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ELONVA ™ ( corifollitropin alfa ): KORAK DALJE U LIJEČENJU NEPLODNOSTI

ELONVA ™ ( corifollitropin alfa ): KORAK DALJE U LIJEČENJU NEPLODNOSTI. HRVOJE VRČIĆ, MD PhD MEDICAL SCHOOL AND UNIVERSITY HOSPITAL CENTER ZAGREB. Patient-Centered Approach in Controlled Ovarian Stimulation (COS). Optimize risk/benefit ratio Reduce OHSS and management strategies

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ELONVA ™ ( corifollitropin alfa ): KORAK DALJE U LIJEČENJU NEPLODNOSTI

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  1. ELONVA™ (corifollitropinalfa): KORAK DALJE U LIJEČENJU NEPLODNOSTI HRVOJE VRČIĆ, MD PhD MEDICAL SCHOOL AND UNIVERSITY HOSPITAL CENTER ZAGREB

  2. Patient-Centered Approach in Controlled Ovarian Stimulation (COS) • Optimize risk/benefit ratio • Reduce OHSS and management strategies • Reduce complexity and patient burden • Shorter treatment cycles • Fewer overall injections • Fewer injections per day • Reduce patient dropout rates • Increase cumulative live birth rates COS = controlled ovarian stimulation; OHSS = ovarian hyperstimulation syndrome.

  3. The Growth of In Vitro Fertilization (IVF)1‒10 Total PubMed Hits for “IVF” in Title/Abstract by Year • 2005: 418,111 cycles • 2006: 458,759 cycles • Increase of 40,648 cycles (+9.7%) IVF = in vitro fertilization. 1. Nygren KG et al. Hum Reprod. 2001;16:384‒391; 2. Nygren KG et al. Hum Reprod. 2001;16:2459‒2471; 3. Nygren KG et al. Hum Reprod. 2002;17:3260‒3274; 4. Nyboe Andersen A et al. Hum Reprod. 2004;19:490‒503; 5. Andersen AN et al. Hum Reprod. 2005;20:1158‒1176; 6. Andersen AN et al. Hum Reprod. 2006;21:1680‒1697; 7. Andersen AN et al. Hum Reprod. 2007;22:1513‒1525; 8. Andersen AN et al. Hum Reprod. 2008;23:756‒771; 9. Andersen AN et al. Hum Reprod. 2009;24:1267‒1287; 10. de Mouzon J et al. Hum Reprod. 2010;25:1851‒1862.

  4. Republic of Croatia 4.5 mil people 1,1 mil women in reproductive age 100.000 infertile or subfertile women 50.000 in Dg/Th treatment of infertility 2000 IVF/1mil people Birth rate >4% from ART 2012. 4000 IVF/ICSI

  5. IVF: It Works, but It Is Burdensome • Current treatments may induce stress1,2 • Discontinuation reduces cumulative pregnancy rates3 • Treatment burden is a major reason for discontinuation4 • Among 384 couples undergoing IVF treatment, 65 (17%) dropped out • The most common reason for dropout (28%) was the physical or psychological burden of treatment IVF = in vitro fertilization. 1. Hammarberg K et al. Hum Reprod. 2001;16:374‒383.2. Huisman D et al. Reprod Biomed Online. 2009;19(suppl 2):5–10. 3. Schröder AK et al. Reprod Biomed Online. 2004;8:600‒606. 4. Verberg MF et al. Hum Reprod. 2008;23:2050‒2055.

  6. Dropouts Negatively Impact Real Cumulative Pregnancy Rates1 • Data from 4,102 IVF cycles in 2,130 women 70 Difference between expected and real pregnancy rates is caused by the diminishing size of the cohort due to dropout frequency 60 50 40 Percent 30 20 10 Dropout rate ECPR RCPR 0 1 2 3 4 5 6 (n=2,130) (n=1,087) (n=518) (n=222) (n=74) (n=36) Cycles IVF = in vitro fertilization; ECPR = expected cumulative pregnancy rate; RCPR = real cumulative pregnancy rate. 1. Adapted with permission from Schröder AK et al. Reprod Biomed Online. 2004;8:600‒606.

  7. 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 Today: Ovarian Stimulation Protocols Require Multiple Injections1,2 Long GnRH agonistprotocol1 GnRH antagonistprotocol2 Flare-up Pituitary downregulation LuteinizingHormone Directgonadotropin suppression Time GnRH = gonadotropin-releasing hormone. 1. Adapted with permission from de Greef R et al. Clin Pharmacol Ther. 2010;88:79‒87. 2. Adapted with permission from Hodgen GD. Contemp Rev Obstet Gynaecol. 1990;35:10‒24.

  8. ELONVA™ (corifollitropin alfa) May Reduce the Number of Necessary Injections1,2 ELONVA rFSH hCG 1 2 3 4 5 6 7 8 9 10 GnRH antagonist LuteinizingHormone Directgonadotropin suppression Time rFSH = recombinant follicle-stimulating hormone; hCG = human chorionic gonadotropin; LH = luteinizing hormone. 1. Adapted with permission from de Greef R et al. Clin Pharmacol Ther. 2010;88:79‒87. 2. Adapted with permission from Hodgen GD. Contemp Rev Obstet Gynaecol. 1990;35:10‒24.

  9. Corifollitropin Alfa Is a Recombinant Hormone -Subunits1 β-Subunits2 Human FSH t½ rFSH ≈ 40 h3 110 aa 92 aa hCG 145 aa 92 aa Corifollitropin alfa 110 aa 29 aa2 t½ corifollitropin alfa = 69 h4 92 aa FSH = follicle-stimulating hormone; hCG = human chorionic gonadotropin ;aa = amino acids; t½ = half life. 1. Adapted with permission from Strauss J et al. Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. 5th edition. Saunders; 2004; 2. Fares FA et al. Proc Natl Acad Sci U S A. 1992;89:4304–4308; 3. PUREGON® (rFSH) summary of product characteristics, 2010; 4. ELONVA™ (corifollitropin alfa) summary of product characteristics, 2010.

  10. Prefilled syringe ELONVA 150 or 100 µg Automatic (passive) safety system with retractable needle to prevent needle stick injuries Administration Self-administration Subcutaneous Preferably in the abdominal wall ELONVA™ (corifollitropin alfa)1 It is important to instruct patients to fully depress the plunger when injecting so all the drug is delivered and the safety system is activated 1. ELONVA™ (corifollitropin alfa) summary of product characteristics, 2010.

  11. Comparative Pharmacokinetics Corifollitropin alfa rFSH t½ corifollitropin alfa = 69 h Tmax = 36–48 h2 FSH Activity1 Therapeutic threshold t½ rFSH ≈ 40 h Tmax = 10–12 h3 1 2 3 4 5 6 7 8 9 10 Stimulation Days FSH = follicle-stimulating hormone; rFSH = recombinant FSH; t1/2 = half-life; Tmax = time to maximum concentration. 1. Adapted with permission from Fauser BC et al. Hum Reprod Update. 2009;15:309–321; 2. ELONVA™ (corifollitropin alfa) summary of product characteristics, 2010; 3. PUREGON® (rFSH) summary of product characteristics, 2010.

  12. Appropriate dosage is determined by the body weight of the patient The recommended doses of ELONVA result in Similar exposure for both body- weight groups Similar ovarian response for both groups A single injection provides an effective alternative to the first 7 daily gonadotropin injections Equal Exposure to ELONVA™ (corifollitropin alfa) Based on Body Weight1 Total Drug Exposure (AUC) 1500 100 µg 150 µg 1000 AUC , h•ng/mL 500 0 ≤60 kg >60 kg AUC = area under the curve. 1. Adapted with permission from Ledger WL et al. Reprod Biomed Online. 2011;23:150‒159.

  13. ELONVA™ (corifollitropin alfa) Phase 3 Clinical Trials rFSH = recombinant follicle-stimulating hormone; RCT = randomized controlled trial; PR = pregnancy rate; AEs = adverse events; SAEs = serious adverse events. 1.Devroey P et al. Hum Reprod. 2009;24:3063‒3072.2. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

  14. Engage Trial: Treatment Regimen1 ELONVA™ (corifollitropin alfa) (150 µg) (n=756) Investigational group Placebo rFSH Daily rFSH (daily dose ≤200 IU) IVF or ICSI Placebo ELONVA (n=750) GnRH antagonist (GANIRELIX® 0.25 mg/d) day 5 through day of hCG Luteal phase support Reference group Daily rFSH (daily dose 200 IU for 7 days) Daily rFSH (daily dose ≤200 IU) Cycle day 2–3 = stimulation day 1 Stimulation day 5 Stimulation day 8 hCG as soon as 3 follicles ≥17 mm (or the day thereafter) rFSH = recombinant follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; hCG = human chorionic gonadotropin. 1.Adapted with permission from Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

  15. Engage Main Inclusion and Exclusion Criteria1 Inclusion criteria • Indication for COS and IVF/ICSI • Normal menstrual cycle length (24–35 days) • ≥18 and ≤36 years of age • Body weight >60 and ≤90 kg, and BMI ≥18 and ≤32 kg/m2 Exclusion criteria • Endocrine abnormality • PCOS • Previous low ovarian response or no ovarian response • Previous OHSS • >20 basal antral follicles COS = controlled ovarian stimulation; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; BMI = body mass index; PCOS = polycystic ovary syndrome; OHSS = ovarian hyperstimulation syndrome. 1.Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

  16. Engage Demographics at Screening1 ITT Group ITT = intent to treat; rFSH = recombinant FSH; SD = standard deviation; BMI = body mass index. 1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

  17. Engage Primary End Point: Ongoing Pregnancy Rate1 Ongoing pregnancy rates were comparable between ELONVA™ (corifollitropin alfa) and rFSH Patients, %a ITT Group 38.9 38.1 No. of embryos transferred:1.7 No. of embryos transferred:1.7 ELONVA 150 µg (n=756) rFSH 200 IU/d (n=750) aOngoing pregnancy rate was defined as the presence of at least 1 fetus with heart activity at least 10 weeks after embryo transfer as assessed by ultrasound scan or Doppler, or confirmed by live birth. ITT = intent to treat; rFSH = recombinant follicle-stimulating hormone. 1.Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

  18. Engage Results: Single vs Double Embryo Transfer— Ongoing Pregnancy Rates per Started Cycle1 Comparable ongoing pregnancy rates for SET vs DET SET = single embryo transfer; DET = double embryo transfer; rFSH = recombinant follicle-stimulating hormone. 1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

  19. Engage Results: Day 3 vs Day 5 (Blastocyst) Transfer― Ongoing Pregnancy Rates per Started Cycle1 Comparable ongoing pregnancy rates for day 3 vs day 5 ET ET = embryo transfer; rFSH = recombinant follicle-stimulating hormone.1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

  20. Engage Co-primary End Point: Number of Oocytes Retrieved1 • Quality of oocytes, by percentage of MII oocytes, was comparable between treatments a P=0.001.Predefined equivalence range: –3 to +5 oocytes. rFSH = recombinant follicle-stimulating hormone; ANOVA = analysis of variance; CI = confidence interval; SD = standard deviation; MII = metaphase II. 1.Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

  21. Engage 2PN Oocytes1 • The fertilization rate, number of 2PN oocytes, and number of good-quality embryos were comparable between treatment groups • Mean fertilization ratea • 66.0% (SD, 23.4%) ELONVA™ (corifollitropin alfa) 150 µg • 67.6% (SD, 22.9%) rFSH 200 IU/d • Mean number of 2PN fertilized oocytes obtaineda • 8.3 (SD, 5.6) ELONVA 150 µg • 7.4 (SD, 4.8) rFSH 200 IU/d • Mean number of good-quality embryos • 4.6 (SD, 4.3) ELONVA 150 µg • 4.4 (SD, 3.9) rFSH 200 IU/d aRestricted to patients with IVF/ICSI (ITT group). PN = pronuclear; SD = standard deviation; rFSH = recombinant follicle-stimulating hormone; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; ITT = intent to treat. 1.Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

  22. Engage Clinical Outcome per Started Cycle1 ITT Group • There was no difference between groups in number of embryos transferred or biological pregnancy rate ITT = intent to treat; rFSH = recombinant FSH; SD = standard deviation; hCG = human chorionic gonadotropin. 1.Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

  23. Engage Implantation Rate (Mean %) per Started Cycle1 Implantation rates were comparable between ELONVA™ (corifollitropin alfa) and rFSH ITT Group Patients, % (SD) 36.2 32.2 ELONVA 150 µg (n=756) rFSH 200 IU/d (n=750) SD = standard deviation; ITT = intent to treat; rFSH = recombinant follicle-stimulating hormone. 1.Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

  24. Engage Day of IVF Cycle When hCG Criterion Was Met1 ™ Patients, % Stimulation Day One-third of the patients did not require any rFSH hCG = human chorionic gonadotropin; rFSH = recombinant follicle-stimulating hormone. 1. Adapted with permission from Fauser BC et al. Reprod Biomed Online. 2010;21:593‒601.

  25. Engage Number and Size of Follicles During Stimulation1 Comparable ovarian stimulation with ELONVA vs rFSH AST Group Day of hCG (Restricted to patients with hCG) 18 16 6 Day 8 14 6 2 12 3 3 10 4 Mean Number of Follicles 3 8 3 8 6 Day 5 6 6 5 4 2 0 ELONVA™ (corifollitropin alfa) ELONVA ELONVA Daily rFSH Daily rFSH Daily rFSH 11–14 mm 15–16 mm 17 mm The mean number in each follicle category is rounded off to the nearest whole number. AST = all subjects treated; rFSH = recombinant follicle-stimulating hormone; hCG = human chorionic gonadotropin 1. Adapted with permission from Fauser BC et al. Reprod Biomed Online. 2010;21:593‒601.

  26. Serum Estradiol (E2) Levels1 Engage Serum E2 levels were comparable between ELONVA and rFSH ITT Group ELONVA™ (corifollitropin alfa) 100 µg rFSH 150 IU/d Serum E2 Levels, pmol/L 5 8 hCG Stimulation Days E2 = estradiol; rFSH = recombinant follicle-stimulating hormone. 1. Fauser BC et al. Reprod Biomed Online. 2010;21:593‒601.

  27. Engage Live Birth Rate1 Live birth rates were comparable between ELONVA™ (corifollitropin alfa) and rFSH Patients, %a ITT Group 35.6 34.4 ELONVA 150 µg (n=756) rFSH 200IU/d (n=750) aLive birth rate calculated as the number of patients with an ongoing pregnancy with at least 1 liveborn infant relative to the total number of patients in that arm of the Engage trial (ie, per started COS cycle). ITT = intent to treat; rFSH = recombinant follicle-stimulating hormone; COS = controlled ovarian stimulation. 1. Boostanfar R et al. Fertil Steril. 2012;97:1351–1358.

  28. Engage Cumulative Ongoing Pregnancy Rates From Fresh Embryo Transfer (ET) and Frozen-Thawed Embryo Transfer (FTET) Cycles1 • Cumulative ongoing pregnancy rate after a single cycle of COS, ie, the percentage of patients from Engage who had an ongoing pregnancy after a fresh ET or after 1 or more FTET cycles following embryo cryopreservationa Estimated difference between treatment groups (adjusted for region and ageb): 2.4% in favor of ELONVA (95% CI, 2.6%‒7.4%, NS) aTotal FTET cycles = 225 for ELONVA vs 224 for rFSH. Patients in FTET cycle 1: 148 vs 147; cycle 2: 38 vs 31; cycle 3: 9 vs 4; cycles 4, 5, or 6: 3 vs 1. bRegion: Europe or North America, age: <32 years or ≥32 years. ET = embryo transfer; FTET= frozen-thawed embryo transfer; COS = controlled ovarian stimulation; rFSH = recombinant follicle-stimulating hormone; CI =confidence interval; NS = not significant. 1.Boostanfar R et al. FertilSteril. 2012;97:1351–1358.

  29. Engage Association Between Endogenous LH and Pregnancy Outcomes • Retrospective analysis to evaluate the impact of endogenous LH levels on pregnancy outcome in a double-blind, double-dummy, randomized trial of ELONVA™ (corifollitropin alfa) (Engage Trial Substudy)1 • In total, 750 IVF/ICSI patients in Europe and North America (34 sites) were treated in the reference group with an rFSH/GnRH antagonist protocol2 rFSH = recombinant follicle-stimulating hormone; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; GnRH = gonadotropin-releasing hormone. 1. Doody KJ et al. Reprod Biomed Online. 20112011;23:449–456. 2. Devroey P et al. Hum Reprod. 2009;24:3063–3072.

  30. Engage Serum LH Measurements1 • LH measured on stimulation days 1, 5, and 8 • Central laboratory (fluoroimmunoassay, DELFIA) • Patients grouped by LH levels into 3 categories (<P25, P25–P75, >P75) at each of the 3 cycle days • Comparison of ongoing pregnancy rates by category DELFIA = dissociation-enhanced lanthanide fluorescent immunoassay; LH = luteinizing hormone; P = progesterone. 1. Doody KJ et al. Reprod Biomed Online. 20112011;23:449–456.

  31. Engage Comparable Ongoing Pregnancy Rates per Started Cycle Regardless of Day 8 Serum LH1 ELONVA™ (corifollitropin alfa) rFSH Ongoing Pregnancy Rate, % 39.6 38.6 38.5 36.8 35.5 35.6 N = 216a 316 176 N = 169 340 169 a>25% of patients had a value below the lower limit of quantification and were all included in the <P25 group. LH = luteinizing hormone; P = progesterone; rFSH = recombinant follicle-stimulating hormone. 1. Doody KJ et al. Reprod Biomed Online. 2011;23:449–456.

  32. Engage Comparable Ongoing Pregnancy Rates per Started Cycle Regardless of Serum LH on Day of hCG1 ELONVA™ (corifollitropin alfa) rFSH Ongoing Pregnancy Rate, % 42.9 42.5 41.0 37.5 36.1 36.0 N = 208a 307 170 N = 175 352 174 a >25% of patients had a value below the lower limit of quantification and were all included in the <P25 group. LH = luteinizing hormone; hCG = human chorionic gonadotropin; P = progesterone; rFSH = recombinant follicle-stimulating hormone. 1. Doody KJ et al. Reprod Biomed Online. 2011;23:449–456.

  33. Engage Summary • Serum LH levels vary considerably throughout stimulation in women undergoing rFSH/GnRH antagonist cycles1 • Increased serum LH levels were associated with increased age, whereas the number of follicles and oocytes decreased with increasing LH level1 • The ongoing pregnancy rates were similar in women with the lowest or highest LH levels on days 1, 5, and 8 of stimulation1,2 LH = luteinizing hormone; rFSH = recombinant follicle-stimulating hormone; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; GnRH = gonadotropin-releasing hormone. 1. Doody KJ et al. Reprod Biomed Online. 2011. In press.2. Doody K et al. Reprod Biomed Online. 2010;20:565‒567.

  34. Engage Subjects with SAEs, AEs, and OHSS1 SAEs were similar with ELONVA vs rFSH 37 SAEs occurred in 34 subjects treated with ELONVA, vs 37 SAEs in 28 subjects treated with daily rFSH aInadvertently, 2 patients randomized to ELONVA were treated with daily rFSH,and 1 patient randomized to daily rFSH was treated with ELONVA. Patients are analyzed “as randomized” for efficacy and “as treated” for safety parameters. SAE = serious adverse event; rFSH = recombinant follicle-stimulating hormone; OHSS = ovarian hyperstimulation syndrome. No significant differences between groups. 1.Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

  35. ELONVA™ (corifollitropin alfa) Phase 3 Clinical Trials rFSH = recombinant follicle-stimulating hormone; RCT = randomized controlled trial; PR = pregnancy rate; AEs = adverse events; SAEs = serious adverse events. 1.Devroey P et al. Hum Reprod. 2009;24:3063‒3072.2. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

  36. Ensure Ensure Trial: Treatment Regimen1 ELONVA™ (corifollitropin alfa) (100 µg) (n=268) Investigational group Placebo rFSH Daily rFSH (daily dose ≤200 IU) Placebo ELONVA (n=128) IVF or ICSI GnRH antagonist (GANIRELIX® 0.25 mg/d) day 5 through day of hCG Luteal phase support Reference group Daily rFSH (daily dose 150 IU for 7 days) Daily rFSH (daily dose ≤200 IU) Cycle day 2–3 = stimulation day 1 Stimulation day 5 Stimulation day 8 hCG as soon as 3 follicles≥17 mm (or the day thereafter) rFSH = recombinant follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; hCG = human chorionic gonadotropin. 1. Adapted with permission from Adapted with permission from Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

  37. Ensure Main Inclusion and Exclusion Criteria1 Inclusion criteria • Indication for COS and IVF/ICSI • Normal menstrual cycle length (24–35 days) • ≥18 and ≤36 years of age • Body weight ≤60 kg, and BMI ≥18 and ≤32 kg/m2 Exclusion criteria • Endocrine abnormality • PCOS • Previous low ovarian response or no ovarian response • Previous OHSS • >20 basal antral follicles COS = controlled ovarian stimulation; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; BMI = body mass index; PCOS = polycystic ovary syndrome; OHSS = ovarian hyperstimulation syndrome. 1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

  38. Ensure Key Patient Characteristics at Screening1 rFSH = recombinant follicle-stimulating hormone; SD = standard deviation. 1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

  39. Ensure Primary End Point: Number of Oocytes Retrieved1 • Quality of oocytes, by percentage of MII oocytes, was comparable between treatments aPrimary end point is to show equivalence in number of cumulus-oocyte complexes retrieved. Predefined equivalence range: -3 to +5 oocytes. bP<0.001. rFSH = recombinant follicle-stimulating hormone; SD = standard deviation; ANOVA = analysis of variance. 1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

  40. Ensure Serum E2 Levels1 Serum E2 levels were comparable between ELONVA and rFSH ITT Group ELONVA™ (corifollitropin alfa) 100 µg rFSH 150 IU/d Serum E2 Levels, pmol/L 5 8 hCG Stimulation Days . E2 = estradiol; rFSH = recombinant follicle-stimulating hormone. 1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

  41. Ensure Serum LH Levels in Patients With hCG Injection1 ITT Group ELONVA™ (corifollitropin alfa) 100 µg rFSH 150 IU/d Serum LH Levels, IU/L 3 5 8 hCG Stimulation Days All values are median. LH = luteinizing hormone; ITT = intent-to-treat; rFSH = recombinant follicle-stimulating hormone; hCG = human chorionic gonadotropin. 1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

  42. Ensure Implantation Rate (Mean %) per started Cycle1 Implantation rates were comparable between ELONVA and rFSH ITT Group Patients, % (SD) 28.5 23.4 ELONVA™ (corifollitropin alfa) 100 µg(n=268) rFSH 150 IU/d (n=128) ITT = intent to treat; rFSH = recombinant follicle-stimulating hormone; SD = standard deviation. 1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

  43. Ensure Ongoing Pregnancy Rate per Started Cycle1 ITT Group Patients, % 34.4 25.4 No. of embryos transferred:1.8 No. of embryos transferred:1.8 ELONVA™ (corifollitropin alfa) 100 µg(n=268) rFSH 150 IU/d (n=128) This trial was not powered to measure a difference in ongoing pregnancy rates ITT = intent to treat; rFSH = recombinant follicle-stimulating hormone. 1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

  44. Ensure Ensure: Percentage of Patients With AEs/SAEs1 AST Group AE = adverse event; SAE = serious adverse event; AST = all-subjects-treated; rFSH = recombinant follicle-stimulating hormone; OHSS = ovarian hyperstimulation syndrome 1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

  45. Trust Clinical Trial1 • Design • Phase 3, uncontrolled, repeated-cycle trial • Primary objective • To assess the immunogenicity and safety of ELONVA™ (corifollitropin alfa) in repeated COS cycles • Primary end points • Antibody formation against corifollitropin alfa • Occurrence of SAEs and AEs • Occurrence of OHSS • Hypersensitivity reactions • Local tolerance COS = controlled ovarian stimulation; SAE = serious adverse event; AE = adverse event; OHSS = ovarian hyperstimulation syndrome. 1. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.

  46. Cycle day 2–3 = stimulation day 1 Stimulation day 5 or 6 Stimulation day 8 Trust: Treatment for up to 3 Cycles1 ELONVA™ (corifollitropin alfa) 150 µg hCG FSH daily≤225 IU 7 days Oocyte retrieval IVF ICSI ET (max 3) GnRH antagonist (0.25 mg/d) day 5 or 6 through day of hCG Luteal phase support(vaginal P) hCG as soon as3 follicles ≥17 mm FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; ET = embryo transfer; P = progesterone; hCG = human chorionic gonadotropin. 1. Adapted with permission from Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.

  47. Trust Immunogenicity Testing in Exposed Patients1 1. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.

  48. Trust OHSS Incidence1 • OHSS incidence (all-subjects-treated group) decreased with each subsequent cycle • 1st cycle: 3.5% (1.8% mild, 0.9% moderate, 0.9% severe) • 2nd cycle: 1.9% (0.8% mild, 0.5% moderate, 0.5% severe) • 3rd cycle: 0% • In total, 2.6% of patients experienced mild OHSS, 1.4% moderate, and 1.4% severe OHSS = ovarian hyperstimulation syndrome. 1. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.

  49. Pooled Analysis of OHSS Risk: ELONVA™ (corifollitropin alfa) vs rFSH1 • Assessed OHSS risk in 3 clinical trials of ELONVA (Engage, Ensure, and Trust; N=1,705) • Overall OHSS incidence of 5.6% over these 3 trials • Pooled incidence: • ELONVA: 6.9% (71/1023) • rFSH: 6.0% (53/880) • Adjusted corifollitropin alfa to rFSH odds ratio: 1.18(95% CI, 0.81–1.71) • No difference in OHSS risk OHSS = ovarian hyperstimulation syndrome. 1. Tarlatzis BC et al. Reprod Biomed Online. 2012;24:410–419.

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