ELONVA ™ (corifollitropin alfa): KORAK DALJE U LIJEČENJU NEPLODNOSTI HRVOJE VRČIĆ, MD PhD...

ELONVA (corifollitropin alfa): KORAK DALJE U LIJEENJU NEPLODNOSTI HRVOJE VRI, 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 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.

The Growth of In Vitro Fertilization (IVF) 1 10 IVF = in vitro fertilization. 1. Nygren KG et al. Hum Reprod. 2001;16:384391; 2. Nygren KG et al. Hum Reprod. 2001;16:24592471; 3. Nygren KG et al. Hum Reprod. 2002;17:32603274; 4. Nyboe Andersen A et al. Hum Reprod. 2004;19:490503; 5. Andersen AN et al. Hum Reprod. 2005;20:11581176; 6. Andersen AN et al. Hum Reprod. 2006;21:16801697; 7. Andersen AN et al. Hum Reprod. 2007;22:15131525; 8. Andersen AN et al. Hum Reprod. 2008;23:756771; 9. Andersen AN et al. Hum Reprod. 2009;24:12671287; 10. de Mouzon J et al. Hum Reprod. 2010;25:18511862. 2005: 418,111 cycles 2006: 458,759 cycles Increase of 40,648 cycles (+9.7%) Total PubMed Hits for IVF in Title/Abstract by Year

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

Total market share for medicine ART in Croatia Sales WHS [EUR] 200820092010201120122013 Q1/2013Q1/2014 Total market share ART2.026.1182.100.7252.483.0242.772.6532.477.180 2.523.661687.553703.094 Increase market % 4%18%12%-11% 2% Total market share ART, gonadotrophins and % EUR Sales WHS [EUR] 200820092010201120122013 Q1/2013Q1/2014 Ukupno trite2.026.1182.100.7252.483.0242.772.6532.477.180 2.523.661687.553703.094 FSH1.676.9161.762.4452.108.6522.282.8411.959.911 1977465 550.668524.892 Udio FSH83%84%85%82%79% 78%80%75% Total market share of gonadotrophins eqivalent 75 IU Units equiv. 75 i.j. 200820092010201120122013 Q1/2013Q1/2014 Total n of Amp (75i.j.)73.91978.92895.507104.97290.376 87.415 24.22723.036 Increase market %7%21%10%-14% -3%-5% 22 amp/cycl4000 cycles *ART: Gonal-f, Menopur, Puregon, Ovitrelle, Cetrotide, Orgalutran, Brevactide, Clomifen, Crinone ** All gonadotrophins. Gonal-f, Menopur, Puregon

IVF: It Works, but It Is Burdensome Current treatments may induce stress 1,2 Discontinuation reduces cumulative pregnancy rates 3 Treatment burden is a major reason for discontinuation 4 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;16:374383. 2. Huisman D et al. Reprod Biomed Online. 2009;19(suppl 2):510. 3. Schrder AK et al. Reprod Biomed Online. 2004;8:600606. 4. Verberg MF et al. Hum Reprod. 2008;23:20502055.

123456 IVF = in vitro fertilization; ECPR = expected cumulative pregnancy rate; RCPR = real cumulative pregnancy rate. 1. Adapted with permission from Schrder AK et al. Reprod Biomed Online. 2004;8:600606. Difference between expected and real pregnancy rates is caused by the diminishing size of the cohort due to dropout frequency Dropouts Negatively Impact Real Cumulative Pregnancy Rates 1 Data from 4,102 IVF cycles in 2,130 women Cycles 0 10 20 30 40 50 60 70 Percent Dropout rateECPRRCPR (n=2,130)(n=1,087)(n=518)(n=222)(n=74)(n=36)

Today: Ovarian Stimulation Protocols Require Multiple Injections 1,2 GnRH = gonadotropin-releasing hormone. 1. Adapted with permission from de Greef R et al. Clin Pharmacol Ther. 2010;88:7987. 2. Adapted with permission from Hodgen GD. Contemp Rev Obstet Gynaecol. 1990;35:1024. GnRH antagonist protocol 2 Long GnRH agonist protocol 1 12345678910 123456789 Flare-up Pituitary downregulation Direct gonadotropin suppression Time Luteinizing Hormone

ELONVA (corifollitropin alfa) May Reduce the Number of Necessary Injections 1,2 ELONVA rFSH 12345678910 hCG 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;88:7987. 2. Adapted with permission from Hodgen GD. Contemp Rev Obstet Gynaecol. 1990;35:1024. Direct gonadotropin suppression Luteinizing Hormone Time GnRH antagonist

Corifollitropin Alfa Is a Recombinant Hormone -Subunits 1 -Subunits 2 Corifollitropin alfa t corifollitropin alfa = 69 h 4 92 aa 110 aa 145 aa 110 aa29 aa 2 hCG Human FSH t rFSH 40 h 3 FSH = follicle-stimulating hormone; hCG = human chorionic gonadotropin ;aa = amino acids; t = 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;89:43044308; 3. PUREGON (rFSH) summary of product characteristics, 2010; 4. ELONVA (corifollitropin alfa) summary of product characteristics, 2010.

ELONVA (corifollitropin alfa) 1 Prefilled syringe ELONVA 150 or 100 g Automatic (passive) safety system with retractable needle to prevent needle stick injuries Administration Self-administration Subcutaneous Preferably in the abdominal wall 1. ELONVA (corifollitropin alfa) summary of product characteristics, 2010. 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

FSH = follicle-stimulating hormone; rFSH = recombinant FSH; t 1/2 = half-life; T max = time to maximum concentration. 1. Adapted with permission from Fauser BC et al. Hum Reprod Update. 2009;15:309321; 2. ELONVA (corifollitropin alfa) summary of product characteristics, 2010; 3. PUREGON (rFSH) summary of product characteristics, 2010. Comparative Pharmacokinetics 10987654321 Stimulation Days FSH Activity 1 Therapeutic threshold Corifollitropin alfa rFSH t rFSH 40 h T max = 1012 h 3 t corifollitropin alfa = 69 h T max = 3648 h 2

Equal Exposure to ELONVA (corifollitropin alfa) Based on Body Weight 1 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 100 g150 g AUC, hng/mL Total Drug Exposure (AUC) 60 kg >60 kg 1500 1000 500 0 AUC = area under the curve. 1. Adapted with permission from Ledger WL et al. Reprod Biomed Online. 2011;23:150159.

ELONVA (corifollitropin alfa) Phase 3 Clinical Trials Engage 1 Ensure 2 Study armsELONVA 150 g vs rFSH 200 IU/d in women >60 kg ELONVA 100 g vs rFSH 150 IU/d in women 60 kg DesignDouble-blind RCT 1 cycle Double-blind RCT 1 cycle Patients (n)1,506396 Primary end point Coprimary end point Ongoing PR/cycle Number of oocytes retrieved Safety evaluationsAEs/SAEs, including OHSS Local tolerance Anticorifollitropin alfa antibodies AEs/SAEs, including OHSS Local tolerance Anticorifollitropin alfa antibodies SitesEurope 20, North America 14Europe 14, Asia 5 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;24:30633072. 2. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:6676.

Engage Trial: Treatment Regimen 1 ELONVA (corifollitropin alfa) (150 g) (n=756) ELONVA (corifollitropin alfa) (150 g) (n=756) Placebo ELONVA (n=750) Placebo ELONVA (n=750) GnRH antagonist (GANIRELIX 0.25 mg/d) day 5 through day of hCG GnRH antagonist (GANIRELIX 0.25 mg/d) day 5 through day of hCG Stimulation day 5 hCG as soon as 3 follicles 17 mm (or the day thereafter) Stimulation day 8 Cycle day 23 = stimulation day 1 Daily rFSH (daily dose 200 IU for 7 days) Daily rFSH (daily dose 200 IU for 7 days) Investigational group Reference group Placebo rFSH Daily rFSH (daily dose 200 IU) Daily rFSH (daily dose 200 IU) Daily rFSH (daily dose 200 IU) Daily rFSH (daily dose 200 IU) IVF or ICSI IVF or ICSI Luteal phase support Luteal phase support 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;24:30633072.

Main Inclusion and Exclusion Criteria 1 Inclusion criteria Indication for COS and IVF/ICSI Normal menstrual cycle length (2435 days) 18 and 36 years of age Body weight >60 and 90 kg, and BMI 18 and 32 kg/m 2 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;24:30633072. Engage

Demographics at Screening 1 ELONVA (corifollitropin alfa) 150 g (n=756) rFSH 200 IU/d (n=750) Age, years Mean (SD)31.5 (3.3)31.5 (3.2) Body weight, kg Mean (SD)68.8 (7.6)68.4 (7.3) BMI, kg/m 2 Mean (SD)24.8 (2.8)24.8 (2.7) Race, % Asian Black Caucasian Other 2.8 4.4 85.1 7.8 2.8 3.7 86.7 6.8 ITT Group ITT = intent to treat; rFSH = recombinant FSH; SD = standard deviation; BMI = body mass index. 1. Devroey P et al. Hum Reprod. 2009;24:30633072. Engage

Primary End Point: Ongoing Pregnancy Rate 1 Patients, % a No. of embryos transferred: 1.7 ITT Group 38.9 38.1 a Ongoing 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;24:30633072. rFSH 200 IU/d (n=750) ELONVA 150 g (n=756) Ongoing pregnancy rates were comparable between ELONVA (corifollitropin alfa) and rFSH Engage No. of embryos transferred: 1.7

Comparable ongoing pregnancy rates for SET vs DET Results: Single vs Double Embryo Transfer Ongoing Pregnancy Rates per Started Cycle 1 SET = single embryo transfer; DET = double embryo transfer; rFSH = recombinant follicle-stimulating hormone. 1. Devroey P et al. Hum Reprod. 2009;24:30633072. Engage Ongoing Pregnancy Rate, % ELONVA (corifollitropin alfa) 150 g rFSH 200 IU/d SET (n/N) 34.7 (60/173) 28.9 (55/190) DET (n/N) 46.9 (234/499) 44.9 (231/514)

Results: Day 3 vs Day 5 (Blastocyst) Transfer Ongoing Pregnancy Rates per Started Cycle 1 ET = embryo transfer; rFSH = recombinant follicle-stimulating hormone. 1. Devroey P et al. Hum Reprod. 2009;24:30633072. Engage Comparable ongoing pregnancy rates for day 3 vs day 5 ET Ongoing Pregnancy Rate, % ELONVA (corifollitropin alfa) 150 g rFSH 200 IU/d Day 3 (n/N) 41.7 (169/405) 35.1 (156/445) Day 5 (n/N) 47.1 (121/257) 50.6 (126/249)

Co-primary End Point: Number of Oocytes Retrieved 1 Quality of oocytes, by percentage of MII oocytes, was comparable between treatments ELONVA (corifollitropin alfa) 150 g (n=756) rFSH 200 IU/d (n=750) Estimated Difference, ANOVA (95% CI) Mean (SD) number of oocytes retrieved 13.7 (8.2)12.5 (6.7)1.2 a (0.51.9) Mean percentage of MII oocytes 78.977.4 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;24:30633072. Engage

2PN Oocytes 1 The fertilization rate, number of 2PN oocytes, and number of good-quality embryos were comparable between treatment groups Mean fertilization rate a 66.0% (SD, 23.4%) ELONVA (corifollitropin alfa) 150 g 67.6% (SD, 22.9%) rFSH 200 IU/d Mean number of 2PN fertilized oocytes obtained a 8.3 (SD, 5.6) ELONVA 150 g 7.4 (SD, 4.8) rFSH 200 IU/d Mean number of good-quality embryos 4.6 (SD, 4.3) ELONVA 150 g 4.4 (SD, 3.9) rFSH 200 IU/d a Restricted 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;24:30633072. Engage

Clinical Outcome per Started Cycle 1 ELONVA (corifollitropin alfa) 150 g (n=756) rFSH 200 IU/d (n=750) No. of embryos transferred, mean (SD) 1.7 Positive hCG, %48.146.9 ITT Group ITT = intent to treat; rFSH = recombinant FSH; SD = standard deviation; hCG = human chorionic gonadotropin. 1. Devroey P et al. Hum Reprod. 2009;24:30633072. There was no difference between groups in number of embryos transferred or biological pregnancy rate Engage

Implantation Rate (Mean %) per Started Cycle 1 Patients, % (SD) ITT Group 36.2 32.2 SD = standard deviation; ITT = intent to treat; rFSH = recombinant follicle-stimulating hormone. 1. Devroey P et al. Hum Reprod. 2009;24:30633072. rFSH 200 IU/d (n=750) ELONVA 150 g (n=756) Implantation rates were comparable between ELONVA (corifollitropin alfa) and rFSH Engage

Day of IVF Cycle When hCG Criterion Was Met 1 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;21:593601. Patients, % Stimulation Day Engage

Number and Size of Follicles During Stimulation 1 Day 5 Day 8 Day of hCG (Restricted to patients with hCG) ELONVA (corifollitropin alfa) Daily rFSH Daily rFSH Daily rFSH ELONVA Mean Number of Follicles 8 3 2 6 3 3 6 4 6 5 3 6 0 2 4 6 8 10 12 14 16 18 1114 mm1516 mm 17 mm AST Group 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;21:593601. Comparable ovarian stimulation with ELONVA vs rFSH Engage

Serum Estradiol (E 2 ) Levels 1 E 2 = estradiol; rFSH = recombinant follicle-stimulating hormone. 1. Fauser BC et al. Reprod Biomed Online. 2010;21:593601. Serum E 2 levels were comparable between ELONVA and rFSH Engage ITT Group Serum E 2 Levels, pmol/L ELONVA (corifollitropin alfa) 100 g rFSH 150 IU/d Stimulation Days 58hCG

Live Birth Rate 1 Patients, % a ITT Group a Live 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;97:13511358. 35.6 34.4 ELONVA 150 g (n=756) rFSH 200IU/d (n=750) Live birth rates were comparable between ELONVA (corifollitropin alfa) and rFSH Engage

a Total 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. b Region: Europe or North America, age:

Comparable Ongoing Pregnancy Rates per Started Cycle Regardless of Day 8 Serum LH 1 a >25% of patients had a value below the lower limit of quantification and were all included in the

Comparable Ongoing Pregnancy Rates per Started Cycle Regardless of Serum LH on Day of hCG 1 a >25% of patients had a value below the lower limit of quantification and were all included in the

ELONVA (corifollitropin alfa) Phase 3 Clinical Trials Engage 1 Ensure 2 Study armsELONVA 150 g vs rFSH 200 IU/d in women >60 kg ELONVA 100 g vs rFSH 150 IU/d in women 60 kg DesignDouble-blind RCT 1 cycle Double-blind RCT 1 cycle Patients (n)1,506396 Primary end point Coprimary end point Ongoing PR/cycle Number of oocytes retrieved Safety evaluationsAEs/SAEs, including OHSS Local tolerance Anticorifollitropin alfa antibodies AEs/SAEs, including OHSS Local tolerance Anticorifollitropin alfa antibodies SitesEurope 20, North America 14Europe 14, Asia 5 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;24:30633072. 2. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:6676.

Ensure Trial: Treatment Regimen 1 ELONVA (corifollitropin alfa) (100 g) (n=268 ) ELONVA (corifollitropin alfa) (100 g) (n=268 ) Placebo ELONVA (n=128 ) Placebo ELONVA (n=128 ) GnRH antagonist (GANIRELIX 0.25 mg/d) day 5 through day of hCG Stimulation day 5 hCG as soon as 3 follicles 17 mm (or the day thereafter) Stimulation day 8 Cycle day 23 = stimulation day 1 Daily rFSH (daily dose 150 IU for 7 days) Daily rFSH (daily dose 150 IU for 7 days) Investigational group Reference group Placebo rFSH Daily rFSH (daily dose 200 IU) Daily rFSH (daily dose 200 IU) Daily rFSH (daily dose 200 IU) Daily rFSH (daily dose 200 IU) IVF or ICSI IVF or ICSI Luteal phase support Luteal phase support 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;21:6676. Ensure

Main Inclusion and Exclusion Criteria 1 Inclusion criteria Indication for COS and IVF/ICSI Normal menstrual cycle length (2435 days) 18 and 36 years of age Body weight 60 kg, and BMI 18 and 32 kg/m 2 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;21:6676. Ensure

Key Patient Characteristics at Screening 1 rFSH = recombinant follicle-stimulating hormone; SD = standard deviation. 1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:6676. Ensure ELONVA (corifollitropin alfa) 100 g (n=268) rFSH 150 IU/d (n=128) Age, mean (SD), y30.9 (3.2)31.1 (3.0) Body weight, mean (SD), kg54.1 (4.2)54.4 (4.2)

Primary End Point: Number of Oocytes Retrieved 1 a Primary end point is to show equivalence in number of cumulus-oocyte complexes retrieved. Predefined equivalence range: -3 to +5 oocytes. b P

ELONVA (corifollitropin alfa) 1 Therapeutic Indication Controlled ovarian stimulation (COS) in combination with a GnRH antagonist for the development of multiple follicles in women participating in an assisted reproductive technology (ART) program Dosage In women with a body weight 60 kilograms a single dose of 100 g should be administered In women with a body weight > 60 kilograms a single dose of 150 g should be administered Administration ELONVA should be administered as a single subcutaneous injection, preferably in the abdominal wall, during the early follicular phase of the menstrual cycle 1. ELONVA (corifollitropin alfa) summary of product characteristics. MSD Oss B.V., a subsidiary of Merck & Co., Inc.; 2012.

ELONVA ™ (corifollitropin alfa): KORAK DALJE U LIJEČENJU NEPLODNOSTI HRVOJE VRČIĆ, MD PhD...

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