specified by mass since that is intended for the final product. A phase I trial showed that single subcutaneous administration of 4-256 pg FE 999302, and repeated administration of 8 pg / day and 16 pg / day FE 999302, were safe and well tolerated and did not cause any safety concerns. FE 999302 demonstrated improved pharmacokinetics (AUG) over a CHO cell derived hCG product.

[0094] The product or composition is for the treatment of infertility. The treatment of infertility may comprise COS prior to ART. The product composition may be used, for example, in medical indications where known FSH preparations are used, in accordance with the methods and treatment protocols disclosed herein.

[0095] The recombinant FSH and recombinant hCG in the product and / or composition or pharmaceutical composition can be formulated into well-known compositions for any route of drug administration, e.g., oral, rectal, parenteral, transdermal (e.g., patch technology), intravenous, intramuscular, subcutaneous (e.g., for subcutaneous injection), intracisternal, intravaginal, intraperitoneal, local (powders, ointments or drops) or as a buccal or nasal spray. A typical composition comprises a pharmaceutically acceptable carrier, such as aqueous solution, nontoxic excipients, including salts and preservatives, buffers and the like, as described in Remington’s Pharmaceutical Sciences fifteenth edition (Matt Publishing Company, 1975), at pages 1405 to 1412 and 1461 - 87, and the national formulary XIV fourteenth edition (American Pharmaceutical Association, 1975), among others. For example, the recombinant FSH, composition or pharmaceutical composition can be formulated for injection, such as for subcutaneous injection.

[0096] Examples of suitable aqueous and non-aqueous pharmaceutical carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.

[0097] The recombinant FSH and recombinant hCG products and / or compositions may also comprise additives such as but not limited to preservatives, wetting agents, emulsifying agents, surfactants and dispersing agents. Antibacterial and antifungal agents can be included to 1 prevent growth of microbes and includes, for example, m-cresol, benzyl alcohol, paraben, chlorobutanol, phenol, sorbic acid, and the like. If a preservative is included, benzyl alcohol, phenol and / or m-cresol are preferred; however, the preservative is by no means limited to these examples. Furthermore, it may be desirable to include isotonic agents such as sugars, sodium chloride, amino acids and the like.

[0098] For example, the product or composition may include a formulation comprising recombinant FSH and one or more of polysorbate 20, L-methionine, phenol, and arginine hydrochloride. Such a composition may be formulated for injection, such as for subcutaneous injection. For example, the product or composition may include the REKOVELLE® formulation (rFSH with excipients phenol, polysorbate 20, L-methionine, sodium sulphate decahydrate, disodium phosphate dodecahydrate, phosphoric acid [concentrated, for pH-adjustment], sodium hydroxide [for pH-adjustment], and water for injection).

[0099] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

[0100] Injectable formulations can be supplied in any suitable container, e.g., vial, pre-filled syringe, injection cartridges, and the like.

[0101] The product and / or composition may be formulated for single use or for multiple use (multiple dose). If the product and / or composition is formulated for multiple use, typically one or more preservatives is included. If a preservative is included, benzyl alcohol, phenol or m-cresol, are preferred; however, the preservative is by no means limited to these examples. The single use or multiple use formulated composition or medicament may further comprise an amino acid or combination of amino acids. Typically, the amino acid is arginine, for example added as arginine or more typically arginine hydrochloride.

[0102] The product and / or composition may be included in a container such as a vial, prefilled cartridge (e.g., for single administration or multiple use) or an injection device such as a “pen” for e.g., administration of multiple doses.

[0103] The product and / or composition can be supplied in any appropriate package. For example, a composition or medicament can include a number of containers (e.g., pre-filled syringes or vials) containing FSH. The syringes or vials may be packaged in a blister package or other means to maintain sterility. Any composition or medicament can optionally include instructions for using the product and / or composition. The pH and exact concentration of the various components of the pharmaceutical composition are adjusted in accordance with routine practice in this field. See GOODMAN and OILMAN’S THE PHARMACOLOGICAL BASIS FOR THERAPEUTICES, 7thed. In a typical embodiment, the recombinant FSH, composition or medicament are supplied as compositions for parenteral administration. General methods for the preparation of the parenteral formulations are known in the art and are described in REMINGTON; THE SCIENCE AND PRACTICE OF PHARMACY, supra, at pages 780-820. The parenteral compositions can be supplied in liquid formulation or as a solid which will be mixed with a sterile injectable medium just prior to administration. The parenteral compositions may be supplied in dosage unit form for ease of administration and uniformity of dosage.

[0104] Further aspects are illustrated in the following examples, which are not limiting in any respect.

[0105] Example 1 : A randomised, partially double-blind, placebo-controlled, parallel-group exploratory trial to investigate the effect of FE 999302 in women undergoing controlled ovarian stimulation with a fixed dose of follitropin delta in a gonadotropin-releasing hormone antagonist protocol (Trial 000426)

[0106] BACKGROUND

[0107] The efficacy and safety of FE 999302 as add-on treatment to the recombinant follicle-stimulating hormone (rFSH) follitropin delta (REKOVELLE, Ferring) was investigated in the phase 2 trial 000289 (RAINBOW), which included women undergoing controlled ovarian stimulation with an individualised dose of follitropin delta in a long gonadotropin-releasing hormone (GnRH) agonist protocol. Since the therapeutic window of CG beta was unknown, the trial was designed to investigate the efficacy and safety of a broad range of CG beta doses to enable the selection of the optimal CG beta dose or a range of doses for further development. All tested CG beta doses were well-tolerated and no safety concerns were identified. However, regardless the CG beta dose, a reduction in the number of intermediate follicles available at end-of stimulation was observed impacting all down-stream parameters, including the number of good-quality blastocysts and pregnancy rates.

[0108] Trial 000426 will include two different doses of rFSH (follitropin delta; 10 and 15 pg) and three different doses of FE 999302 (0.25 pg every second day, 0.25 pg daily, and 1 pg daily). The purpose is to explore if lowering the dose of FE 999302 could prevent the reduction of the number of sub-ordinate follicles and promote a beneficial effect on follicular development and / or other downstream parameters influencing pregnancy rates. The lowest daily dose was selected with the aim of confirming that lowering the dose of FE 999302 could prevent the reduction of the number of intermediate follicles previously observed with higher doses (1 to 12 pg) of FE 999302 in the RAINBOW trial, and promote a beneficial effect on follicular development and / or other downstream parameters influencing pregnancy rates. Nonclinical rat data indicate that very low doses of FE 999302 can augment the FSH treatment, and therefore a dose of 0.25 pg every second day has also been included. The dose 1 pg, which was the lowest dose tested in the RAINBOW trial, has been included to investigate the effect of FE 999302 in a GnRH antagonist protocol and with different follitropin delta dosing.

[0109] Overall Design and Control Methods

[0110] Trial Design

[0111] This will be a multicentre, randomised, partially double-blind, placebo-controlled, parallel-group exploratory trial to investigate the effect of FE 999302 (rhCG) on parameters influencing pregnancy rates in women aged 18 to 40 years undergoing controlled ovarian stimulation with a fixed dose of follitropin delta in a GnRH antagonist protocol. The trial has been designed to explore if lowering the dose of FE 999302 could prevent the reduction of the number of subordinate follicles previously observed with higher doses of FE 999302 and promote a beneficial effect on follicular development and / or other downstream parameters influencing pregnancy rates. Furthermore, it will be explored if the dose of follitropin delta has an impact on the effect of 0.25 pg FE 999302. The trial is partially double-blind in the sense that the subjects will know which dose of follitropin delta they receive but not if they receive FE 999302 or FE 999302 placebo.

[0112] Subjects will be screened within 90 days before randomisation for compliance with the inclusion and exclusion criteria. On day 2-3 of the menstrual cycle, eligible subjects will be randomised to one of six treatment groups below (approximately 100 subjects / group) and start controlled ovarian stimulation:

[0113] Follitropin delta will be provided as a solution for injection in a pre-filled pen (72 pg / 2.16 mL) and administered daily as a subcutaneous (SC) injection in the abdominal wall. FE 999302 will be provided as a solution for injection (5 pg / mL) and administered as a SC injection (50 pL every second day, 50 pL daily, or 200 pL daily) in the abdominal wall using a 0.5 mL syringe. To ensure that the injection volume does not reveal whether a subject is randomised to FE 999302 or FE 999302 placebo, subjects in treatment group 1 (FE 999302 placebo + 10 pg follitropin delta) will be randomised in a 1 :1 ratio to two different injection volumes of FE 999302 placebo (50 pL and 200 pL). In addition, to ensure that the dosing regimen does not reveal whether a subject is randomised to daily or every-second-day dosing of FE 999302, subjects in treatment group 2 will alternate between FE 999302 and FE 999302 placebo with daily injections. The doses of FE 999302 / FE 999302 placebo and follitropin delta are fixed during stimulation. The maximum duration of stimulation is 20 days and coasting by withholding follitropin delta and / or FE 999302 / FE 999302 placebo is not allowed. The randomisation will be stratified by trial site and age (<34 and >35years).

[0114] During stimulation, subjects will be monitored by transvaginal ultrasound on stimulation days 1 and 6 and hereafter at least every second day. When the leading follicle reaches >15 mm, transvaginal ultrasound must be performed daily. Treatment with GnRH antagonist (ganirelix acetate; FYREMADEL, SUN Pharma) to prevent premature LH surge will be initiated on stimulation day 6 at a daily dose of 0.25 mg and continued throughout the stimulation period. Triggering of final follicular maturation will be done as soon as >3 follicles with a diameter >17 mm are observed on transvaginal ultrasound. If there are <20 follicles with a diameter >12 mm, a single dose of 250 pg hCG (choriogonadotropin alfa; OVITRELLE, Merck) will be administered to trigger final follicular maturation. If there are >20 follicles with a diameter >12 mm, 0.2 mg GnRH agonist (triptorelin acetate; GONAPEPTYL, Ferring) can be administered or the cycle can be cancelled. If it is judged by the investigator that >3 follicles with a diameter >17 mm cannot be reached, but 1 or 2 follicles with a diameter >17 mm are observed, the investigator can decide to either cancel the cycle due to poor follicular development or to trigger final follicular maturation. In case of excessive ovarian response, the cycle may be cancelled if the investigator judges that triggering of final follicular maturation is not advisable due to safety concerns.

[0115] Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation. All follicles with an estimated diameter >12 mm should be punctured. The maturity of each oocyte will be assessed (germinal vesicle, metaphase I, metaphase II [MH], degenerated, other) and each MH oocyte will be inseminated by intracytoplasmic sperm injection (ICS I) regardless of the cause of infertility. Fertilisation will be assessed on day 1 after oocyte retrieval. Assessment of blastocyst quality on day 5 after oocyte retrieval will consist of assessment of three parameters: blastocyst expansion and hatching status (grade 1 -6), blastocyst inner cell mass grading (grade A-D) and trophectoderm grading (grade A-D). Blastocysts will be scored by using the system of Gardner & Schoolcraft with the addition of D-categories for inner cell mass and trophectoderm.

[0116] For subjects who undergo triggering of final follicular maturation with hCG and have <20 oocytes retrieved, blastocyst transfer is performed on day 5 after oocyte retrieval. Single blastocyst transfer is mandatory if they have at least one good-quality blastocyst. Double blastocyst transfer is allowed if they have no good-quality blastocysts (if two blastocysts are available). Remaining blastocysts may be cryopreserved in accordance with local guidelines and regulations. For subjects who undergo triggering of final follicular maturation with GnRH agonist or have >20 oocytes retrieved after triggering with hCG, no transfer will take place in the fresh cycle and the blastocysts available will be cryopreserved. Cryopreserved blastocysts can be used by the subject after completion of the trial, in accordance with local guidelines and regulations.

[0117] Vaginal progesterone suppositories (CYCLOGEST / AMELGEN, Gedeon Richter; provided as vaginal suppositories, each containing 400 mg of progesterone. Dose 2 x 400 mg daily from the day after oocyte retrieval and continued at least until the clinical pregnancy visit) will be provided as luteal phase support. Thereafter luteal phase support may continue until the ongoing pregnancy visit, according to local practice. Progesterone administration should not continue in case of menses, negative phCG, or pregnancy loss.

[0118] A serum phCG test will be performed 13-15 days after transfer, clinical pregnancy will be confirmed by transvaginal ultrasound 5-6 weeks after transfer, and ongoing pregnancy will be confirmed by transvaginal or abdominal ultrasound 10-11 weeks after transfer. Blood samples will be collected throughout the trial to evaluate the endocrine profile, clinical chemistry and haematology parameters, and hCG and follicle-stimulating hormone (FSH) concentrations. Endocrine parameters are assessed at screening, on stimulation days 1 and 6, at end-of-stimulation, and at oocyte retrieval. Clinical chemistry and haematology parameters are assessed at screening and at end-of-stimulation. Serum hCG and FSH concentrations are assessed on stimulation days 1 , 6, and 8, and at end-of-stimulation. Additional blood samples for potential analysis of anti-hCG treatment-induced antibodies will be taken on stimulation day 1 (pre-dose) and at two occasions post-dosing: at end-of-stimulation and 19-28 days after the last FE 999302 or placebo dose (may coincide with the phCG test visit).

[0119] Local tolerability of FE 999302 following SC administration will be assessed by the subject three times daily: immediately, 30 minutes, and 24 hours after each injection. The assessment of injection site reactions will be made throughout the stimulation period and recorded by the subjects in a diary.

[0120] Pregnancy and Cryopreserved Cycle Follow-up Activities

[0121] All subjects with an ongoing pregnancy achieved in the fresh cycle will be followed until delivery to gather information on live birth. Furthermore, data will be collected on neonatal health, including minor / major congenital anomalies, at birth and 4 weeks after birth.

[0122] Subjects who within 3 months after randomisation initiate a cryopreserved cycle with blastocyst(s) obtained in this trial will also be followed. In other words, this applies only for subjects that did not have fresh cycle transfer, i.e. only first transfer cycle included in the trial (not cumulative). One single good-quality blastocyst can be transferred in a cryopreserved cycle (double blastocyst transfer is allowed if no good-quality blastocyst is available).

[0123] Information on the transfer will be collected. Data will be collected on blastocyst survival and quality after thawing, positive phCG, clinical pregnancy, vital pregnancy, ongoing pregnancy as well as live birth and neonatal health, including minor / major congenital anomalies, at birth and 4 weeks after birth.

[0124] Pregnancy and cryopreserved cycle follow-up data will be reported in addendum(s) to the clinical trial report.

[0125] Planned Number of Trial Sites and Subjects It is planned to randomise approximately 600 subjects from approximately 10-15 sites. It is estimated that approximately 700 subjects should be screened to achieve 600 subjects eligible for randomisation.

[0126] Discussion of Overall Trial Design and Choice of Control Groups

[0127] Trial Design

[0128] This trial has a randomised, parallel-group, placebo-controlled design. The randomisation will be stratified by trial site and age as blastocyst quality and pregnancy outcomes are known to vary between trials sites and to decrease with increasing age. The trial will be conducted at multiple trial sites across several different countries to ensure that the required number of subjects can be recruited within a reasonable time frame and to facilitate subsequent generalisation of the results. A GnRH antagonist protocol will be used in this trial since the GnRH antagonist protocol is the most commonly used stimulation protocol in clinical practice and the majority of clinical trial data for follitropin delta has been generated in a GnRH antagonist protocol.

[0129] Selection of Endpoints

[0130] In this exploratory trial, the number of good-quality blastocysts (grade 3BB or higher) on day 5 after oocyte retrieval has been selected as the primary endpoint. The effect of FE 999302 may be best reflected by the quality of the oocytes retrieved but currently, there are no widely recognised and validated methods to adequately assess oocyte competence. Morphological assessment of the oocyte is an essential part of ART with ICSI, but it is simple compared to the multistep process for embryo assessment. Oocyte quality likely relies on a multitude of factors, including the microenvironment of the ovary during follicu logenesis, the cytoplasmic and metabolic pathways in the oocyte, and other potential markers that impact oocyte quality and later embryonic developmental competence. As morphologic evaluation is too simple to adequately predict oocyte competence, blastocyst quality is the current best reflection of oocyte quality leading to normal fertilisation and embryo development, in addition to consideration for the totality of data collected through the secondary endpoints.

[0131] The quality evaluation of blastocysts on day 5 after oocyte retrieval will consist of assessment of three parameters: blastocyst expansion and hatching status (grade 1 -6), blastocyst inner cell mass grading (grade A-D) and trophectoderm grading (grade A-D). Blastocysts will be scored by using the system of Gardner & Schoolcraft [Gardner DK, Schoolcraft WB. In vitro culture of human blastocysts. In: Towards reproductive certainty (Eds. Jansen R & Mortimer D). The plenary proceedings of the 11th world congress on in vitro fertilization and human reproductive genetics. The Parthenon Publishing Group. 1999: 378-88] with the addition of D-categories for inner cell mass and trophectoderm.

[0132] Selection of Doses in the Trial

[0133] FE 999302 (rhCG)

[0134] This trial will use three different doses of FE 999302 (0.25 pg every second day, 0.25 pg daily, and 1 pg daily). The lowest daily dose was selected to investigate if lowering the dose of FE 999302 could prevent the reduction of the number of intermediate follicles previously observed with higher doses (1 to 12 pg) of FE 999302 in the RAINBOW trial and promote a beneficial effect on follicular development and / or other downstream parameters influencing pregnancy rates. Nonclinical rat data indicate that very low doses of FE 999302 can augment the FSH treatment, and therefore a dose of 0.25 pg every second day has also been included. The dose 1 pg, which was the lowest dose tested in the RAINBOW trial, has been included to investigate the effect of FE 999302 in a GnRH antagonist protocol with different follitropin delta dosing.

[0135] Follitropin Delta (tFSH)

[0136] This trial will use two different doses of follitropin delta (10 and 15 pg) to investigate if the dose of follitropin delta has an impact on the effect of 0.25 pg FE 999302 on parameters influencing pregnancy rates.

[0137] Selection of the Trial Population

[0138] This trial will include women with regular menstrual cycles and who have had no more than two previous controlled ovarian stimulation cycles. Eligible subjects have been diagnosed with tubal infertility, unexplained infertility, endometriosis stage l / ll or have partners diagnosed with male factor infertility and are considered eligible for IVF and / or ICSI using fresh or frozen sperm from male partner or donor.

[0139] The trial will include women up to 40 years of age and will thereby cover the patient age span in which most ART treatments are performed. Eligible subjects must be considered suitable for treatment with either 10 or 15 pg follitropin delta daily. In accordance with the individualised dosing regimen of follitropin delta, patients with low AMH (<15 pmol / L) should receive a daily dose of 12 pg irrespective of body weight. Thus, a daily dose of 10 pg may not be sufficiently high to recruit an adequate number of follicles in these patients. To limit the number of subjects receiving a follitropin delta dose lower than that determined by the dosing algorithm, the trial will only include subjects with a serum AMH concentration of 15.0-35.0 pmol / L at screening. Thus, predicted poor responders will not be included in the trial and thereby the risk of low ovarian response and cycle cancellation will be lowered. The upper AMH limit of 35 pmol / L will restrict the number of predicted high responders at risk of OHSS in the trial. The allowed body mass index (BMI) is 18.0-32.0 kg / m2, thus including underweight, normal weight, overweight and obese patients. The exclusion criteria incorporate the contraindications for the use of gonadotropins.

[0140] Follow-up Procedures

[0141] Follow-up activities cover cryopreserved cycles with transfer within 3 months after the subject’s date of randomisation and pregnancy and neonatal health follow-up at birth and at 4 weeks after birth after the fresh cycle and cryopreserved cycles. This includes follow-up of ongoing pregnancies achieved in the fresh cycle and follow-up of ongoing pregnancy achieved after transfer in the first cryopreserved cycle within 3 months after the subject’s date of randomisation.

[0142] Inclusion Criteria

[0143] Subjects must meet all of the criteria listed below to be eligible for participation in the trial.

[0144] 1. Subject informed consent form signed before any trial-related activities.

[0145] 2. Informed consent form for data collection on the neonate signed before randomisation.

[0146] 3. In good physical and mental health as judged by the investigator.

[0147] 4. Serum anti-Mullerian hormone (AMH) levels of 15.0-35.0 pmol / L at screening (measured at central laboratory).

[0148] 5. Pre-menopausal women between the ages of 18 and 40 years. The subjects must be at least 18 years (including the 18thbirthday) and no more than 40 years (up to the day before the 41stbirthday) when they sign the informed consent.

[0149] 6. Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage l / ll or with partners diagnosed with male factor infertility, eligible for in vitro fertilisation (IVF) and / or intracytoplasmic sperm injection (ICSI) using fresh or frozen ejaculated sperm from male partner or sperm donor. 7. Infertility for at least 1 year before screening for subjects <35 years or for at least 6 months for subjects >35 years (not applicable in case of tubal or severe male factor infertility).

[0150] 8. No more than two controlled ovarian stimulation cycles initiated, regardless outcome (taking exclusion criteria 2 and 3 into account) and the subject must be suitable for treatment with 10 or 15 pg / day follitropin delta.

[0151] 9. Regular menstrual cycles of 24-35 days (both inclusive), presumed to be ovulatory.

[0152] 10. Hysterosalpingography, hysteroscopy, saline infusion sonography, or transvaginal ultrasound documenting a uterus consistent with expected normal function (e.g., no evidence of clinically interfering uterine fibroids defined as submucous or intramural fibroids larger than 3 cm in diameter, no polyps, and no congenital structural abnormalities which are associated with a reduced chance of pregnancy) within 6 months before screening.

[0153] 11. Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, without evidence of significant abnormality (e.g., enlarged ovaries which would contraindicate the use of gonadotropins) and normal adnexa (e.g., no hydrosalpinx) within 1 year before screening. Both ovaries must be accessible for oocyte retrieval.

[0154] 12. Early follicular phase (cycle day 2-5) serum levels of follicle-stimulating hormone (FSH) between 1 and 15 IU / L (measured at central laboratory).

[0155] 13. Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) antibody tests within 1 year before randomisation.

[0156] 14. Body mass index (BMI) between 18.0 and 32.0 kg / m2(both inclusive) at screening.

[0157] 15. Willing to accept ICSI regardless the cause of infertility.

[0158] 16. Willing to accept transfer of a single good-quality blastocyst (double blastocyst transfer is allowed if no good-quality blastocyst is available).

[0159] Exclusion Criteria

[0160] Subjects meeting any of the criteria listed below will not be eligible for participation in the trial.

[0161] 1 . Known polycystic ovary syndrome (PCOS) or known endometriosis stage lll-IV (American Society for Reproductive Medicine, 2012). 2. Poor response in a previous controlled ovarian stimulation cycle using a gonadotropin starting dose of 150 lU / day or higher. Poor response is defined as <4 oocytes retrieved, or cycle cancellation before oocyte retrieval due to inadequate follicular development.

[0162] 3. Excessive ovarian response in a previous controlled ovarian stimulation cycle for IVF / ICSI using a daily FSH / human menopausal gonadotropin (hMG) dose of <225 IU, defined as >25 oocytes retrieved or cycle cancellation before oocyte retrieval due to excessive ovarian response, including risk of ovarian hyperstimulation syndrome (OHSS).

[0163] 4. One or more follicles >10 mm (including cysts) observed on the transvaginal ultrasound before randomisation on stimulation day 1 (puncture of cysts is allowed before randomisation).

[0164] 5. Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound confirmation of pregnancy [excluding ectopic pregnancy] and before week 24 of pregnancy).

[0165] 6. Known abnormal karyotype of subject or of her partner / sperm donor, as applicable, depending on source of sperm used for insemination in this trial. In case partner sperm will be used and the sperm production is severely impaired (concentration <1 million / mL) , normal karyotype, including no Y-chromosome microdeletion, must be documented.

[0166] 7. Any known clinically significant systemic disease (e.g., insulin-dependent diabetes).

[0167] 8. Known inherited or acquired thrombophilia disease.

[0168] 9. Known active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events.

[0169] 10. Known or suspected porphyria.

[0170] 11 . Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver, or kidney) with the exception of controlled thyroid function disease.

[0171] 12. Known tumours of the ovary, breast, uterus, adrenal gland, pituitary, or hypothalamus which would contraindicate the use of gonadotropins.

[0172] 13. Known impairment of renal or hepatic function. 14. Any abnormal finding of clinical chemistry and haematology at screening or vital signs at randomisation, which is judged clinically relevant by the investigator and / or requires intervention.

[0173] 15. Currently breast-feeding.

[0174] 16. Undiagnosed vaginal bleeding.

[0175] 17. Known abnormal cervical cytology of clinical significance observed within 3 years before screening (unless the clinical significance has been resolved).

[0176] 18. Findings at the gynaecological examination at screening which preclude gonadotropin stimulation or are associated with a reduced chance of pregnancy, e.g., congenital uterine abnormalities or retained intrauterine device.

[0177] 19. Pregnancy (negative urinary pregnancy tests must be documented at screening and before randomisation) or contraindication to pregnancy.

[0178] 20. Known current active pelvic inflammatory disease.

[0179] 21 . Use of fertility modifiers during the last menstrual cycle before screening, including dehydroepiandrosterone (DHEA) and metformin or cycle programming with oral contraceptives, progestogen, or estrogen preparations.

[0180] 22. Use of hormonal preparations (except for thyroid medication) during the last menstrual cycle before screening.

[0181] 23. Use of glucagon-like peptide-1 (GLP-1 ) receptor agonists within 60 days before randomisation.

[0182] 24. Known history of chemotherapy (except for gestational conditions) or radiotherapy.

[0183] 25. Current or past (within 1 year before screening) abuse of alcohol or drugs, and / or current (last month) intake of more than 14 units of alcohol per week.

[0184] 26. Current or past (within 90 days before screening) smoking habit of more than 10 cigarettes per day.

[0185] 27. Hypersensitivity to any active ingredient or excipients in the medicinal products used in the trial.

[0186] 28. Previous participation in the trial (i.e. , re-screening is not allowed).

[0187] 29. Use of any non-registered investigational drugs during the last 90 days before screening. The participating subjects will be recruited among the patients attending the sites included in the trial. Advertisements may be used if approved by the local independent ethics committee (I EC) and regulatory authorities, as applicable according to local regulations.

[0188] Trial Stopping Criteria Occurrence of the following may warrant consideration of trial termination:

[0189] • Life-threatening SAEs with suspected causality to an IMP

[0190] The internal safety management team at the sponsor will review each occurrence and take appropriate action as described in the safety management team charter.

[0191] Investigational Medicinal Products (IMPs) On day 2-3 of the menstrual cycle, eligible subjects will be randomised to one of six treatment groups as in the following Table.

[0192] Table: Treatment Groups

[0193] Details on the IMPs are listed in the folowing Table: Table Error! No text of specified style in document. -1 Investigational Medicinal Products

[0194] The first administration of IMPs will take place at the trial site and can be done by either the trial medication delegate or the subject under supervision by the trial medication delegate.

[0195] Subsequent injections can be done at home or at the trial site. The trial medication delegate will instruct the subject on how to administer the IMPs.

[0196] The IMPs should preferably be administered at the same time each day during the stimulation period (with the possible exception of stimulation day 1 ).

[0197] FE 999302 FE 999302 Placebo Dosing Regimen

[0198] FE 999302 or FE 999302 placebo will be administered as a subcutaneous injection in the abdominal wall using a 0.5 mL syringe The injection volumes and dosing regimen are presented in the following Table:

[0199] Table: Injection Volumes and Dosing Regimen of FE 999302 and FE 999302 Placebo

[0200] To minimise local injection site reactions, it is advisable to change the injection site regularly, but it should always be on the subject’s left side of the navel to allow for distinction between injection site reactions related to FE 999302 and those related to follitropin delta.

[0201] Dosing will continue until the criterion for triggering of final follicular maturation has been met. Subjects can be treated with FE 999302 for a maximum of 20 days, and coasting is not allowed.

[0202] Follitropin Delta

[0203] Follitropin delta is authorised in EU under the trade name REKOVELLE. It will be administered as daily subcutaneous injections in the abdominal wall. To minimise local injection site reactions, it is advisable to change injection site regularly, but it should always be on the subject’s right side of the navel to allow for distinction between injection site reactions related to FE 999302 and those related to follitropin delta.

[0204] Dosing will continue until the criterion for triggering of final follicular maturation has been met. Subjects can be treated with follitropin delta for a maximum of 20 days, and coasting is not allowed.

[0205] Non-lnvestigational Medicinal Products (NIMPs)

[0206] As concomitant therapy in the controlled ovarian stimulation cycle, subjects will use the NIMPs presented in the following Table. All NIMPs are authorised in EU. Table: Non-lnvestigational Medicinal Products

[0207] All NIMPs are used in line with the recommendations in the respective products’ labelling for the indication of ART and / or standard clinical practice supported by literature.

[0208] FYREMADEL is administered by the subject as daily subcutaneous injections in the upper thigh to allow for distinction between injection site reactions related to FE 999302 and those related to FYREMADEL. FYREMADEL and IMPs should be administered at approximately the same time. Table Error! No text of specified style in document. -2 Characteristics and Source of Supply of Medicinal Products

[0209] FSH: follicle-stimulating hormone, IMP: investigational medicinal product, NIMP: non- investigational medicinal product EXAMPLE 2- rFSH REKOVELLE

[0210] REKOVELLE® is a recombinant FSH expressed in a PER. C6® cell line engineered by the methods disclosed in WO2013 / 020996 and WO2009 / 127826A. The Marketing Authorisation holder for REKOVELLE® is Ferring Pharmaceuticals A / S of Kay Fiskers Plads 11 , 2300 Copenhagen S, Denmark, and it is available in the UK from Ferring Pharmaceuticals of Drayton Hall, Church Road, West Drayton, UB7 7PS, UK. The active substance in REKOVELLE® is follitropin delta (FE999049). REKOVELLE® is highly sialylated and includes a2,3- and a2,6- sialylation, with about 85% to 90% of the total sialylation being a2,3-sialylation and about 10% to 15% of the total sialylation being a2,6-sialylation. REKOVELLE® is a clear and colourless solution for injection. One millilitre of solution contains 33.3 micrograms of follitropin delta in each millilitre of solution. The other ingredients are phenol, polysorbate 20, L-methionine, sodium sulphate decahydrate, disodium phosphate dodecahydrate, concentrated phosphoric acid, sodium hydroxide and water for injection.

[0211] EXAMPLE S- rhCG FE999302

[0212] FE999302 is a recombinant hCG expressed in a PER. C6® cell line engineered by the methods disclosed in WO2011 / 042688A (PCT / GB2010 / 001854) and WO2016 / 170113A. FE999302 is highly sialylated and includes a2,3- and a2,6- sialylation, and a mix of mono-, di, tri and tetra sialylated structures. FE999302 includes a2,6-sialylation and a2,3-sialylation, and includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures, wherein between 0.5% and 1 .5%, for example 0.8% of the glycan structures are tetra (4S) sialylated glycan structures.

[0213] FE 999302 is being developed by Ferring Pharmaceuticals and intended for treatment of infertility given as daily administrations in e.g. combination with rFSH. FE 999302 is produced in the same human cell line as FE999049 (follitropin delta, REKOVELLE®). This is a human derived cell line, PER.C6®, differentiating it from OVITRELLE®, a recombinant hCG produced from CHO cells. The PER.C6® cell line has been generally commercially available for many years. Further, the Per.C6 cell was deposited under the accession number 96022940 with the European Collection of Cell Cultures ECACC, UK. The European patent application which refers to the deposited biological material is EP 1 445 3322 A1 filed by Crucell Holland B.V. on June 14, 1996. The cell line was available by request under Rule 33 EPC at the present filing date, as well as commercially available.

[0214] References

[0215] Baenziger JU and Green ED. (1988). Pituitary glycoprotein hormone oligosaccharides: structure, synthesis and function of the asparagine-linked oligosaccharides on lutropin, follitropin and thyrotropin. Biochim Biophys Acta. 947(2), 287-306.

[0216] Dias JA, Van Roey P. (2001 ). Structural biology of human follitropin and its receptor. Arch Med Res. 32(6), 510-519

[0217] Kagawa Y, Takasaki S, Utsumi J, Hosoi K, Shimizu H, Kochibe N, and Kobata A. (1988).

[0218] Comparative study of the asparagine-linked sugar chains of natural human interferon-beta 1 and recombinant human interferon-beta 1 produced by three different mammalian cells. J Biol Chem. 263(33), 17508-17515.

[0219] Pierce JG, and Parsons TF (1981 ) Glycoprotein hormones: structure and function Annu Rev Biochem. 50, 465-495.

[0220] Rathnam P, and Saxena BB. (1975). Primary amino acid sequence of follicle-stimulating hormone from human pituitary glands. I. alpha subunit. J Biol Chem.;250(17):6735-6746.

[0221] Saxena BB and Rathnam P. (1976) Amino acid sequence of the beta subunit of follicle- stimulating hormone from human pituitary glands. J Biol Chem. 251(4), 993-1005

[0222] Takeuchi M, Takasaki S, Miyazaki H, Kato T, Hoshi S, Kochibe N, and Kobata A (1988).

[0223] Comparative study of the asparagine-linked sugar chains of human erythropoietins purified from urine and the culture medium of recombinant Chinese hamster ovary cells. J Biol Chem. 263(8), 3657-3663.

Claims

Claims1 . A product comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered daily; and the recombinant hCG is to be administered every other day.

2. A product for use according to claim 1 wherein the recombinant FSH is to be administered daily from day 1 of treatment (stimulation); and the recombinant hCG is to be administered every other day starting from day 1 of treatment (stimulation).

3. A product for use according to claim 1 or claim 2 wherein the recombinant FSH is to be administered at a dose of 9 to 18 pg, e.g. 9 to 12 pg, e.g. 10 pg FSH per day starting from day 1 of treatment (stimulation).

4. A product for use according to claim 1 or claim 2 wherein the recombinant hCG is to be administered at a dose of 0.1 to 1 pg hCG, e.g. 0.1 to 0.5 pg hCG, e.g. 0.25 pg hCG every other day starting from day 1 of treatment (stimulation).

5. A product comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 9 to 12, e.g. 10 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.25 pg hCG every other day starting from day 1 of treatment.

6. A composition (e.g. pharmaceutical composition) comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 9 to 12, e.g. 10 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.15 pg to 1 .1 pg hCG per day, for example 0.25 pg or 1 pg hCG per day starting from day 1 of treatment.

7. A composition (e.g. pharmaceutical composition) comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation), wherein the recombinant FSH is to be administered at a dose of 12 to 18, e.g. 13 to 17, e.g. 15 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.15 pg to 1 pg hCG per day, for example 0.15 pg to 0.35 pg hCG per day, for example 0.25 pg hCG per day starting from day 1 of treatment.

8. A product or composition for use according to any preceding claim wherein the recombinant FSH includes a2,6-sialylation and a2,3-sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6-sialyation, and 50% to 99% of the total sialylation is a 2,3- sialyation or optionally wherein 50 % to 99% of the total sialylation is a2, 6-sialyation, and 1% to 50% of the total sialylation is a 2,3-sialyation.

9. A product or composition for use according to any preceding claim wherein the recombinant hCG includes a2,6-sialylation and a2,3-sialylation, optionally wherein the hCG includes mono (1 S), di (2S), tri (3S) and tetra (4S) sialylated glycan structures.

10. A product or composition for use according to any preceding claim wherein a GnRH antagonist is administered starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation).

11. A product or composition for use according to any preceding claim wherein a GnRH antagonist is administered (e.g. daily) starting from day 5 to 7 (e.g starting from day 6) of treatment (stimulation) until the end of treatment.

12. A method of treating infertility (e.g. by controlled ovarian stimulation) in a female patient comprising administering recombinant follicle stimulating hormone (rFSH) daily (e.g. starting on day 1 of treatment / stimulation) and administering recombinant hCG (rhCG) every other day (e.g. starting on day 1 of treatment / stimulation).

13. A method of treating infertility (e.g. by controlled ovarian stimulation) in a female patient comprising administering recombinant follicle stimulating hormone (FSH) at a dose of 9 to 12, e.g. 10 pg FSH per day starting from day 1 of treatment and administering recombinant human chorionic gonadotropin (hCG) at a dose of 0.25 pg hCG every other day starting from day 1 of treatment.

14. A method of treating infertility (e.g. by controlled ovarian stimulation) in a female patient comprising administering recombinant follicle stimulating hormone (FSH) at a dose of 9 to 12, e.g. 10 pg FSH per day starting from day 1 of treatment and administering recombinant human chorionic gonadotropin (hCG) at a dose of 0.15 pg to 1 .1 pg hCG per day, for example 0.25 pg or 1 pg hCG per day starting from day 1 of treatment.

15. A method of treating infertility (e.g. by controlled ovarian stimulation) in a female patient comprising administering recombinant follicle stimulating hormone (FSH) at a dose of 12 to 18,e.g. 13 to 17, e.g. 15 pg FSH per day starting from day 1 of treatment and administering recombinant human chorionic gonadotropin (hCG) at a dose of 0.15 pg to 1 pg hCG per day, for example 0.15 pg to 0.35 pg hCG per day, for example 0.25 pg hCG per day starting from day 1 of treatment.

16. A product comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female patient, wherein the recombinant FSH is to be administered daily; and the recombinant hCG is to be administered every other day.

17. A product comprising recombinant follicle stimulating hormone (FSH) and recombinant human chorionic gonadotropin (hCG) for use in the treatment of infertility (e.g. by controlled ovarian stimulation) in a female patient, wherein the recombinant FSH is to be administered at a dose of 9 to 12, e.g. 10 pg FSH per day starting from day 1 of treatment; and the recombinant hCG is to be administered at a dose of 0.25 pg hCG every other day starting from day 1 of treatment.

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