Schering-Plough Corp., announced results from the phase III Engage clinical trial demonstrating that a single injection of corifollitropin alfa, first in the class of sustained follicle stimulants, achieved similar efficacy to recombinant follicle stimulating hormone (rFSH) given once daily for seven days.

The Engage data was presented along with data from the phase III Ensure trial and the phase II Realize trial at the 25th annual meeting of the European Society of Human Reproduction and Embryology (ESHRE) in Amsterdam, The Netherlands.

"The burden of fertility treatment is a major challenge for women experiencing difficulty conceiving," said Thomas Koestler, executive vice president and president, Schering-Plough Research Institute. "Schering-Plough is committed to making fertility treatments easier, and these results demonstrate that corifollitropin alfa in combination with a GnRH antagonist may be an effective treatment that can reduce the number of injections and the length of treatment protocols."

Engage is the largest double-blind fertility agent trial ever performed. The ongoing pregnancy rate, the primary endpoint of the Engage non-inferiority trial, obtained in the 150 mcg corifollitropin alfa treatment arm (38.9 per cent per started cycle) was similar to that achieved in patients receiving a daily dose of 200 IU rFSH (follitropin beta) for seven days (38.1 per cent per started cycle). Engage also demonstrated that a single injection of 150 mcg corifollitropin alfa achieved similar oocyte and embryo quality compared to a daily dose of 200 IU rFSH given for one week. Further sub-analyses of the Engage trial showed a single injection of 150 mcg corifollitropin alfa, compared to the daily rFSH treatment arm, achieved consistently high pregnancy outcomes regardless of fertilization procedure (in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), number of embryos transferred (single or double), or day of embryo transfer (day three or five), confirming the robustness of the main efficacy outcome.

An additional sub-analysis of the Engage data demonstrated that endogenous luteinizing hormone (LH) levels do not affect ongoing pregnancy rates in women undergoing controlled ovarian stimulation (COS) with a standardized rFSH / gonadotropin-releasing hormone (GnRH) antagonist protocol.

An analysis compared data from the Engage trial to data from the Ensure trial. The Ensure trial used a similar protocol to Engage with identical patient inclusion criteria but different body weight categories. It showed that exposure and ovarian response were similar after a single-dose of 100 mcg corifollitropin alfa in patients weighing 60 kg or less, as compared to 150 mcg corifollitropin alfa in patients weighing more than 60 kg. Additional data from the Ensure trial show that in patients weighing 60 kg or less, a single dose of 100 mcg corifollitropin alfa resulted in significantly more oocytes and an equally short duration of treatment as those receiving 150 IU rFSH daily during the first week of stimulation.

Data was also presented from the phase II Realize study, a 50 patient, open-label uncontrolled pilot study. In this study, a single dose of 100 mcg or 150 mcg corifollitropin alfa in a long GnRH agonist protocol was able to support multifollicular development during the first week of ovarian stimulation.

Engage was a non-inferiority trial designed to compare corifollitropin alfa 150 mcg to 200 IU rFSH (follitropin beta). A total of 1,506 patients (greater than 60 kg) at 34 IVF clinics in North America and Europe were randomized to receive either corifollitropin alfa 150 mcg or a daily dose of 200 IU rFSH, followed by rFSH (maximum 200 IU/day) from stimulation day eight onward, when required. Starting on stimulation day five, all patients received 0.25 mg gonadotropin-releasing hormone (GnRH) antagonist until triggering of final oocyte maturation by human chorionic gonadotropin (hCG). The primary endpoint was the ongoing pregnancy rate assessed at ten weeks or more after embryo transfer. The number of oocytes retrieved was the co-primary endpoint. The incidence of ovarian hyperstimulation syndrome (OHSS) was similar between both groups, 7.0 per cent in the corifollitropin alfa group (1.9 per cent severe) and 6.3 per cent in the follitropin beta group (1.3 per cent severe).

The Ensure trial is a multinational (Europe/Asia), double-blind, randomized trial; 396 patients weighing 60 kg or less were randomized in a 2:1 ratio to treatment with either a single dose of 100 mcg corifollitropin alfa or daily 150 IU rFSH (follitropin beta) followed by daily follitropin beta (maximum 200 IU/day) from stimulation day eight onwards when required, to reach the criterion for human chorionic gonadotropin (hCG) administration (at least three follicles 17 mm or greater). Starting on stimulation day five all patients received 0.25 mg gonadotropin-releasing hormone (GnRH) antagonist until induction of final oocyte maturation by hCG. About 34-36 hours after induction of final oocyte maturation, oocyte pick up followed by IVF or ICSI was performed. At embryo transfer, three or five days after oocyte pick up, a maximum of two embryos were transferred. The primary endpoint of the Ensure trial was the number of oocytes retrieved and the predefined equivalence margin was -3 and +5 oocytes for the 95 percent confidence interval (CI) of the difference. The incidence of moderate and severe OHSS was 3.4 per cent in the corifollitropin alfa treatment arm versus 1.6 per cent in the rFSH treatment group.

In this single-centre, open-label, uncontrolled, pilot study, 50 women undergoing ovarian stimulation prior to IVF or ICSI were down-regulated with daily injections of 0.1 mg of GnRH agonist (starting on cycle day 21). Ovarian stimulation was started with a single dose of corifollitropin alfa (100 mcg or 150 mcg) followed by daily rFSH (follitropin beta) from stimulation day eight until the day of triggering oocyte maturation. Final oocyte maturation was induced by administration of hCG as soon as three follicles 17 mm or greater were present. Vaginal progesterone was administered for luteal phase support. Patients with proven poor response were excluded from participation. The main endpoint of this trial was ovarian response. The observed number of follicles, serum estradiol levels and number of oocytes indicated a relatively high ovarian response. Corifollitropin alfa was well tolerated and there were no serious adverse events or cases of OHSS.

Corifollitropin alfa is an investigational product being developed as a potential treatment in Controlled Ovarian Stimulation (COS) for the development of multiple follicles in women participating in an Assisted Reproductive Technology (ART) programme. Corifollitropin alfa is designed as a sustained follicle stimulant (SFS) with the same pharmacodynamic profile as rFSH, but with a markedly prolonged duration of FSH activity. Due to its ability to initiate and sustain multiple follicular growth for an entire week, a single subcutaneous injection of the recommended dose of corifollitropin alfa may replace the first seven injections of rFSH preparation in a COS treatment cycle. The corifollitropin alfa regimen is being developed in a GnRH antagonist protocol. Corifollitropin alfa was filed in the European Union in late 2008.

Infertility is a disease or condition that impairs the body's ability to perform the basic function of reproduction. It is often diagnosed after a couple has not conceived after one year of unprotected, well-timed intercourse.

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