Schering-Plough Announces Phase II and III Data for Corifollitropin Alfa

Schering-Plough Corp.Schering-Plough Corp., (NYSE: SGP) has 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 percent 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 percent per started cycle).(1) 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.(2) 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.(1)

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.(3)

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.(4) 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.(5)

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.(6)

About ENGAGE
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 percent in the corifollitropin alfa group (1.9 percent severe) and 6.3 percent in the follitropin beta group (1.3 percent severe).(1)

Key Findings

  • The ongoing pregnancy rate in the 150 mcg corifollitropin alfa treatment arm (38.9 percent per started cycle) was similar to that achieved in patients receiving daily 200 IU rFSH (follitropin beta) (38.1 percent per started cycle).(1)
  • Corifollitropin alfa achieved similar efficacy regardless of fertilization procedure; number of embryos transferred; or day of embryo transfer;(1)
  • The mean number of oocytes retrieved per attempt was 13.7 (+/-8.2) for the corifollitropin alfa group and 12.5 (+/-6.7) for the rFSH group.(2)
  • The mean number of good quality embryos obtained at day 3 and day 5 was 4.6 (+/-4.3) and 2.6 (+/-3.3) in the corifollitropin alfa group, respectively and 4.4 (+/-3.9) and 2.6 (+/-3.1) in the rFSH group, respectively.(2)

About ENSURE
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 percent in the corifollitropin alfa treatment arm versus 1.6 percent in the rFSH treatment group.(5)

Key Findings

  • The mean (SD) number of oocytes retrieved per started cycle in the corifollitropin alfa group was 13.3 (+/-7.3) versus 10.6 (+/-5.9) in the reference group.(5)
  • Following a single injection of corifollitropin alfa, patients required on average another two days of further stimulation with rFSH to reach the criterion to administer hCG. This was equal to the average duration of stimulation of nine days of the reference group treated with daily rFSH.(5)

About REALIZE
In this single-center, 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.(6)

Key Findings

  • Both the 100 mcg and 150 mcg dose groups recruited a large number of follicles 11 mm or greater with mean (SD) values of 17.5 (+/-5.5) and 18.3 (+/-6.4), respectively on the day of hCG and median serum estradiol levels of 10,019 and 10,221 pmol/L, respectively.(6)
  • The mean (SD) number of oocytes retrieved per started cycle was 15.4 (+/-6.7) in the 100 mcg dose group and 17.8 (+/-5.1) in the 150 mcg dose group.(6)

About corifollitropin alfa
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) program. 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.

Corifollitropin alfa Important Safety Information
The most frequently reported adverse drug reactions during treatment with corifollitropin alfa in clinical trials are Ovarian Hyperstimulation Syndrome (OHSS), pelvic pain and discomfort, headache, nausea, fatigue and breast complaints (including tenderness). They are reported with an incidence between 1% and 6%.

About Infertility
Infertility is a disease or condition that impairs the body's ability to perform the basic function of reproduction.(7) It is often diagnosed after a couple has not conceived after one year of unprotected, well-timed intercourse.(8) Women over the age of 35 are encouraged to seek diagnosis and treatment for infertility following six months of unprotected intercourse.(9) Around 15 percent of couples of reproductive age have a fertility problem.(8)

There are many causes of infertility including problems with the production of sperm or eggs, with the fallopian tubes or the uterus, endometriosis, frequent miscarriage, as well as hormonal and autoimmune (antibody) disorders in both men and women.(8)

With infertile couples, the source of infertility lies with the male in 40 percent of cases and 40 percent with the female. The remaining 20 percent is either a joint problem or unknown, because the cause has not been identified. There are a variety of treatments available for infertility; these include surgery, hormone treatments, insemination, IVF and natural treatments, among others.(8)

About Schering-Plough
Schering-Plough is an innovation-driven, science-centered global health care company. Through its own biopharmaceutical research and collaborations with partners, Schering-Plough creates therapies that help save and improve lives around the world. The company applies its research-and-development platform to human prescription, animal health and consumer health care products. Schering-Plough's vision is to "Earn Trust, Every Day" with the doctors, patients, customers and other stakeholders served by its colleagues around the world. The company is based in Kenilworth, N.J., and its Web site is www.schering-plough.com.

1. Fernandez-Sanchez M et al, Equally high ongoing pregnancy rates with corifollitropin alfa and recombinant FSH irrespective of variations in ART procedures. Oral presentation at 25th European Society of Human Reproduction and Embryology (ESHRE) on June 29, 2009. Abstract no. O-005
2. Behr B, et al Corifollitropin alfa versus recombinant FSH treatment in controlled ovarian stimulation: equal efficacy in terms of oocyte and embryo quality. Oral presentation at 25th European Society of Human Reproduction and Embryology (ESHRE) on June 29, 2009. Abstract no O-003
3. Doody K et al, Puregon reference-'Success rates of a fixed rFSH/GnRH antagonist protocol are not affected by enodgenous LH levels. Oral presentation at 25th European Society of Human Reproduction and Embryology (ESHRE) on July 1, 2009. Abstract no. O-255
4. Ledger W et al, Two doses of corifollitropin alfa allow for similar exposure and ovarian response in patients weighing less than or equal to 60 kg and > 60 kg. Oral presentation at 25th European Society of Human Reproduction and Embryology (ESHRE) on July 1, 2009. Abstract no. O-282
5. Hillensjo T et al, Corifollitropin alfa versus recombinant FSH in a GnRH antagonist protocol for controlled ovarian stimulation in women weighing 60 kg or less. Oral presentation at 25th European Society of Human Reproduction and Embryology (ESHRE) on June 29, 2009. Abstract no. O-004
6. Fatemi HM et al, The first pilot study with corifollitropin alfa in a long GnRH agonist protocol indicates the development of a large cohort of follicles during the first week of ovarian stimulation. Oral presentation at 25th European Society of Human Reproduction and Embryology (ESHRE) on July 1, 2009. Abstract no. O-283
7. Frequently Asked Questions About Infertility. American Society for Reproductive Medicine Web site. http://www.asrm.org/Patients/faqs.html. Accessed May 14, 2009
8. http://www.icsi.ws/about_infertility. Accessed May 14, 2009
9. Frequently Asked Questions; Questions about Infertility. Centre for Fertility and Reproductive Medicine. http://www.csmc.edu/3830.html. Accessed May 14, 2009

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