In order to avoid the first seven of the daily injections of FSH and the hypersensitivity or immune reactions due to this repetitive treatment, a single injection of corifollitropin alfa has been suggested for patients undergoing controlled ovarian stimulation (COS). Now, a multicentered phase III uncontrolled trial has reported that the use of 150 μg corifollitropin alfa in a standard GnRH antagonist protocol is safe and efficient, and has no effect on immunogenicity in normal responders undergoing up to three treatment cycles.
Robert J Norman, Professor, Discipline of Obstetrics and Gynaecology, University of Adelaide, Australia, and coworkers, conducted the study on 682 women (Age=18-39 years; BMI=18-29 kg/m2; Weight>60 kg) having a menstrual cycle every 24-35 days, and indicated for COS. The subjects were administered one injection of 150 µg corifollitropin alfa on the second or third day of their menstrual cycle, and 0.25 mg ganielix on the fifth or sixth day of stimulation. The researchers assessed antibody formation against corifollitropin alfa with highly sensitive radioimmunoprecipitation assay, apart from determining local tolerance, hypersensitivity responses, and adverse events (AEs). Among the 682 women treated in the first cycle, 375 proceeded to the second cycle and 198 to the third cycle.
The following results of the study were published in the journal Human Reproduction:
• Immunogenicity was absent in almost all the post-treatment samples, except for one taken after the second cycle. Higher limit of one-sided 95% CI for occurrence of immunogenicity was noted to be 1.5% among women going through all the three cycles.
• Drug-associated hypersensitivity responses were not noted with the use of corifollitropin alfa.
• Apart from mild local sensitivity reaction, chiefly as redness, in 2.5%, 4.3%, and 2.5% of patients in the first, second, and third cycles, respectively, there was no evidence of moderate or severe local reactions.
• The main adverse events in the cycles included pain associated with oocyte retrieval (17.7%; 95% CI=14.9–20.8%), pelvic pain (7.6%; 95% CI=5.7–9.9%), and headache (9.1%; 95% CI=7.0–11.5%).
• There were comparable results for the number of cumulus-oocyte complexes (COC) recovered, and embryos procured and transferred in all three cycles.
• The occurrence of ovarian hyperstimulation syndrome (OHSS) in cycles one and two was 3.5% and 1.9%, respectively, while it was not reported in cycle three.
• The cumulative ongoing pregnancy rate following all the three cycles was found to be 61% (95% CI=56-65%).
• The rate of miscarriage per clinical pregnancy was 12.8%, 12.5%, and 14.6% for the first, second, and third cycles, respectively.
Based on the study findings, the researchers concluded that ovarian stimulation can be successfully and safely initiated and sustained during the initial seven days of COS in normal responders, with a single injection of 150 μg corifollitropin alfa in repetitive therapeutic cycles, without immunogenicity.
An assessment by The Corifollitropin Alfa Dose-finding Study Group (Human Reproduction, 2008) concluded that a single injection of corifollitropin alfa stimulates a dose-associated rise in the growth of multiple follicles and quantity of oocytes recovered. They suggested that the optimal dose for the first seven days of COS should be in the range of 60 μg to 180 μg, and chosen on the basis of modelling and simulation, while considering both insufficient- and over-stimulation.
In order to compare the ongoing rates of pregnancy following the use of a single injection of 150 μg corifollitropin alfa with a daily dose of 200 IU rFSH in the first week, Devroey et al, (Human Reproduction, 2009) conducted a large, double-blinded, non-inferiority, randomized study. The findings demonstrated that a single dose of corifollitropin alfa is safe, well tolerated, with no immunogenicity reactions, antibody formation, or hypersensitivity response, and sufficient to obtain an ongoing pregnancy rate equivalent to that using rFSH daily. A low incidence of OHSS, comparable to the current rFSH regimen was also noted.
The European Commission has approved corifollitropin alfa (Elonva® | Merck & Co., Inc.) on 25 January, 2010, to be used as the first sustained follicular stimulant in IVF cycles. With the advantages of a prolonged half-life, slower absorption rate, and single injection, compared to rFSH, corifollitropin alfa could emerge as a ground breaking therapeutic choice in women undergoing COS during ART.
References
1. Norman RJ, Zegers-Hochschild F, Salle BS, et al. Repeated ovarian stimulation with corifollitropin alfa in patients in a GnRH antagonist protocol: no concern for immunogenicity. Hum Reprod. 2011 Aug;26(8):2200-2208.
2. Corifollitropin Alfa Dose-finding Study Group. A randomized dose-response trial of a single injection of corifollitropin alfa to sustain multifollicular growth during controlled ovarian stimulation. Hum Reprod. 2008 Nov;23(11):2484-92.
3. Devroey P, Boostanfar R, Koper NP, et al. 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. Hum Reprod. 2009 Dec;24(12):3063-72.
