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.
