A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol

Corifollitropin alfa, a fusion protein lacking LH activity, has a longer elimination half-life and extended time to peak levels than recombinant FSH (rFSH). A single injection of corifollitropin alfa may replace seven daily gonadotrophin injections during the first week of ovarian stimulation. In this large, double-blind, randomized, non-inferiority trial the ongoing pregnancy rates were assessed after one injection of 150 mu g corifollitropin alfa during the first week of stimulation and compared with daily injections of 200 IU rFSH using a standard GnRH antagonist protocol. The study population comprised 1506 treated patients with mean age of 31.5 years and body weight of 68.6 kg. Ongoing pregnancy rates of 38.9% for the corifollitropin alfa group and 38.1% for rFSH were achieved, with an estimated non-significant difference of 0.9% [95% confidence interval (CI): -3.9; 5.7] in favor of corifollitropin alfa. Stratified analyses of pregnancy rates confirmed robustness of this primary outcome by showing similar results regardless of IVF or ICSI, or number of embryos transferred. A slightly higher follicular response with corifollitropin alfa resulted in a higher number of cumulus-oocyte-complexes compared with rFSH [estimated difference 1.2 (95% CI: 0.5; 1.9)], whereas median duration of stimulation was equal (9 days) and incidence of (moderate/severe) ovarian hyperstimulation syndrome was the same (4.1 and 2.7%, respectively P = 0.15). Corifollitropin alfa is a novel and effective treatment option for potential normal responder patients undergoing ovarian stimulation with GnRH antagonist co-treatment for IVF resulting in a high ongoing pregnancy rate, equal to that achieved with daily rFSH. The trial was registered under ClinicalTrials.gov identifier NTC00696800

Innovative drug development for infertility therapy

Innovative drug development is essential to improve therapy over time by offering better efficacy, safety and/or treatment convenience. This thesis summarizes the sequential clinical development of three innovative fertility drugs namely follitropin-b (recombinant FSH), ganirelix (GnRH antagonist) and corifollitropin alfa (recombinant long-acting FSH agonist). Follitropin-b replaced urinary FSH, ganirelix introduced a new and short treatment protocol, and corifollitropin alfa replaced the first 7 daily (r)FSH injections during ovarian stimulation in a GnRH antagonist protocol. The development of these drugs has dramatically changed hormonal treatment of women participating in an ART program from being lengthy and complicated to short and simple. Comparative preclinical pharmacology is essential to determine the mechanism of action, specificity, and bioactivity to predict the potency in humans. The first-in-human phase I studies of follitropin-b and corifollitropin alfa included subjects with hypogonadotropic hypogonadism (HH) as the immunogenicity is hard to predict in preclinical models. Apart from safety and pharmacokinetics, it was examined whether follitropin-b could stimulate multiple follicular growth in the complete absence of LH activity. The first-in-human study of the fusion molecule corifollitropin alfa in HH men was focusing on its potential immunogenicity. Only thereafter, a phase I study in pituitary-suppressed female volunteers was performed with increasing doses of corifollitropin alfa. Phase II research of follitropin-b was limited to the question whether patients down-regulated with different GnRH agonist protocols could be treated with pure recombinant FSH lacking LH activity. In contrast, the GnRH antagonist ganirelix was tested in a double-blind, dose-finding study including 6 dose groups of which the lowest and highest dose group were discontinued and finally one dose was selected for further development. Corifollitropin alfa was initially tested in a feasibility study and thereafter in a phase II controlled dose-finding study that demonstrated that the optimal dose was between the lowest and highest test dose. Subsequent dose selection was based on modeling and simulation taking into account the inverse relationship between exposure to corifollitropin alfa and body weight and that FSH activity has to retain for 7 days above the threshold to support multiple follicular development. In comparative phase III studies of follitropin-b, ganirelix and corifollitropin alfa, the number of oocytes or the pregnancy rate was the primary endpoint. In time, follitropin-b was compared to urinary FSH and developed in a long GnRH agonist protocol. Subsequently, the GnRH antagonist ganirelix was compared to a long GnRH agonist protocol and finally a single dose of corifollitropin alfa was compared to daily follitropin-b using a ganirelix protocol. Main safety endpoints during phase III trials focused on the incidence of adverse events including Ovarian Hyperstimulation Syndrome (OHSS), hypersensitivity, immunogenicity, and the health outcome of offspring. Registration of new drugs requires a positive benefit/risk ratio based on the evaluation of all efficacy and safety parameters. Following drug approval, retrospective analyses may support further development of treatment regimens or for specific subgroups of patients. Prospective Phase IV studies may obtain additional efficacy and/or safety data to extend labeling to the final drug posology and profile

Innovative drug development for infertility therapy

Innovative drug development is essential to improve therapy over time by offering better efficacy, safety and/or treatment convenience. This thesis summarizes the sequential clinical development of three innovative fertility drugs namely follitropin-b (recombinant FSH), ganirelix (GnRH antagonist) and corifollitropin alfa (recombinant long-acting FSH agonist). Follitropin-b replaced urinary FSH, ganirelix introduced a new and short treatment protocol, and corifollitropin alfa replaced the first 7 daily (r)FSH injections during ovarian stimulation in a GnRH antagonist protocol. The development of these drugs has dramatically changed hormonal treatment of women participating in an ART program from being lengthy and complicated to short and simple. Comparative preclinical pharmacology is essential to determine the mechanism of action, specificity, and bioactivity to predict the potency in humans. The first-in-human phase I studies of follitropin-b and corifollitropin alfa included subjects with hypogonadotropic hypogonadism (HH) as the immunogenicity is hard to predict in preclinical models. Apart from safety and pharmacokinetics, it was examined whether follitropin-b could stimulate multiple follicular growth in the complete absence of LH activity. The first-in-human study of the fusion molecule corifollitropin alfa in HH men was focusing on its potential immunogenicity. Only thereafter, a phase I study in pituitary-suppressed female volunteers was performed with increasing doses of corifollitropin alfa. Phase II research of follitropin-b was limited to the question whether patients down-regulated with different GnRH agonist protocols could be treated with pure recombinant FSH lacking LH activity. In contrast, the GnRH antagonist ganirelix was tested in a double-blind, dose-finding study including 6 dose groups of which the lowest and highest dose group were discontinued and finally one dose was selected for further development. Corifollitropin alfa was initially tested in a feasibility study and thereafter in a phase II controlled dose-finding study that demonstrated that the optimal dose was between the lowest and highest test dose. Subsequent dose selection was based on modeling and simulation taking into account the inverse relationship between exposure to corifollitropin alfa and body weight and that FSH activity has to retain for 7 days above the threshold to support multiple follicular development. In comparative phase III studies of follitropin-b, ganirelix and corifollitropin alfa, the number of oocytes or the pregnancy rate was the primary endpoint. In time, follitropin-b was compared to urinary FSH and developed in a long GnRH agonist protocol. Subsequently, the GnRH antagonist ganirelix was compared to a long GnRH agonist protocol and finally a single dose of corifollitropin alfa was compared to daily follitropin-b using a ganirelix protocol. Main safety endpoints during phase III trials focused on the incidence of adverse events including Ovarian Hyperstimulation Syndrome (OHSS), hypersensitivity, immunogenicity, and the health outcome of offspring. Registration of new drugs requires a positive benefit/risk ratio based on the evaluation of all efficacy and safety parameters. Following drug approval, retrospective analyses may support further development of treatment regimens or for specific subgroups of patients. Prospective Phase IV studies may obtain additional efficacy and/or safety data to extend labeling to the final drug posology and profile

A randomized three-way cross-over study in healthy pituitary-suppressed women to compare the bioavailability of human chorionic gonadotrophin (Pregnyl®) after intramuscular and subcutaneous administration

The objective of this study was to compare the bioavailability of s.c. and i.m. administration of human chorionic gonadotrophin (HCG; Pregnyl®). In a randomized, single centre, three-way cross-over study, 18 healthy pituitary-suppressed volunteers were assigned to single HCG injections of 5000 and 10000 IU i.m. and 10000 IU s.c. Rate (C(max), t(max)) and extent [area under curve from zero to infinity (AUC(o-∞))] of absorption of HCG were determined, Serum immunoactive HCG increased from 0.4-0.5 IU/l at baseline to mean peak concentrations, which were reached 20 h after injection of 156 IU/l with 5000 IU i.m., of 307 IU/l with 10000 IU i.m. and of 339 IU/l with 10000 IU s.c. Eight days after administration, < 10% of the maximum HCG activity was found for each regimen. The elimination half-life (t( 1/4 )) was on average 32-33 h, irrespective of the treatment regimen. Intramuscular and s.c. injections of 10000 IU HCG were bioequivalent with respect to AUC(0-∞). The C(max) and t(max) were also similar between the two administration routes but bioequivalence could not be proven due to intersubject variability. Intramuscular doses of 5000 IU and 10000 IU HCG were dose-proportional. Since s.c. HCG is bioequivalent to i.m. HCG with respect to extent of absorption (its major pharmacokinetic variable) and is well tolerated, the s.c. administration route may be effectively and safely used in assisted reproduction. Moreover, since s.c. injection can be performed by the patients themselves, acceptability may be enhanced