Pharmacokinetics and Safety of Follitropin Delta in Gonadotropin Down-Regulated Healthy Chinese Women.

BACKGROUND: Follitropin delta, a novel recombinant follicle-stimulating hormone (rFSH) preparation derived from a human cell line, has different pharmacokinetic and pharmacodynamic properties compared with existing rFSH preparations expressed by Chinese hamster ovary cells (CHO). OBJECTIVES: The objective of this study was to assess the pharmacokinetic characteristics, dose proportionality, and safety of follitropin delta in healthy Chinese women. METHODS: This was a phase I, randomized, open-label study. Twenty-four healthy Chinese women were randomized (1:1:1) to receive a single subcutaneous administration of follitropin delta 12, 18, or 24 µg. The pharmacokinetic parameters (maximum observed serum concentration [Cmax], time to reach Cmax [tmax], area under the serum concentration-time curve from dosing to infinity [AUC∞], and elimination phase half-life [t½]) of follitropin delta were derived using noncompartmental analysis. RESULTS: Following a single subcutaneous administration of follitropin delta 12, 18, or 24 µg, mean Cmax (0.388, 0.677, and 0.825 ng/mL, respectively) and AUC∞ (41.3, 62.9, and 83.1 h·ng/mL, respectively) increased in a dose-proportional manner. The median tmax was 24 h, and the mean t½ was in the range of 50.5-60.9 h. All treatment-related adverse events were categorized as mild, except for one case of urticaria from the follitropin delta 18-µg dose group which was considered moderate. Only one woman presented with elevation of alanine transaminase and aspartate aminotransferase at the follow-up visit, which was reported as a treatment-emergent adverse event. There were no injection-site reactions and none of the participants showed any confirmed presence of treatment-induced anti-FSH antibodies. CONCLUSIONS: The administration of single doses of follitropin delta to healthy Chinese women demonstrated dose-proportional pharmacokinetics over the dose range of 12-24 µg, and these doses were well tolerated. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov registration no. NCT04150861.

A new fully human recombinant FSH (follitropin epsilon): two phase I randomized placebo and comparator-controlled pharmacokinetic and pharmacodynamic trials.

STUDY QUESTION: What are the differences and similarities of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the novel recombinant human FSH follitropin epsilon expressed in the human cell line GlycoExpress compared with a Chinese hamster ovary (CHO) derived compound and a urinary derived product? SUMMARY ANSWER: Overall follitropin epsilon, with a fully human glycosylation, shows a comparable PK profile at single-dose as well as multiple-dose administration compared to recombinant CHO-derived FSH as well as urinary derived FSH, whereas the PD properties differ from product to product with follitropin epsilon being most active in PD parameters. WHAT IS KNOWN ALREADY: Recombinant FSH produced in CHO and FSH obtained from the urine of postmenopausal women show comparable PK and PD properties. However, more recently a comparative study of a recombinant FSH produced in the human cell line PerC6 and a CHO-derived FSH preparation revealed differences in PK and PD properties of the molecule. STUDY DESIGN, SIZE, DURATION: Both studies were randomized, placebo- and comparator-controlled, single-blind phase I studies in healthy pituitary-suppressed female volunteers aged 18 and 40 years. The single-dose, dose escalation study included 19 women (April 2011 to September 2011) with three ascending dose levels per subject or placebo/comparators with a 14-day washout phase between dosings. The multiple-dose study included 57 women (October 2011 to April 2012) in five cohorts with three dose levels versus placebo and two comparators. Randomization to the respective treatment was performed after successful downregulation of the pituitary gland prior to Investigational Medicinal Product dosing. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the single-dose study, 12 subjects received follitropin epsilon (25, 75, 150 and 300 IU) in three of four possible ascending doses and seven subjects received one dose of two comparators (150 IU Bravelle and 150 IU Gonal-f) and placebo in random order in each treatment period. In the multiple-dose study, 30 subjects received follitropin epsilon (75 IU or 150 IU once daily [QD], or 150 IU every other day [QAD], 10 subjects each) and 27 subjects received 150 IU Gonal-f, 150 IU Bravelle, or placebo for 7 days (11/10/6 subjects). Blood samples for measuring PK as well as PD parameters were collected systematically before, during and after dosing. Adverse events (AEs) and other relevant safety parameters were recorded. Data were summarized using descriptive statistics. MAIN RESULTS AND THE ROLE OF CHANCE: The single- and multiple-dose PK parameters maximum concentration (Cmax) and area under the concentration-time curve (AUC0-last) increased in a linear fashion with increasing dose levels of follitropin epsilon. Follitropin epsilon showed PK characteristics comparable to the comparators indicating that well established treatment schemes could be applied. There was a dose-response effect of single and multiple doses of follitropin epsilon on follicular growth, which was shown for the biomarker inhibin B as well as for the mean number and size of follicles. Multiple doses of 75 IU follitropin epsilon given daily, as well as 150 IU follitropin epsilon every second day, showed a follicle growth comparable with 150 IU Gonal-f given daily, while in case of daily administration of 150 IU Bravelle only weak follicle stimulation was observed. Multiple doses of 150 IU follitropin epsilon induced a much higher follicle growth compared to the same dose of Gonal-f. All single and multiple follitropin epsilon doses tested were safe and well tolerated, and overall there were no relevant differences between follitropin epsilon and the comparators in terms of safety. The average number of AEs increased with increasing dose levels. No clinically relevant abnormalities were reported for any of the other safety parameters assessed. No follitropin epsilon anti-drug antibodies were observed. LIMITATIONS, REASONS FOR CAUTION: The studies were conducted as a single-blind design. Hormone levels or other parameters assessed in serum are generally not considered as being subject to bias. Other assessments directly performed by the investigators, such as transvaginal ultrasound assessments, may have been subject to personal bias. No prospective calculations of statistical power had been made, as is common practice for first in human and early phase I studies in healthy volunteers. WIDER IMPLICATIONS OF THE FINDINGS: These early development studies showed that follitropin epsilon exhibits comparable PK characteristics, as well as inducing stronger PD effects in terms of follicle growth and serum inhibin B, than the comparators. Follitropin epsilon induced a dose-dependent increase in follicular growth. The results warrant further studies with this new fully human recombinant FSH. STUDY FUNDING/COMPETING INTEREST(S): The studies were sponsored by GLYCOTOPE GmbH, Berlin, Germany. K.A-E. is an employee of QPS-Netherlands, B.V., which received funding for the studies from Glycotope GmbH; I.D. and C.K. are employees of Dinox B.V., which received funding for the studies from Glycotope GmbH; L.S. and S.G. are employees and shareholders of Glycotope GmbH; B.D. and K.E. are employees of Glycotope GmbH. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov: NCT01354886 (single-dose); NCT01477073 (multiple-dose). TRIAL REGISTRATION DATE: The single-dose trial was registered on 11 May 2011 while the multiple-dose trial was registered on 09 November 2011. DATE OF FIRST SUBJECT'S ENROLMENT: First subject was enroled in the single-dose trial in 27 April 2011 and in the multiple-dose trial in 02 October 2011.

Characterisation of Population Pharmacokinetics and Endogenous Follicle-Stimulating Hormone (FSH) Levels After Multiple Dosing of a Recombinant Human FSH (FE 999049) in Healthy Women.

OBJECTIVE: The aim of this study was to characterise the population pharmacokinetics of FE 999049, a novel recombinant human follicle-stimulating hormone (FSH), after multiple dosing in healthy women, taking into account endogenous FSH levels and the reproductive hormone dynamics. METHODS: Longitudinal measurements of FSH, luteinising hormone, progesterone, estradiol, and inhibin B levels were collected after repeated subcutaneous dosing with 225 IU of FE 999049 in 24 gonadotropin downregulated healthy women. The FSH data were described using nonlinear mixed-effects modelling. RESULTS: The measured FSH levels were modelled as a sum of endogenous FSH and FE 999049. The FE 999049 population pharmacokinetics were best described using a one-compartment model with first-order absorption and elimination, and a transit model for delayed absorption. The apparent clearance and volume of distribution increased with body weight in accordance with an allometrically scaled power exponent of 0.75 and 1, respectively. Endogenous FSH levels were lower in individuals with higher progesterone levels at baseline and were further suppressed over time with increasing inhibin B levels. CONCLUSIONS: This characterisation of FE 999049 population pharmacokinetics after repeated dosing is in line with previous findings after single-dose administration. The results provide a basis for study design and data evaluation in the future development of recombinant FSH products, and show it can be of importance to account for endogenous FSH levels and its variation over time for accurate estimation of exogenously administered FSH pharmacokinetic parameters. Thus, correcting FSH concentrations by the observed endogenous FSH baseline value at all time points may be incorrect.

Impact of patient characteristics on the pharmacokinetics of corifollitropin alfa during controlled ovarian stimulation.

AIM: The aim of the present study was to characterize the pharmacokinetic profile of corifollitropin alfa and examine the relationships between dose, intrinsic factors [body weight, body mass index (BMI), age and race] and corifollitropin alfa pharmacokinetics. METHODS: Data from five phase II and III clinical trials of corifollitropin alfa were evaluated. All subjects included in the analysis received 60 - 180 µg corifollitropin alfa for controlled ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol followed by daily recombinant follicle stimulating hormone (rFSH) from day 8 onwards. Serum corifollitropin alfa levels (across the entire range of treatment) and total follicle stimulating hormone immunoreactivity levels (up to the start of rFSH treatment) were indicators of drug exposure. The analyses were performed using a nonlinear mixed-effects modelling approach. RESULTS: A total of 2630 subjects were treated with corifollitropin alfa, and 2557 subjects were evaluable for analysis. Body weight, BMI and race (Asian and Black vs. Caucasian) were significant determinants of corifollitropin alfa exposure. Dose-normalized corifollitropin alfa exposure was ~89% higher in women with a body weight of 50 kg vs. 90 kg (in subjects with a similar BMI of 24 kg m(-2) ); 14% higher in women with a BMI of 18 kg m(-2) vs. 32 kg m(-2) (provided they were of similar body weight); and ~15.7% lower in Asian subjects and 13% higher in Black subjects vs. Caucasian subjects. CONCLUSIONS: Body weight was the major determinant of corifollitropin alfa exposure; BMI and race (Asian and Black) were also determinants but to a lesser extent and without associated effects on clinical outcomes. Corifollitropin alfa dose adjustment is indicated, based on body weight but not for BMI or race. These recommendations are consistent with the product label.

Population Pharmacokinetic Modelling of FE 999049, a Recombinant Human Follicle-Stimulating Hormone, in Healthy Women After Single Ascending Doses.

OBJECTIVE: The purpose of this analysis was to develop a population pharmacokinetic model for a novel recombinant human follicle-stimulating hormone (FSH) (FE 999049) expressed from a human cell line of foetal retinal origin (PER.C6(®)) developed for controlled ovarian stimulation prior to assisted reproductive technologies. METHODS: Serum FSH levels were measured following a single subcutaneous FE 999049 injection of 37.5, 75, 150, 225 or 450 IU in 27 pituitary-suppressed healthy female subjects participating in this first-in-human single ascending dose trial. Data was analysed by nonlinear mixed effects population pharmacokinetic modelling in NONMEM 7.2.0. RESULTS: A one-compartment model with first-order absorption and elimination rates was found to best describe the data. A transit model was introduced to describe a delay in the absorption process. The apparent clearance (CL/F) and apparent volume of distribution (V/F) estimates were found to increase with body weight. Body weight was included as an allometrically scaled covariate with a power exponent of 0.75 for CL/F and 1 for V/F. CONCLUSIONS: The single-dose pharmacokinetics of FE 999049 were adequately described by a population pharmacokinetic model. The average drug concentration at steady state is expected to be reduced with increasing body weight.

Comparison of pharmacokinetic and safety profiles between Bemfola(®) and Gonal-f(®) after subcutaneous application.

Recombinant human follicle stimulating hormone (r-hFSH) is effective and safe for controlled ovarian stimulation. Bemfola(®) (Finox AG, Burgdorf, Switzerland), a new biosimilar r-hFSH, has proven comparable non-clinical pharmacological profiles to those of the widely used Gonal-f(®) (Serono Pharma S.p.A., Bari, Italy). The objective of this study was to show that Bemfola(®) yields comparable clinical pharmacokinetic (PK) and safety profiles to Gonal-f(®) in healthy female subjects. In this randomized, Phase I trial conducted in healthy female volunteers (N = 32), a 2-period, balanced 2-treatment crossover design was used. A single subcutaneous dose of 225 IU Bemfola(®) or Gonal-f(®) was administered in each treatment period per sequence. Blood was collected for pharmacokinetic analysis until 10 days after each r-hFSH treatment. For down-regulation of endogenous FSH subjects were given a depot injection with leuprolide acetate prior to the study drug in either sequence. Pharmacokinetic data was available for 23 subjects. No appreciable differences in key PK parameters were detected between the r-hFSH products as per non-compartmental PK analysis [i.e. for Bemfola(®) and Gonal-f(®) respectively AUC0-192 424.90 and 432.75 IU h/L, C max 0.98 and 0.95 IU/L, T max 24.0 h (range 6.0-24.0) and 24.0 h (range 9.0-24.0), t 1/2 43.58 h [standard deviation (SD 14.17)] and 42.58 h (SD 16.47), and K e 0.0075 1/h (SD 0.003) and 0.0077 1/h (SD 0.002)]. Subgroup analysis for estradiol (E2) response was similar for Bemfola(®) and Gonal f(®) (AUC(0--120) p = 0.21 and C max p = 0.82). No major safety issues were identified and no immunogenic reaction to r-hFSH was observed. The results of this study indicate that a single dose of Bemfola(®) exhibits pharmacokinetic and safety profiles comparable to Gonal-f(®) in healthy young women.

Phase I, two-way, crossover study to demonstrate bioequivalence and to compare safety and tolerability of single-dose XM17 vs Gonal-f® in healthy women after follicle-stimulating hormone downregulation.

BACKGROUND: XM17 is a recombinant human follicle-stimulating hormone (rhFSH) intended mainly for use in controlled ovarian hyperstimulation and the treatment of anovulation. The purpose of the current study was to establish bioequivalence, safety and tolerability of single 300-IU subcutaneous (sc) doses of XM17 to that of the reference follitropin alfa (Gonal-f(®)) in healthy young women. METHODS: This open-label, Phase I, single-dose, single-center, two-way crossover study was conducted from February to May 2009. Thirty-six women aged 18-39 years were included, with a study duration of ~27 days per participant. After endogenous FSH downregulation with goserelin (3.6 mg) on study Day 0, XM17 and Gonal-f(®) were administered on Days 11 and 19 in random sequence. Frequent serum samples were drawn for standard pharmacokinetics until 168 h postdosing. Laboratory values, adverse events (AEs) and local tolerability were assessed throughout the study period. Primary endpoints included Cmax and AUC0-t. Secondary endpoints included additional pharmacokinetic (PK) parameters, safety and tolerability. RESULTS: Ratios of XM17 to Gonal-f(®) for Cmax and AUC0-t equaled 1.017 (90 % confidence interval [CI]: 0.958, 1.080) and 1.028 (90 % CI: 0.931, 1.134), respectively, with the CIs contained within the predefined interval (0.8, 1.25). Ratios for AUC0-168h, AUC0-∞ and t1/2 were also ~1, and no difference in tmax was detected. Both XM17 and Gonal-f(®) were well tolerated, with no detectable anti-FSH antibodies, serious AEs or AEs leading to discontinuation or dose reduction. CONCLUSIONS: PK bioequivalence of single 300-IU sc doses of XM17 to the reference product Gonal-f® was statistically demonstrated. XM17 was well tolerated both systemically and locally. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02592031 ; date of registration: 28 October, 2015.

Single therapeutic and supratherapeutic doses of corifollitropin alfa, a sustained follicle stimulant, do not prolong the QTcF-interval in healthy postmenopausal volunteers.

OBJECTIVE: Corifollitropin alfa (Elonva®) is the first hybrid follicle-stimulating hormone molecule with demonstrated sustained follicle-stimulating activity after a single subcutaneous injection. This trial evaluated if corifollitropin alfa is associated with QT/QTc prolongation and/ or proarrhythmic potential as compared to placebo in healthy post-menopausal women. MATERIALS: Participants were healthy, postmenopausal women. Study treatments were corifollitropin alfa 150 µg, corifollitropin alfa 240 µg, and moxifloxacin 400 mg with placebo. METHODS: This randomized, double blind, double-dummy, 4-period crossover trial compared single doses of corifollitropin alfa 150 µg (therapeutic dose), corifollitropin alfa 240 µg (supratherapeutic dose), and moxifloxacin 400 mg (positive control) with placebo. Corifollitropin alfa was administered on day 1 and moxifloxacin on day 2. RESULTS: The largest time-matched mean QTcF difference versus placebo for the therapeutic dose of corifollitropin alfa was 1.4 ms (upper limit of 1-sided 95% confidence interval (UL 95% CI) = 3.4 ms), and for the supratherapeutic dose was 1.2 ms (UL 95% CI = 3.6 ms). CONCLUSIONS: For both the therapeutic and the supratherapeutic dose of corifollitropin alfa and at all time points, the UL 95% CI for the time matched QTcF differences compared with placebo was below 10 ms, the threshold of relevance defined by the ICH E14 guideline. Single therapeutic and supratherapeutic doses of corifollitropin alfa are not associated with clinically relevant QT/QTc-interval prolongation in healthy post-menopausal women.

Different pharmacokinetic and pharmacodynamic properties of recombinant follicle-stimulating hormone (rFSH) derived from a human cell line compared with rFSH from a non-human cell line.

Pharmacokinetic and pharmacodynamic properties of a novel recombinant follicle-stimulating hormone (rFSH) preparation (FE 999049), expressed by a human cell line (PER.C6), was compared with an rFSH preparation (follitropin α) expressed by a Chinese hamster ovary (CHO) cell line in healthy pituitary-suppressed women. Following single intravenous administration of 225 IU (Steelman-Pohley assay), the clearance was lower, 0.31 versus 0.44 L/h, for FE 999049 than for follitropin α. Likewise, the apparent clearance after repeated daily subcutaneous administrations was lower, 0.58 versus 0.99 L/h, and AUC and C(max) higher, 1.7- and 1.6-fold. The absolute bioavailability after a single subcutaneous dose of 450 IU was similar for both preparations, 60-65%. After repeated subcutaneous administration the elimination half-life was approximately 30 and 24 hours for FE 999049 and follitropin α. The ovarian responses by number of follicles and serum concentrations of inhibin B and estradiol, were higher with FE 999049 than with follitropin α, AUC and C(max) for the two latter being >1.6-fold greater with FE 999049 than with follitropin α. These results indicate that administration of equal doses of FE 999049, expressed in a human cell line, and follitropin α, expressed in a CHO cell line, display different pharmacokinetic and pharmacodynamic properties in humans.

LAPS-FSH: a new and effective long-acting follicle-stimulating hormone analogue for the treatment of infertility.

Although several long-acting follicle-stimulating hormone (FSH) therapies have been developed to enhance the ovarian response, a disadvantage of FSH therapy is its relatively short half-life, which requires women to receive one to two injections per day for almost 2 weeks. In the present study, we developed a novel FSH analogue by conjugating recombinant human FSH (rhFSH) and the constant region of the human immunoglobulin G4 fragment via non-peptidyl linkers. The efficacy of the FSH analogue was evaluated in vitro by cAMP level assessments, pharmacokinetic studies and a determination of ovarian weight and by comparing these findings with the results from other FSH analogues. In addition, the total number of antral and Graafian follicles was determined after 7 days of treatment with control, 6µgkg(-1) follitropin ß, 6, 12 or 42µgkg(-1) corifollitropin α or 3, 6 or 12µgkg(-1) long acting protein/peptide discovery-follicle-stimulating hormone (LAPS-FSH). As a result, the animals treated with 12µgkg(-1) LAPS-FSH produced additional and larger healthy follicles. These data demonstrate that LAPS-FSH promotes growth and inhibits atresia of the ovarian follicle compared with other available drugs, suggesting that our new drug enhances the efficacy and duration of treatment. It is expected that our new FSH analogue will result in a higher chance of pregnancy in patients who are unresponsive to other drugs.

Corifollitropin alfa for female infertility.

INTRODUCTION: Follicle-stimulating hormone (FSH) is essential for the development of ovarian follicles. Urinary-derived and recombinant FSH (rFSH) preparations are widely used in infertility treatment but have to be administered daily to achieve steady-state serum levels. Corifollitropin alfa is a hybrid molecule with a prolonged half-life. AREAS COVERED: The development and clinical testing of corifollitropin alfa, including the pharmacodynamics and kinetics, efficacy and drug safety. Searches were performed using the Medline database. EXPERT OPINION: Corifollitropin alfa is composed of the FSH α-subunit and a hybrid of the FSH ß-subunit and the C-terminal peptide (CTP) of the human chorionic gonadotropin (hCG) ß-subunit. The rationale of developing such a molecule was to reduce patient burden, by reducing the number of injections required to sustain multifollicular growth. Two strengths of corifollitropin are available (for patients ≤ 60 kg and > 60 kg). Compared with a daily dose of 200 IU of rFSH, 150 mcg of corifollitropin is equivalent in safety and pregnancy outcomes in women > 60 and < 90 kg using an antagonist protocol. Another RCT in women ≤ 60 kg also confirmed safety and efficacy of follicular stimulation (100 mcg of corifollitropin versus 150 IU of rFSH), but it was not powered to demonstrate equivalence in terms of pregnancy rates.

Corifollitropin alfa: a new option to treat female infertility.

Corifollitropin alfa (Elonva®) is the first hybrid follicle-stimulating hormone (FSH) molecule with demonstrated sustained follicle-stimulating activity. The ß subunit of this molecule contains the carboxy-terminal peptide of human chorionic gonadotropin, which alters the pharmacokinetic profile of the molecule. It demonstrates a longer circulation half-life and extended time to peak levels when compared with recombinant FSH (rFSH). Like rFSH, it lacks luteinizing hormone activity and binds specifically to the FSH receptor in vitro. Clinical trials show that corifollitropin alfa is able to sustain multiple follicular growth for a week, with a similar ovarian response and safety profile as rFSH. A single injection of corifollitropin alfa can replace 7 daily injections of rFSH during the first week of ovarian stimulation in gonadotropin-releasing hormone antagonist protocols. Therefore, corifollitropin alfa addresses the need for a simplified treatment approach to lessen the burden of multiple daily injections for in vitro fertilization.

Pharmacologic profiling of corifollitropin alfa, the first developed sustained follicle stimulant.

Corifollitropin alfa (Elonva®, MSD, previously N.V. Organon or Schering-Plough Oss, The Netherlands) is a newly developed sustained follicle stimulant composed of the α subunit of human follicle-stimulating hormone (FSH) and a hybrid ß subunit formed by fusion of the human chorionic gonadotropin ß subunit carboxy terminal peptide with the ß subunit of human FSH. Binding characteristics of corifollitropin alfa at the rat FSH receptor and transactivation properties at the rat FSH receptor, human luteinizing hormone (LH) receptor, and human thyroid-stimulating hormone receptor (TSH receptor) were assessed in vitro. Bioactivity of corifollitropin alfa in rats was also assessed. Serum corifollitropin alfa levels in rats and dogs were used to derive the main pharmacokinetic parameters of corifollitropin alfa. Binding and transactivation profile of corifollitropin alfa to rat FSH receptor was specific and comparable to that of recombinant human FSH, with no intrinsic TSH receptor or LH receptor activation. From pharmacokinetic studies, circulating half-life of corifollitropin alfa was calculated to be 17.3h in rats and 46.9h in dogs, 1.5- to 2-fold longer than recombinant FSH. Corifollitropin alfa demonstrated a 2- to 4-fold increase in bioactivity (ovarian weight, serum estradiol and progesterone, ovulated ova) over recombinant FSH across all in vivo parameters assessed. These data demonstrate that corifollitropin alfa is a specific ligand with high affinity for FSH receptor, lacking intrinsic activity for LH receptor and TSH receptor. By virtue of its increased in vivo half-life, corifollitropin alfa can be a valuable alternative to FSH by acting as a sustained follicle stimulant.

Corifollitropin alfa: a novel long-acting recombinant follicle-stimulating hormone agonist for controlled ovarian stimulation.

The advent of recombinant technology has made the production of modified proteins with desired properties possible. Corifollitropin alfa is a successful example of the first available long-acting, follicle stimulating hormone. Corifollitropin alfa has prolonged half-life and a slower absorption rate, but has the same receptor-binding and biological activity as recombinant FSH (rFSH). Its application is associated with the arrival of a novel simplified approach for controlled ovarian stimulation in IVF patients. Different studies have proven the efficiency of a single corifollitropin alfa dose to initiate and sustain multiple follicular development in a gonadotropin-releasing hormone antagonist protocol. Finally, corifollitropin alfa is well tolerated and is not correlated with serious adverse events, except for the slightly higher incidence of ovarian hyperstimulation syndrome compared with traditional management with recombinant FSH.

Pharmacokinetics and follicular dynamics of corifollitropin alfa versus recombinant FSH during ovarian stimulation for IVF.

A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. This double-blind randomized controlled trial assessed the pharmacokinetics and pharmacodynamics of 150µg corifollitropin alfa versus daily 200IU rFSH in 1509 patients. Comparative analyses were performed on serum concentrations of FSH immunoreactivity (pharmacokinetics), and the number and size of growing follicles, and inhibin B and oestradiol concentrations as biomarkers of ovarian response (pharmacodynamics). The rate of follicular development was similar in both treatment groups. By stimulation day 8, 33% of patients treated with corifollitropin alfa reached the criterion for human chorionic gonadotrophin (HCG) injection. The number of follicles ⩾11mm was slightly higher after corifollitropin alfa compared with daily rFSH at stimulation day 8 (difference, 1.2; 95% confidence interval (CI) 0.5-1.8; P<0.01) and on the day of HCG injection (difference, 2.1; 95% CI 1.4-2.8; P<0.01). The rise of inhibin B and oestradiol concentrations was similar in both treatment groups. Although the pharmacokinetics of corifollitropin alfa and rFSH are quite different their pharmacodynamic profiles at the dosages used are similar. A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. The objective of this study was to compare the pharmacokinetics and pharmacodynamics of corifollitropin alfa versus daily rFSH. A total of 1509 patients were randomized in a double-blind, controlled trial to either a single injection of 150µg corifollitropin alfa or to daily injections of 200IU rFSH for the first 7 days of ovarian stimulation. Serum levels of FSH immunoreactivity were analysed (pharmacokinetic analysis), together with the number and size of growing follicles and serum inhibin B and oestradiol concentrations as biomarkers of the ovarian response (pharmacodynamic analysis). Serum FSH immunoreactivity levels were higher up to stimulation day 5 for corifollitropin alfa compared with the daily rFSH regimen but were similar from day 8 onwards, when patients started rFSH if the criteria for human chorionic gonadotrophin were not yet reached. Corifollitropin alfa treatment resulted in a similar growth rate of follicles though a slightly higher number of follicles were recruited compared with daily rFSH. It is concluded that the pharmacokinetics of corifollitropin alfa and rFSH are quite different but their induced pharmacodynamic effects at the dosages used are similar.

Dose selection of corifollitropin alfa by modeling and simulation in controlled ovarian stimulation.

In controlled ovarian stimulation (COS), a single subcutaneous dose of corifollitropin alfa is used to initiate and sustain multifollicular growth for 7 days. The objective of this study was to determine the optimal dose of corifollitropin alfa. A pharmacokinetic model was developed to describe the time profile of corifollitropin alfa concentrations. Multiple parameters reflecting ovarian response were included in a pharmacokinetic-pharmacodynamic (PK-PD) model framework. An early decline in serum inhibin B was shown to be a sensitive marker for COS failure. Simulations were performed to select the lowest corifollitropin alfa dose that would result in a minimal cancellation rate: 100 microg for a group of women weighing 60 kg. With these doses, the predicted mean number of oocytes per started COS cycle was similar in the two groups, i.e., 12.1 and 13.2, respectively. The selected doses were tested in prospective clinical trials and were proven to be adequate.

Corifollitropin alfa, a long-acting follicle-stimulating hormone agonist for the treatment of infertility.

Corifollitropin alfa is being developed by Schering-Plough Corp as an injectable, long-acting follicle-stimulating hormone (FSH) agonist for the treatment of infertility. A single dose of corifollitropin alfa could initiate and sustain multifollicular growth in patients undergoing controlled ovarian stimulation, such as during in vitro fertilization or intracytoplasmic sperm injection. The agent comprises an alpha-subunit, which is identical to that of FSH, and a beta-subunit, which is produced by the fusion of the C-terminal peptide from the beta-subunit of chorionic gonadotropin to the beta-subunit of FSH. Corifollitropin alfa has a longer half-life compared with FSH and thus requires less frequent dosing. The drug was well tolerated and does not appear to be associated with any serious adverse events or the formation of antibodies. The initial results from a large, phase III, double-blind clinical trial indicated that the ongoing pregnancy rate achieved with corifollitropin alfa treatment was high and similar to the rate established with daily treatment of recombinant FSH. The number of oocytes retrieved following the administration of corifollitropin alfa was slightly higher compared with the number observed with daily recombinant FSH treatment. Thus, corifollitropin alfa has the potential to serve as a viable fertility agent and to gain a place in the infertility market.

Advances in recombinant DNA technology: corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency.

BACKGROUND: Recombinant DNA technologies have been used to develop longer-acting therapeutic proteins. One approach is to introduce sequences containing additional glycosylation sites. Using this technique, a new chimeric gene has been developed containing the coding sequences of the FSH beta-subunit and the C-terminal peptide of the hCG beta-subunit, which bears four O-linked oligosaccharide binding sites. Co-expression of the alpha-subunit and the chimeric FSH beta-subunit produces a new recombinant molecule, named corifollitropin alfa, with a prolonged elimination half-life and enhanced in vivo bioactivity compared with wild-type FSH. METHODS: Medline searches by subject and additional searching by hand. RESULTS: Initial studies in pituitary suppressed female volunteers confirmed the extended half-life of the compound. Phase II studies have shown that corifollitropin alfa is able to induce and sustain multi-follicular growth for an entire week in women undergoing ovarian stimulation using GnRH antagonist co-treatment for IVF. Corifollitropin alfa regimens have been developed with dosages of 100 and 150 microg, for patients with body weight 60 kg, respectively. CONCLUSIONS: Corifollitropin alfa is the first long-acting hybrid molecule with sustained follicle-stimulating activity developed for the induction of multi-follicular growth along with GnRH antagonist co-treatment for IVF. This new treatment option may be simpler and more convenient for patients compared with conventional long protocols of daily FSH injections in combination with GnRH agonist co-treatment. The safety and efficacy of such regimens is currently being evaluated in large comparative phase III clinical trials. The development of corifollitropin alfa is the first step towards a new generation of recombinant gonadotrophins.

A randomized dose-response trial of a single injection of corifollitropin alfa to sustain multifollicular growth during controlled ovarian stimulation.

BACKGROUND: This study primarily investigated the dose-response relationship of corifollitropin alfa to initiate multifollicular development for the first 7 days of controlled ovarian stimulation (COS). METHODS: Women aged 20-39 years undergoing COS for in vitro fertilization or intracytoplasmic sperm injection were randomized to a single dose of corifollitropin alfa 60, 120 or 180 microg, or daily injections of 150 IU recombinant follicle-stimulating hormone (rFSH). Patients treated with corifollitropin alfa started fixed daily treatment with 150 IU rFSH on stimulation Day 8. Patients received a GnRH antagonist (ganirelix 0.25 mg/day) from stimulation Day 5 until the day of human chorionic gonadotrophin. RESULTS: Pharmacokinetics of corifollitropin alfa were dose-proportional. The main reason for not having embryo transfer was insufficient ovarian response in 30.8, 2.6, 3.8 and 7.4% of patients in the corifollitropin alfa 60, 120, 180 microg and rFSH groups, respectively. On Day 8, the mean (standard deviation) number of follicles >or=11 mm was 6.8 (4.4), 10.1 (6.1) and 12.8 (7.5), respectively. The number of cumulus-oocyte complexes retrieved showed a clear dose-response relationship (P < 0.0001), being 5.2 (5.5), 10.3 (6.3) and 12.5 (8.0) in the three dose groups, respectively. CONCLUSIONS: A single injection of corifollitropin alfa induces dose-related increase in multifollicular development and in the number of retrieved oocytes. The optimal dose for a 1-week interval is higher than 60 microg and lower than 180 microg and will be selected based on modelling and simulation taking into account insufficient stimulation as well as overstimulation. Clinical Trials gov: NCT00598208.

Bioequivalence of recombinant human FSH and recombinant human LH in a fixed 2:1 combination: two phase I, randomised, crossover studies.

OBJECTIVES: To assess bioequivalence of recombinant human follicle stimulating hormone (r-hFSH, follitropin alfa) and recombinant human luteinising hormone (r-hLH, lutropin alfa) in a fixed 2:1 combination (Pergoveris) compared with injection of each of the hormones separately. RESEARCH DESIGN AND METHODS: Two, two-way crossover, phase I studies in healthy female volunteers after gonadotrophin-releasing hormone agonist down-regulation. Volunteers were randomised to the order in which they received subcutaneous injections. In the r-hFSH study, volunteers received one injection of r-hFSH (300 IU) and one of r-hFSH (300 IU)/r-hLH (150 IU) > or = 7 days apart; in the r-hLH study they received r-hLH (450 IU) and r-hFSH (900 IU)/r-hLH (450 IU) > 21 days apart. MAIN OUTCOME MEASURES: The serum concentration-time profiles of FSH in the r-hFSH study and LH in the r-hLH study from zero to the last measurable concentration (AUC(0-last)) and the peak FSH/LH serum concentrations (C(max)) were assessed by non-compartmental analysis. The pre-defined range for bioequivalence was 0.8-1.25 for 90% confidence intervals (CI) of the ratio (fixed combination/single gonadotrophin) of the mean for each pharmacokinetic parameter. RESULTS: Bioequivalence criteria were met for the r-hFSH study (n = 34) for C(max) (ratio of means 1.0024, 90% confidence interval (CI) 0.9611-1.0454) and AUC(0-last) (ratio of means 1.0167, 90% CI 0.9933-1.0407), and for the r-hLH study (n = 63) for C(max) (ratio of means 0.9687, 90% CI 0.9194-1.0207) and AUC(0-last) (ratio of means 0.9753, 90% CI 0.8990-1.0581). In the r-hFSH study, 20 adverse events (AEs) were reported after injection of r-hFSH and 20 after r-hLH/r-hFSH. In the r-hLH study, 179 AEs were reported after injection of r-hLH and 193 after the fixed-dose combination. Across both studies, headache was the most commonly reported AE. No serious AEs occurred. CONCLUSIONS: These studies demonstrated bioequivalence between r-hFSH and r-hLH administered alone or in fixed 2:1 combination. The 2:1 combination of follitropin alfa and lutropin alfa allows administration of both recombinant gonadotrophins in a single injection.