Real-world Evidence on Follitropin Delta Individual Dosing

As part of the in vitro fertilisation treatment, ovarian stimulation is routinely performed. For this purpose, FSH preparations are used. Follitropin delta is a FSH preparation that is approved for a wide range of applications and is dosed individually according to body weight and serum anti-Müllerian hormone (AMH). Body weight is used to estimate the distribution volume of the glycoprotein FD in the patient and is thus a proxy of exposure. The AMH is used to estimate the ovarian reserve and thus the number of follicles in the ovaries that can be recruited by Follitropin delta stimulation. An algorithm is used for individual dosing. The aim of individual dosing is to reduce the probability of an under or overreaction of the ovaries to FSH therapy.

In contrast to phase III registration studies, patients with severe overweight and underweight, as well as very high and very low AMH values and associated disorders of the menstrual cycle and oocyte maturation, are also found in the reality of care. The performance of the dosing algorithm and thus the results of ovarian stimulation in these subgroups of patients have so far been insufficiently investigated in the phase III registration trials.

In the present study no statistical hypothesis will be tested. The study is descriptive by design and the analyses are descriptive and exploratory. NIS is chosen in order to explore how the individualized dosing regimen of REKOVELLE® performs in routine clinical practice and to investigate the effectiveness and safety of REKOVELLE® under real-world conditions. This is a monocentric, prospective, non-interventional cohort study conducted in normal care setting in a fertility clinic that will collect information from 850 women undergoing up to two cycles of IVF or ICSI treatment with controlled ovarian stimulation with REKOVELLE®.

Infertility is often defined as the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse. Many factors (age, gynaecological problems, life style factors) can cause infertility and may involve the male, the female or both.

Global estimates suggest that the 12-month prevalence rate of infertility ranged from 3.5% to 16.7% in developed countries, with a median prevalence of 9% worldwide for women aged 20 - 44 years. A recent study estimated that 1.9% of child-seeking women aged 20 - 44 years experienced primary infertility (unable to have a live birth) and 10.5% secondary infertility (at least one live birth). The proportion of infertile couples seeking any infertility medical care ranges from 51% in less developed countries to 56% in developed countries, and 22% actually received infertility treatment.

Among fertility treatment, controlled ovarian stimulation (COS) with recombinant or urinary follicle stimulating hormone (FSH) and human menotropin gonadotropin (hMG) aims to obtain an adequate number of competent oocytes to be used for assisted reproductive technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI), with minimum risks for the woman.

The ovarian response is influenced by the dose of gonadotropin, but there is a large variability across patients for the same dose of gonadotropin. A standard starting dose of gonadotropin in women with a low ovarian reserve may result in a poor ovarian response. In women with a high ovarian reserve, the same dose may result in an excessive response and therefore increases the risk of complications such as the ovarian hyperstimulation syndrome (OHSS). OHSS is a rare but critical complication associated with gonadotropin use. Severe OHSS occurs in approximately 1.4 % of all COS cycles.

Individualizing COS regimens is therefore crucial to ensure an appropriate dosing from the start of stimulation in order to reduce the risk of cycle cancellation due to poor response and minimize the iatrogenic risks due to an excessive response.The use of biomarkers, which can predict ovarian response to exogenous FSH stimulation, has been extensively investigated. Among the different biomarkers, the serum level of anti-müllerian hormone (AMH) is currently considered as the most robust marker of the ovarian reserve. In addition, AMH serum levels shows relative stability and consistency during the menstrual cycle, and can therefore be measured at any time of the menstrual cycle.

In December 2016, Ferring received Marketing Authorisation approval from the European Commission for follitropin delta (FE 999049) under the trade name REKOVELLE®, a new human recombinant FSH (rFSH). The indication is: "Controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycle." This is the first rFSH treatment to be administered with an individualised dosing regimen, based on a woman's serum AMH level as well as her body weight.

This individualised dosing regimen was established in a phase-2 AMH-stratified trial conducted in 265 IVF/ICSI patients using pharmacokinetic (PK) and pharmacodynamic (PD) modelling and simulation. A robust assay was developed in collaboration with Roche Diagnostics to ensure a reliable assessment of AMH levels at the standards intended for companion diagnostics.

The efficacy and safety of Follitropin Delta was first evaluated in the ESTHER-1 (Evidence- based Stimulation Trial with Human rFSH in Europe and Rest of World) phase-3 trial, which compared the individualized Follitropin Delta dosing based on AMH level and body weight with conventional Follitropin Alfa (Gonal-F®) dosing. Patients who did not achieve an ongoing pregnancy could continue in the ESTHER-2 phase-3 trial, which evaluated the immunogenicity in repeated COS cycles. The results of the phase-3 trials showed that individualized Follitropin Delta was non-inferior to conventional Follitropin Alfa for ongoing pregnancy and ongoing implantationrates. Overall, women treated with individualized Follitropin Delta dosing reached more frequently the prespecified optimum oocyte yield (8-14 oocytes), with fewer cases of extreme ovarian responses, and a reduced need for OHSS preventive measures.

The phase III clinical program has demonstrated that REKOVELLE® is an effective and well-tolerated treatment for controlled ovarian stimulation. Nevertheless, while clinical trials provide crucial information about drug efficacy and safety under controlled conditions in a selected group of patients, broader information is needed to explore how the individualized dosing regimen of REKOVELLE® is used in routine clinical practice and to investigate the effectiveness and safety of REKOVELLE® under real-world conditions.

Eligibility Criteria:
Inclusion Criteria:

* Age ≥18 to ≤ 44 years at enrolment

  * Planned stimulation in a fixed or flexible GnRH antagonist protocol
  * Planned use of follitropin delta for ovarian stimulation as per SmPC
  * Planned IVF or ICSI treatment with ejaculated or cryopreserved male germ cells, autologous or heterologous, with or without planned genetic testing of the oocytes or embryos
  * Planned preservation of MII oocytes (fertility preservation)
  * Planned triggering of final oocyte maturation with hCG or a GnRH agonist
  * Willingness and consent to participate

Exclusion Criteria:

* Serum AMH within 12 months prior to treatment ≤0.3 ng/ml
* Most recent serum AMH value before start of stimulation older than 12 months
* Serum AMH value not determined in Roche Elecsys immunoassays
* Pre-treatment with a combined oral contraceptive "pill" consisting of ethinyl estradiol and a synthetic progestogen