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

HRVOJE VRČIĆ, MD PhDMEDICAL 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;16:384‒391; 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.

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 Croatia4.5 mil people1,1 mil women in reproductive age100.000 infertile or subfertile women50.000 in Dg/Th treatment of infertility2000 IVF/1mil peopleBirth rate >4% from ART2012. 4000 IVF/ICSI

Total market share for medicine ART in Croatia

Sales WHS [EUR] 2008 2009 2010 2011 2012 2013 Q1/2013 Q1/2014

Total market share ART 2.026.118 2.100.725 2.483.024 2.772.653 2.477.180 2.523.661 687.553 703.094Increase market %   4% 18% 12% -11% 2% 2%

Total market share ART, gonadotrophins and %EUR

Sales WHS [EUR]2008 2009 2010 2011 2012 2013 Q1/2013 Q1/2014

Ukupno tržište 2.026.118 2.100.725 2.483.024 2.772.653 2.477.180 2.523.661 687.553 703.094FSH 1.676.916 1.762.445 2.108.652 2.282.841 1.959.911 1977465 550.668 524.892Udio FSH 83% 84% 85% 82% 79% 78% 80% 75%

Total market share of gonadotrophins eqivalent 75 IU

  Units equiv. 75 i.j.   2008 2009 2010 2011 2012 2013 Q1/2013 Q1/2014

Total n of Amp (75i.j.) 73.919 78.928 95.507 104.972 90.376 87.415 24.227 23.036Increase market % 7% 21% 10% -14% -3% -5%

22 amp/cycl 4000 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 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.

1 2 3 4 5 6

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.

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 Rates1

• Data from 4,102 IVF cycles in 2,130 women

Cycles

0

10

20

30

40

50

60

70

Perc

ent

Dropout rate ECPR RCPR

(n=2,130) (n=1,087) (n=518) (n=222) (n=74) (n=36)

Today: Ovarian Stimulation Protocols Require Multiple Injections1,2

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.

GnRH antagonistprotocol2

Long GnRH agonistprotocol1

1 2 3 4 5 6 7 8 9 10

1 2 3 4 5 6 7 8 9 10

Flare-up

Pituitary downregulation Direct

gonadotropinsuppression

Time

Lute

iniz

ing

Horm

one

ELONVA™ (corifollitropin alfa) May Reduce the Number of Necessary Injections1,2

ELONVA rFSH

1 2 3 4 5 6 7 8 9 10

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;88:79‒87. 2. Adapted with permission from Hodgen GD. Contemp Rev Obstet Gynaecol. 1990;35:10‒24.

Directgonadotropinsuppression

Lute

iniz

ing

Horm

one

Time

GnRH antagonist

Corifollitropin Alfa Is a Recombinant Hormone

-Subunits1 β-Subunits2

Corifollitropin alfat½ corifollitropin alfa = 69 h4

92 aa

92 aa

92 aa

110 aa

145 aa

110 aa 29 aa2

hCG

Human FSHt½ rFSH ≈ 40 h3

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.

ELONVA™ (corifollitropin alfa)1

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

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; 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.

Comparative Pharmacokinetics

10987654321Stimulation Days

FSH

Activ

ity1

Therapeutic threshold

Corifollitropin alfarFSH

t½ rFSH ≈ 40 hTmax = 10–12 h3

t½ corifollitropin alfa = 69 hTmax = 36–48 h2

Equal Exposure to ELONVA™

(corifollitropin alfa) Based on Body Weight1

• 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 µg 150 µg

AU

C , h

•ng/

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;23:150‒159.

ELONVA™ (corifollitropin alfa) Phase 3 Clinical Trials

Engage1 Ensure2

Study arms ELONVA 150 µg vs rFSH 200 IU/d in women >60 kg

ELONVA 100 µg vs rFSH 150 IU/d in women ≤60 kg

Design Double-blind RCT1 cycle

Double-blind RCT1 cycle

Patients (n) 1,506 396

Primary end pointCoprimary end point

Ongoing PR/cycleNumber of oocytes retrieved

Number of oocytes retrieved

Safety evaluations AEs/SAEs, including OHSSLocal toleranceAnti–corifollitropin alfa antibodies

AEs/SAEs, including OHSSLocal toleranceAnti–corifollitropin alfa antibodies

Sites Europe 20, North America 14 Europe 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;24:3063‒3072. 2. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

Engage Trial: Treatment Regimen1

ELONVA ™

(corifollitropin alfa)(150 µg) (n=756)

PlaceboELONVA (n=750)

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 2–3 =stimulation day 1

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)

IVF

or

ICSI

Lutealphase

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;24:3063‒3072.

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.

Engage

Demographics at Screening1

ELONVA™

(corifollitropin alfa)150 µg(n=756)

rFSH200 IU/d (n=750)

Age, yearsMean (SD) 31.5 (3.3) 31.5 (3.2)

Body weight, kgMean (SD) 68.8 (7.6) 68.4 (7.3)

BMI, kg/m2

Mean (SD) 24.8 (2.8) 24.8 (2.7)

Race, % AsianBlackCaucasianOther

2.84.485.17.8

2.83.7

86.76.8

ITT Group

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

Engage

0

25

50

75

100

Primary End Point: Ongoing Pregnancy Rate1

Patie

nts,

%a

No. of embryos transferred:

1.7

ITT Group

38.9 38.1

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.

rFSH 200 IU/d

(n=750)

ELONVA 150 µg (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 Cycle1

SET = single embryo transfer; DET = double embryo transfer; rFSH = recombinant follicle-stimulating hormone.1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

Engage

Ongoing Pregnancy Rate, %

ELONVA™ (corifollitropin alfa)

150 μgrFSH

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 Cycle1

ET = embryo transfer; rFSH = recombinant follicle-stimulating hormone.1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

Engage

Comparable ongoing pregnancy rates for day 3 vs day 5 ET

Ongoing Pregnancy Rate, %

ELONVA™ (corifollitropin alfa)

150 μgrFSH

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 Retrieved1

• Quality of oocytes, by percentage of MII oocytes, was comparable between treatments

ELONVA™ (corifollitropin alfa)

150 µg(n=756)

rFSH200 IU/d(n=750)

Estimated Difference,ANOVA (95% CI)

Mean (SD) number of oocytes retrieved

13.7 (8.2) 12.5 (6.7) 1.2a (0.5–1.9)

Mean percentage of MII oocytes

78.9 77.4

aP=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.

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.

Engage

Clinical Outcome per Started Cycle1

ELONVA™ (corifollitropin alfa)

150 µg(n=756)

rFSH200 IU/d(n=750)

No. of embryos transferred, mean (SD) 1.7 1.7

Positive hCG, % 48.1 46.9

ITT Group

ITT = intent to treat; rFSH = recombinant FSH; SD = standard deviation; hCG = human chorionic gonadotropin.1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

There was no difference between groups in number of embryos transferred or biological pregnancy rate

Engage

0

25

50

75

100

Implantation Rate (Mean %) per Started Cycle1

Patie

nts,

% (S

D)

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;24:3063‒3072.

rFSH 200 IU/d

(n=750)

ELONVA 150 µg (n=756)

Implantation rates were comparable between ELONVA™ (corifollitropin alfa) and rFSH

Engage

Day of IVF Cycle When hCG Criterion Was Met1

0

5

10

15

20

25

30

35

40

5 6 7 8 9 10 11 12 13 14 15 16 17 18

ELONVA (corifollitropin alfa) 150 µgrFSH 200 IU/d

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.

™

Patie

nts,

%

Stimulation Day

Engage

Number and Size of Follicles During Stimulation1

Day 5

Day 8

Day of hCG(Restricted to patients with hCG)

ELONVA™

(corifollitropin alfa)

Daily rFSH

Daily rFSH

Daily rFSH

ELONVA ELONVA

Mea

n N

umbe

r of F

ollic

les

8

3

2

6

3

3

6

4

6

5

3

6

0

2

4

6

8

10

12

14

16

18

11–14 mm 15–16 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 gonadotropin1. Adapted with permission from Fauser BC et al. Reprod Biomed Online. 2010;21:593‒601.

Comparable ovarian stimulation with ELONVA vs rFSH

Engage

Serum Estradiol (E2) Levels1

E2 = estradiol; rFSH = recombinant follicle-stimulating hormone.1. Fauser BC et al. Reprod Biomed Online. 2010;21:593‒601.

Serum E2 levels were comparable between ELONVA and rFSH

Engage

ITT Group

0

2.000

4.000

6.000

8.000

10.000

12.000

Seru

m E

2 Le

vels

, pm

ol/L

ELONVA™ (corifollitropin alfa) 100 µgrFSH 150 IU/d

Stimulation Days

5 8 hCG

0

25

50

75

100

Live Birth Rate1Pa

tient

s, %

a

ITT Group

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.

35.6 34.4

ELONVA 150 µg (n=756)

rFSH 200IU/d (n=750)

Live birth rates were comparable between ELONVA™ (corifollitropin alfa) and rFSH

Engage

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. Fertil Steril. 2012;97:1351–1358.

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)

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.

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.

Engage

Comparable Ongoing Pregnancy Rates per Started Cycle Regardless of Day 8 Serum LH1

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.

Engage

0102030405060708090

100

P25<0.6 P50=0.96 P75=1.58

ELONVA™ (corifollitropin alfa) rFSH

N = 216a 316 176

0102030405060708090

100

P25=0.91 P50=1.57 P75=2.66

N = 169 340 169

Ong

oing

Pre

gnan

cy R

ate,

%

35.639.6 38.6

35.5 36.8 38.5

Comparable Ongoing Pregnancy Rates per Started

Cycle Regardless of Serum LH on Day of hCG1

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.

Engage

0102030405060708090

100

P25<0.6 P50=1.00 P75=1.77

ELONVA™ (corifollitropin alfa) rFSH

N = 208a 307 170

0102030405060708090

100

P25=0.75 P50=1.39 P75=2.57

N = 175 352 174

Ong

oing

Pre

gnan

cy R

ate,

%

36.141.0 42.9

36.0 37.542.5

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.

Engage

Subjects with SAEs, AEs, and OHSS1

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.

SAEs were similar with ELONVA vs rFSH

Engage

37 SAEs occurred in 34 subjects treated with ELONVA, vs 37 SAEs in 28 subjects treated with daily rFSH

Patients, % (n)

ELONVATM (corifollitropin alfa) 150 µg (n=755a) rFSH 200 IU/d (n=751a)Discontinued due to AE 2.1 (16) 0.4 (3)SAEs, Total

OHSS Ectopic Pregnancy

4.9 (37)1.9 (14)0.9 (7)

4.9 (37)1.2 (9)1.2 (9)

AEs, Procedural Pain Pregnancy-related Events Pelvic Pain Pelvic Discomfort Headache

22.313.812.111.510.5

20.111.212.311.615.2

OHSS, overallOHSS, moderate/severe

7.0 (53)4.1 (31)

6.3 (47)2.7 (20)

ELONVA™ (corifollitropin alfa) Phase 3 Clinical Trials

Engage1 Ensure2

Study arms ELONVA 150 µg vs rFSH 200 IU/d in women >60 kg

ELONVA 100 µg vs rFSH 150 IU/d in women ≤60 kg

Design Double-blind RCT1 cycle

Double-blind RCT1 cycle

Patients (n) 1,506 396

Primary end pointCoprimary end point

Ongoing PR/cycleNumber of oocytes retrieved

Number of oocytes retrieved

Safety evaluations AEs/SAEs, including OHSSLocal toleranceAnti–corifollitropin alfa antibodies

AEs/SAEs, including OHSSLocal toleranceAnti–corifollitropin alfa antibodies

Sites Europe 20, North America 14 Europe 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;24:3063‒3072. 2. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

Ensure Trial: Treatment Regimen1

ELONVA™

(corifollitropin alfa)(100 µg) (n=268)

PlaceboELONVA (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 2–3 =stimulation day 1

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)

IVF

or

ICSI

Lutealphase

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;21:66‒76.

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.

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.

Ensure

ELONVA™ (corifollitropin alfa)100 μg(n=268)

rFSH150 IU/d(n=128)

Age, mean (SD), y 30.9 (3.2) 31.1 (3.0)

Body weight, mean (SD), kg 54.1 (4.2) 54.4 (4.2)

Primary End Point: Number of Oocytes Retrieved1

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.

Ensure

• Quality of oocytes, by percentage of MII oocytes, was comparable between treatments

ELONVA™ (corifollitropin alfa)

100 μg(n=268)

rFSH150 IU/d(n=128)

Estimated Difference,ANOVA (95% CI)

Number of oocytes retrieved, mean (SD)a

13.3 (7.3) 10.6 (5.9) 2.5 (1.2–3.9)b

Serum E2 Levels1

.E2 = estradiol; rFSH = recombinant follicle-stimulating hormone.1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

Serum E2 levels were comparable between ELONVA and rFSH

ITT Group

0

2.000

4.000

6.000

8.000

10.000

12.000

Seru

m E

2 Lev

els,

pm

ol/L

Stimulation Days

5 8 hCG

ELONVA™ (corifollitropin alfa) 100 µgrFSH 150 IU/d

Ensure

Serum LH Levels in Patients With hCG Injection1

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.

Ensure

0

2

4

6

8

10

Stimulation Days

Seru

m LH

Leve

ls, IU

/L

3 5 8 hCG

ELONVA™ (corifollitropin alfa) 100 µgrFSH 150 IU/d

ITT Group

0

25

50

75

100

Implantation Rate (Mean %) per started Cycle1 P

atie

nts,

% (S

D)

23.428.5

ITT Group

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.

ELONVA™ (corifollitropin alfa) 100 µg(n=268)

rFSH 150 IU/d(n=128)

Implantation rates were comparable between ELONVA and rFSH

Ensure

0

25

50

75

100

Ongoing Pregnancy Rate per Started Cycle1

This trial was not powered to measure a difference in ongoing pregnancy rates

Pat

ient

s, %

No. of embryos transferred:

1.8

No. of embryos transferred:

1.8

25.434.4

ITT Group

ITT = intent to treat; rFSH = recombinant follicle-stimulating hormone.1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

ELONVA™ (corifollitropin alfa) 100 µg(n=268)

rFSH 150 IU/d(n=128)

Ensure

Ensure: Percentage of Patients With AEs/SAEs1

AE = adverse event; SAE = serious adverse event; AST = all-subjects-treated; rFSH = recombinant follicle-stimulating hormone; OHSS = ovarian hyperstimulation syndrome1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

AST Group

Ensure

ELONVA™ (corifollitropin alfa)

100 μg(n=268)

rFSH150 IU/d(n=129)

SAEs, % (n) 7.5 (20) 6.3 (8)

Total AEs, % (n) 55.2 (148) 53.5 (69)

Discontinued due to an AE, % 0 0

OHSS, %Moderate or severe OHSS, %

6.73.4

4.71.6

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.

Trust: Treatment for up to 3 Cycles1

IVF ICSI

Oocyte retrieval

ET (max 3)

Luteal phase support(vaginal P)

hCG as soon as3 follicles ≥17 mm

Cycle day 2–3 =stimulation day 1

GnRH antagonist (0.25 mg/d)day 5 or 6 through day of hCG

Stimulation day 5 or 6

7 days

Stimulation day 8

FSH daily≤225 IU

hCG

ELONVA™ (corifollitropin alfa)

150 µg

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.

Immunogenicity Testing in Exposed Patients1

Number of Subjects Treated With

ELONVA™

(corifollitropin alfa)

Number of Subjects Testedfor Antibodies

Observed Clinically Relevant

Immunogenicity Incidence

Cycle 1 682 681 0.0

Cycle 2 375 372 0.0

Cycle 3 198 192 0.0

1. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.

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.

Trust

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.

Subjects With AEs/SAEs • A total of 63 SAEs reported in 47 patients; among the most common were

ectopic pregnancy (n=8) and missed abortion (n=3)– 15 SAEs considered related to study drug, including all 10 cases of

OHSS• Most common AEs

– Procedural pain related to oocyte retrieval (17.7%)– Headache (9.1%)– Pelvic pain (7.6%)

• No drug-related hypersensitivity reactions• Only mild local injection-site reactions (2.5%, 4.3%, and 2.5% in cycles 1, 2,

and 3, respectively)

SAE = serious adverse event; AE = adverse event; OHSS = ovarian hyperstimulation syndrome.1. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.

Trust

Summary

• In combination with GnRH antagonist, ELONVA™ (corifollitropin alfa) compared with daily rFSH results in1,2

– Similar pregnancy rates– Reduced injection frequency– Comparable OHSS rates

• A single injection of ELONVA may effectively replace daily rFSH for the first 7 days of COS1

• In the Engage Trial, 1/3 of patients required no additional rFSH3

• In the Trust Trial, there were no concerns for immunogenicity4

GnRH = gonadotropin-releasing hormone; rFSH = recombinant follicle-stimulating hormone; OHSS = ovarian hyperstimulation syndrome; COS = controlled ovarian stimulation. 1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.2. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76. 3. Fauser BC et al. Reprod Biomed Online. 2010;21:593–601.4. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.

Conclusion• ELONVA™ (corifollitropin alfa) in combination with a GnRH antagonist may

be an option for anticipated normal responders entering an IVF/ICSI program

GnRH = gonadotropin-releasing hormone; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; OI = ovulation induction; IUI = intrauterine insemination; rFSH = recombinant follicle-stimulating hormone.1. ELONVA™ (corifollitropin alfa) summary of product characteristics, 2010; 2. Borm G et al. Hum Reprod. 2000;15:1490–1498; 3. PUREGON® (rFSH) summary of product characteristics, 2010. 4. Devroey P et al. Hum Reprod. 2009;24:3063‒3072; 5. Arslan M et al. Fertil Steril. 2005;84:555‒569; 6. European and Middle East Orgalutran Study Group. Hum Reprod. 2001;16:644‒651.

IVF/ICSIResponder Status

Poor Normal High OI/IUI

GnRH1–4

antagonist

ELONVA ELONVArFSH

rFSH

rFSH rFSH

If needed from day 8

GnRH5,6

agonistrFSH rFSH rFSH

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.