1. ELONVA™ (corifollitropin alfa): KORAK DALJE U LIJEČENJU NEPLODNOSTI
WOMN /13
ELONVA™ (corifollitropin alfa): KORAK DALJE U LIJEČENJU NEPLODNOSTI
HRVOJE VRČIĆ, MD PhD
MEDICAL SCHOOL AND
UNIVERSITY HOSPITAL CENTER ZAGREB
This is the core slide deck for presentations on ELONVA™ (corifollitropin alfa).
It is designed to be a simple, ≈30-minute presentation to highlight the scientific and clinical rationale behind the development of ELONVA and the clinical data that support the next logical development in making controlled ovarian stimulation more patient-friendly.
Additional backup slides are available and can be added into this presentation to individualize the talk for different audiences or speaker preferences.

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
This outlines the “ideal” patient-centered approach to IVF and COS.
The ideal treatment reduces risks, reduces the treatment burden (which may reduce patient dropout rates), and ultimately improves cumulative live birth rates.
Anything that can move the field in this direction will be an improvement on the current paradigm.
COS = controlled ovarian stimulation; OHSS = ovarian hyperstimulation syndrome.
IVF = in vitro fertilization; COS = controlled ovarian stimulation.

3. The Growth of In Vitro Fertilization (IVF)1‒10
Total PubMed Hits for “IVF” in Title/Abstract by Year
These data can be used to illustrate how far we have come since the first IVF procedure in the late 1970s and show that the trend is increasing.
The figure on the left shows data reported by the European Society of Human Reproduction and Embryology from the European IVF-monitoring report that collected data from existing country registers.1-10
There were about 459,000 IVF cycles in
Data were collected from clinics in European countries. Data from 2006 include 3 more countries (Austria, Cyprus, and Latvia) and 1 fewer (Croatia) than the 2005 report.1
The proportion of reporting clinics rose to 86.0% (998 out of 1,160 clinics) in 2006, compared with 81.4% in 2005 (923 out of 1,134).1
Note: Total cycle numbers are a conservative low estimate, since registries are not complete, and actual numbers may be higher.1
The figure on the right shows the number of publications reported in the PubMed database with “IVF” in the title or abstract.
The clinical interest and research efforts in the field are steadily growing.
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.
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
infertile or subfertile women
in Dg/Th treatment of infertility
2000 IVF/1mil people
Birth rate >4% from ART
IVF/ICSI

5. 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
Increase market % 4%
18%
12%
-11% 2%
Total market share ART, gonadotrophins and %
EUR
Ukupno tržište
FSH
Udio FSH
83%
84%
85%
82%
79%
78%
80%
75%
Total market share of gonadotrophins eqivalent 75 IU
Units equiv. 75 i.j.
Total n of Amp (75i.j.)
73.919
78.928
95.507
90.376
87.415
24.227
23.036 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

6. 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
As the previous slide demonstrated, IVF is becoming commonplace. Along the way, there have been many advances in the field, including
Intracytoplasmic sperm injection (ICSI)
Development of GnRH antagonists
Preimplantation genetic diagnosis, comparative genomic hybridization
Single embryo transfer instead of multiple embryo transfer
Cryopreservation techniques
However, the one area that has been largely ignored is the impact of treatment on the patient.
Current treatments are burdensome and may cause stress and anxiety in patients.1
In a study of 384 patients undergoing IVF treatment, the incidence of dropout from IVF treatment with either a GnRH antagonist–based protocol or a GnRH agonist–based protocol was evaluated.2
Among the 384 couples undergoing IVF treatment, 17% dropped out.2
Sixty-five patients elected to discontinue treatment following stimulation. Fifty dropped out after the first or second cycle.2
The physical or psychological burden of treatment was the most frequent (28%) reason given for voluntarily discontinuing treatment.2
IVF = in vitro fertilization.
1. Hammarberg K et al. Hum Reprod. 2001;16:374‒ Huisman D et al. Reprod Biomed Online. 2009;19(suppl 2):5– Schröder AK et al. Reprod Biomed Online. 2004;8:600‒ Verberg MF et al. Hum Reprod. 2008;23:2050‒2055.
IVF = in vitro fertilization; GnRH = gonadotropin-releasing hormone.
1. Hammarberg K et al. Hum Reprod. 2001;16:374‒383.
2. Verberg MF et al. Hum Reprod. 2008;23:2050‒2055.

7. 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
As is seen here, the expected cumulative pregnancy rate (dark blue) is considerably higher than the real cumulative pregnancy rate (light blue).1
The difference in the rates (absolute difference of 31%) over 6 cycles illustrates the impact that patient dropout has on the cumulative pregnancy rate.1
Reduction of the dropout rate is one of the goals behind the development of the patient-centric approach to IVF treatment. 10
Dropout rate
ECPR
RCPR 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.
IVF = in vitro fertilization.
1. Schröder AK et al. Reprod Biomed Online. 2004;8:600‒606.

8. Today: Ovarian Stimulation Protocols Require Multiple Injections1,2
Long GnRH
agonist protocol1 1 2 3 4 5 6 7 8 9 10
GnRH
antagonist protocol2 1 2 3 4 5 6 7 8 9 10
Flare-up
Current treatments for COS are still complex.
The long GnRH agonist protocol involves treatment for several weeks before the start of stimulation and requires many injections.
The duration of analogue administration and FSH stimulation is significantly longer with a long GnRH agonist protocol than with a GnRH antagonist protocol (19 fewer GnRH analogue injections and 1 fewer stimulation injection).1
This was the conclusion of a systematic review and meta-analysis of RCTs that compared the probability of live birth with the use of GnRH analogues in IVF.1
In this analysis, 7 studies compared GnRH antagonist with long GnRH agonist protocols. The duration of stimulation was significantly shorter with the GnRH antagonist protocol (WMD, –19.48; 95% CI, –21.05 to –17.91). Fifteen studies looked at the duration of FSH stimulation, which was also significantly shorter in the GnRH antagonist group (WMD, –1.13; -95% CI, –1.83 to –0.44).1
The GnRH antagonist protocol (developed in the early 2000s) has reduced the impact of COS on patient treatment burden by reducing the required number of injections, but the protocol still involves daily gonadotropin for follicular development.
Pituitary downregulation
Luteinizing Hormone
Direct gonadotropin
suppression
Time
GnRH = gonadotropin-releasing hormone.
1. Adapted with permission from de Greef R et al. Clin Pharmacol Ther. 2010;88:79‒ Adapted with permission from Hodgen GD. Contemp Rev Obstet Gynaecol. 1990;35:10‒24.
COS = controlled ovarian stimulation; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; RCT = randomized controlled trial; IVF = in vitro fertilization; WMD = weighted mean difference.
1. Kolibianakis EM et al. Hum Reprod Update. 2006;12:651–671.

9. ELONVA™ (corifollitropin alfa) May Reduce the Number of Necessary Injections1,2
rFSH
hCG 1 2 3 4 5 6 7 8 9 10
GnRH
antagonist
Corifollitropin alfa is a novel fertility hormone and belongs to a new class of recombinant gonadotropins: sustained follicle stimulants1
One injection of ELONVA™ (corifollitropin alfa) may replace the first 7 daily injections of rFSH during COS.2
The number of injections is reduced by 26 compared with the long agonist protocol (19 analogue injections and 1 stimulation injection in antagonist protocol, 6 fewer injections with ELONVA vs daily rFSH).3
The numbers on analogue and stimulation injections were drawn from a systematic review and meta-analysis of RCTs that compared the probability of live birth with the use of GnRH analogues in IVF.3
In this analysis, 7 studies compared GnRH antagonist with long GnRH agonist protocols. The duration of stimulation was significantly shorter with the GnRH antagonist protocol (WMD, –19.48; 95% CI, –21.05 to –17.91). Fifteen studies looked at the duration of FSH stimulation, which was also significantly shorter in the GnRH antagonist group (WMD, –1.13; -95% CI, –1.83 to –0.44).3
Additional daily rFSH after day 7 is to be determined by physician assessment.2
So what exactly is ELONVA? Let’s take a look at the molecular makeup of corifollitropin alfa on the next slide to see how it can perform as a sustained follicle stimulant.
Luteinizing Hormone
Direct gonadotropin
suppression
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‒ Adapted with permission from Hodgen GD. Contemp Rev Obstet Gynaecol. 1990;35:10‒24.
Time
COS = controlled ovarian stimulation; rFSH = recombinant follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; RCT = randomized controlled trial; IVF = in vitro fertilization; WMD = weighted mean difference.
1. Corifollitropin alfa Dose-finding Study Group. Hum Reprod. 2008;23:2484–2492;
2. ELONVA™ (corifollitropin alfa) summary of product characteristics. MSD Oss B.V., a subsidiary of Merck & Co., Inc.; Kolibianakis EM et al. Hum Reprod Update. 2006;12:651–671.

10. Corifollitropin Alfa Is a Recombinant Hormone
-Subunits1
β-Subunits2
Human FSH
92 aa
110 aa
t½ rFSH ≈ 40 h3
hCG
92 aa
145 aa
Corifollitropin alfa is a recombinant glycoprotein that was created from the fusion of the β-subunit of FSH with a part of the β-subunit of hCG called the carboxy-terminal peptide.1
The gonadotropic hormones include thyroid-stimulating hormone, FSH, LH, and hCG.
All of these glycoprotein hormones consist of 2 linked protein chains, which are called α- and β-subunits. They all have an identical α-subunit, which is 92 amino acids long, but each has a unique β-subunit. The number of amino acids in the β-subunit varies between the hormones, and the β-subunit is therefore responsible for the specific biologic action of each hormone.1
The corifollitropin alfa molecule consists of
The α-subunit, which is identical for all gonadotropins, and1
A hybrid β-subunit created through the fusion of the β-subunit of human FSH with the carboxy-terminal peptide of the β-subunit of hCG.1
The carboxy-terminal peptide is the last 29 amino acids of the β-subunit of the hCG molecule; it is not found on other gonadotropins,1 and it has a significant impact on the biologic activity of corifollitropin alfa (increases the half-life of the molecule from ≈40 hours to 69 hours).2,3
These are the molecular details; the clinical details are next (what you will see when it is used in your clinic/patients).
Corifollitropin alfa
92 aa
110 aa
29 aa2
t½ corifollitropin alfa = 69 h4
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.
FSH = follicle-stimulating hormone; LH = luteinizing hormone; hCG = human chorionic gonadotropin.
1. Fares FA et al. Proc Natl Acad Sci U S A. 1992;89:4304– PUREGON® (rFSH) summary of product characteristics. MSD Oss B.V., a subsidiary of Merck & Co., Inc.; ELONVA™ (corifollitropin alfa) summary of product characteristics. MSD Oss B.V., a subsidiary of Merck & Co., Inc.; 2012.

11. 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
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
List of excipients in ELONVA™ (corifollitropin alfa)1
Sodium citrate
Sucrose
Polysorbate 20
Methionine
Sodium hydroxide (for pH adjustment)
Hydrochloric acid (for pH adjustment)
Water for injections
Passive safety system means that you do not need to take/do any additional action when using the device to activate it (at the end of a full stroke/injection).1
Special precautions for storage1
Store in a refrigerator (2°–8°C). For convenience, the patient is allowed to store the product at or below 25°C for a period of not more than 1 month.
Do not freeze.
Keep the syringe in the outer carton in order to protect it from light.
1. ELONVA™ (corifollitropin alfa) summary of product characteristics, 2010.
1. ELONVA™ (corifollitropin alfa) summary of product characteristics. MSD Oss B.V., a subsidiary of Merck & Co., Inc.; 2012.

12. Comparative Pharmacokinetics
Corifollitropin alfa
rFSH
t½ corifollitropin alfa = 69 h
Tmax = 36–48 h2
FSH Activity1
Therapeutic threshold
As mentioned earlier, the elimination half-life of corifollitropin alfa is longer than the elimination half-life of rFSH.1
The time to reach maximum serum concentration is 2 to 3 times longer for corifollitropin alfa; it is reached within approximately half a day for each rFSH injection (but the serum concentration accumulates over 3–5 days to reach steady-state levels).2,3
A single subcutaneous injection of ELONVA™ (corifollitropin alfa) is able to initiate and sustain multiple follicular development for an entire week. This is depicted by the blue curve, which shows FSH activity above the necessary threshold level.3
Corifollitropin alfa is still detectable 24 hours after injection.4
Two different doses were tested and developed: 100 µg in patients weighing ≤60 kg and 150 µg in patients weighing >60 kg.5
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.
rFSH = recombinant follicle-stimulating hormone.
1. Devroey P et al. J Clin Endocrinol Metab. 2004;89:2062‒ Duijkers IJ et al. Hum Reprod. 2002;17:1987‒ Fauser BC et al. Hum Reprod Update. 2009;15:309– Fares FA et al. Proc Natl Acad Sci U S A. 1992;89:4304–4308.
5. ELONVA™ (corifollitropin alfa) summary of product characteristics. MSD Oss B.V., a subsidiary of Merck & Co., Inc.; 2012.

13. 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
Total Drug Exposure (AUC)
1500
100 µg
150 µg
1000
AUC , h•ng/mL
500
A single injection of ELONVA™ (corifollitropin alfa) administered at body-weight–appropriate doses results in comparable corifollitropin alfa exposure.1
The total drug exposure (AUC) is similar with both the 150- and 100-µg doses.
The optimal dose is based on the 1-week interval that a single injection needs to support follicular growth.2
Using data from the earlier studies, pharmacokinetic and pharmacodynamic models and simulations were developed to predict the optimal dose of ELONVA in a 1-week controlled ovarian stimulation regimen.1,2
Optimal doses selected for prospective phase 3 clinical trials1,2:
100 µg for patients with a body weight ≤60 kg
150 µg for patients with a body weight >60 kg
The recommended doses of ELONVA, ie, 100 µg for patients weighing ≤60 kg and 150 μg for patients weighing >60 kg, were expected to result in1,2:
Similar exposure for both body-weight groups
Similar ovarian response for both groups
Low cancellation rate (<10%)2
This was confirmed in the Ensure and Engage trials (see following slides).1
Similar ovarian response for both groups (number of oocytes, 13.3 vs 13.7 in the Ensure and Engage trials, respectively)
≤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.
AUC = area under the curve.
1. Ledger WL et al. Reprod Biomed Online. 2011;23:150‒ de Greef R et al. Clin Pharmacol Ther. 2010;88:79‒87.

14. 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 RCT
1 cycle
Patients (n)
1,506
396
Primary end point Coprimary end point
Ongoing PR/cycle
Number of oocytes retrieved
Safety evaluations
AEs/SAEs, including OHSS
Local tolerance
Anti–corifollitropin alfa antibodies
Sites
Europe 20, North America 14
Europe 14, Asia 5
The Engage and Ensure trials are the 2 pivotal clinical trials in which the 2 different doses of ELONVA™ (corifollitropin alfa) were tested in 2 patient populations with different body weights but otherwise comparable demographics.
Let’s focus on the Engage trial, the larger trial that was powered for the co-primary end points of ongoing pregnancy rate and number of oocytes retrieved.1
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‒ Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

15. Engage Trial: Treatment Regimen1
ELONVA ™
(corifollitropin alfa)
(150 µg) (n=756)
Placebo
ELONVA
(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)
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 dose ≤200 IU)
IVF or
ICSI
Luteal
phase
support
The Engage trial design1
Phase 3 (pivotal efficacy and safety trial)
Active-controlled (vs daily rFSH), noninferiority
Double-blind, double-dummy
Randomization in a 1:1 ratio per center and stratified by age (<32 vs ≥32 years)
Planned number of patients: 1,400
Multicenter (34 sites: 20 in Europe, 14 in North America)
This slide depicts the treatment regimen used in the Engage trial.
Patients were randomized to receive1:
A single 0.5-mL injection of ELONVA™ (corifollitropin alfa) (150 µg) on cycle day 2 or 3 (stimulation day 1) and daily rFSH placebo injections (equivalent to 200 IU) for 7 days, or
An injection of placebo ELONVA (0.5 mL) on cycle day 2 or 3 and daily rFSH (200 IU/d) for 7 days
Daily rFSH was administered only when required in the opinion of the investigator, and a reduced dose of rFSH could be administered from stimulation day 6 onwards if a high response was observed.
Both groups received daily GnRH antagonist (GANIRELIX® 0.25 mg/d) from stimulation day 5 through the day of hCG.1
Both groups received daily rFSH (≤200 IU) from stimulation day 8 through the day of hCG.1
On the day that 3 follicles were ≥17 mm (or the day thereafter), final oocyte maturation was induced with hCG (10,000 or 5,000 IU), and oocytes were collected.1
Patients underwent IVF or ICSI.1
Luteal phase support was micronized progesterone (≥600 mg/d vaginally or ≥50 mg/d intramuscularly).1
Initiated on the day of oocyte collection and continued for at least 6 weeks or until either menses or negative pregnancy test performed at least 14 days after embryo transfer
Primary end point : Ongoing pregnancy rate
Preset noninferiority margin: the lower limit of the 2-sided confidence interval of the difference is -8%
Coprimary end point: Number of oocytes retrieved
Preset margins: the lower and upper limits of the 2-sided confidence interval of the difference are -3 and +5 oocytes, respectively
Safety evaluations: AEs/SAEs, including OHSS, local tolerance, anti–corifollitropin alfa antibodies.
Please note: Efficacy analyses were based on the intention-to-treat (ITT) population. Both ITT and per-protocol analyses were performed, but as the results were very similar, only the ITT results were presented in the study.
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.
COS = controlled ovarian stimulation; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; hCG = human chorionic gonadotropin.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

16. Main Inclusion and Exclusion Criteria1
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
Main inclusion criteria1
Females of couples with an indication for controlled ovarian stimulation and IVF/ICSI and a normal menstrual cycle length (24–35 days)
≥18 and ≤36 years of age
Body weight >60 and ≤90 kg, and body mass index ≥18 and ≤32 kg/m2
Main exclusion criteria1
History of or any current (treated) endocrine abnormality
History of ovarian hyperresponse or OHSS (modified World Health Organization criteria)
History of or current polycystic ovarian syndrome (Rotterdam criteria)
More than 20 basal antral follicles <11 mm (both ovaries combined)
History of low or no ovarian response to FSH/human menopausal gonadotropin treatment
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.
IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; FSH = follicle-stimulating hormone; OHSS = ovarian hyperstimulation syndrome.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

17. Demographics at Screening1
Engage
Demographics at Screening1
ITT Group
ELONVA™ (corifollitropin alfa)
150 µg
(n=756)
rFSH
200 IU/d
(n=750)
Age, years
Mean (SD)
31.5 (3.3)
31.5 (3.2)
Body weight, kg
68.8 (7.6)
68.4 (7.3)
BMI, kg/m2
24.8 (2.8)
24.8 (2.7)
Race, %
Asian
Black
Caucasian
Other
2.8
4.4
85.1
7.8
3.7
86.7
6.8
This slide shows that the demographics of the ITT groups at screening were similar between treatments.
Mean age for both groups was 31.5 years.1
Mean body weight1
ELONVA™ (corifollitropin alfa): 68.8 kg
Daily rFSH: 68.4 kg
Mean BMI1
ELONVA: 24.8 kg/m2
Daily rFSH: 24.8 kg/m2
Distribution of races was comparable between groups; the majority of subjects in the trial were Caucasian.1
Please note: Efficacy analyses were based on the intention-to-treat (ITT) population. Both ITT and per-protocol analyses were performed, but as the results were very similar, only the ITT results were presented in the study.
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.
ITT = intent to treat; rFSH = recombinant follicle-stimulating hormone; BMI = body mass index.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

18. Primary End Point: Ongoing Pregnancy Rate1
Engage
Primary End Point: Ongoing Pregnancy Rate1
Ongoing pregnancy rates were comparable between ELONVA™ (corifollitropin alfa) and rFSH
Patients, %a
ITT Group
This slide shows the ongoing pregnancy outcome per started cycle (as a percentage of patients).
For all of the measured end points, rates were comparable between ELONVA™ (corifollitropin alfa) and daily rFSH.1
Ongoing pregnancy rate is 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.1
Estimated difference ELONVA vs rFSH: 0.9% (95% confidence interval, -3.9–5.7).1
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.
rFSH = recombinant follicle-stimulating hormone.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

19. Engage
Results: Single vs Double Embryo Transfer— Ongoing Pregnancy Rates per Started Cycle1
Comparable ongoing pregnancy rates for SET vs DET
Ongoing Pregnancy Rate, %
ELONVA™ (corifollitropin alfa)
150 μg
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)
This slide shows the ongoing pregnancy rates in patients who received SET vs DET. As expected, the rates were higher in the DET group compared with the SET group. In both groups, the ELONVA™ (corifollitropin alfa) arm had a slightly higher numerical ongoing pregnancy rate.1
The ongoing pregnancy rates in each subgroup were similar for ELONVA and rFSH, and there was no significant interaction for the number of embryos transferred (1 or 2).1
SET = single embryo transfer; DET = double embryo transfer; rFSH = recombinant follicle-stimulating hormone.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.
SET = single embryo transfer; DET = double embryo transfer; rFSH = recombinant follicle-stimulating hormone.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

20. 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
Ongoing Pregnancy Rate, %
ELONVA™ (corifollitropin alfa)
150 μg
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)
This slide shows the ongoing pregnancy rate in patients who had embryos transferred on day 3 vs day 5.1
A borderline significant interaction with the type of treatment was observed for the day of transfer (P=0.045) as a result of higher pregnancy rates for day 3 transfers with ELONVA™ (corifollitropin alfa) (for day 5 transfers, the rFSH group showed marginally higher pregnancy rates).1
ET = embryo transfer; rFSH = recombinant follicle-stimulating hormone. 1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.
rFSH = recombinant follicle-stimulating hormone.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

21. Co-primary End Point: Number of Oocytes Retrieved1
Engage
Co-primary End Point: Number of Oocytes Retrieved1
ELONVA™ (corifollitropin alfa)
150 µg
(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)
1.2a (0.5–1.9)
Mean percentage of MII oocytes
78.9
77.4
Quality of oocytes, by percentage of MII oocytes, was comparable between treatments
This table shows that the mean number of oocytes retrieved was significantly higher (P=0.001) in ELONVA™ (corifollitropin alfa)–treated patients compared with patients who received rFSH over the entire controlled ovarian stimulation period.1
The estimated difference between treatments (using a 95% confidence interval) was 1.2 (0.5–1.9) oocytes more in the ELONVA treatment group.1
Equivalence margins for the difference in the number of oocytes retrieved were predefined to be -3 and +5 oocytes.1
The quality of oocytes, as indicated by the percentage of MII oocytes, was comparable between treatments.1
The mean percentage of MII oocytes for the ELONVA treatment group was 78.9%; for the rFSH treatment group it was 77.4%.
a P= 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.
rFSH = recombinant follicle-stimulating hormone; MII = metaphase II.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

22. 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
This slide shows the mean fertilization rate, the mean number of 2PN fertilized oocytes obtained on day 3, and the mean number of good-quality embryos, restricted to patients with IVF and/or ICSI.1
Each of these outcomes were comparable between the ELONVA™ (corifollitropin alfa) and daily recombinant FSH groups. The fertilization rate slightly favored rFSH, while the number of 2PN fertilized oocytes on day 3 slightly favored ELONVA.1
A total of 413 patients in the ELONVA treatment group and 417 patients in the rFSH treatment group received ICSI.1
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.
PN = pronuclear; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; rFSH = recombinant follicle-stimulating hormone.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

23. Clinical Outcome per Started Cycle1
Engage
Clinical Outcome per Started Cycle1
ITT Group
ELONVA™ (corifollitropin alfa)
150 µg
(n=756)
rFSH
200 IU/d
(n=750)
No. of embryos transferred, mean (SD)
1.7
Positive hCG, %
48.1
46.9
This table presents positive hCG outcome per started cycle (as a percentage of patients).1
For all of the measured end points, rates were comparable between ELONVA™ (corifollitropin alfa) and daily rFSH.1
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.
rFSH = recombinant follicle-stimulating hormone; hCG = human chorionic gonadotropin.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

24. Implantation Rate (Mean %) per Started Cycle1
Engage
Implantation Rate (Mean %) per Started Cycle1
Implantation rates were comparable between ELONVA™ (corifollitropin alfa) and rFSH
ITT Group
Patients, % (SD)
36.2
This slide shows the implantation rate per started cycle (as a percentage of patients).1
Implantation rate is defined as 100 times the maximum number of gestational sacs, as assessed by any ultrasound scan after embryo transfer, divided by the number of embryos transferred (per patient), maximized to 100%.1
For all of the measured end points, rates were comparable between ELONVA™ (corifollitropin alfa) and daily rFSH.1
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.
rFSH = recombinant follicle-stimulating hormone.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

25. Day of IVF Cycle When hCG Criterion Was Met1
Engage
Day of IVF Cycle When hCG Criterion Was Met1 ™
Patients, %
This graph shows the distribution of the percentage of patients meeting the hCG criterion of at least 3 follicles ≥17 mm by stimulation day.
The criterion for hCG was reached at or before stimulation day 8 in 33% of patients treated with ELONVA™ (corifollitropin alfa).1
This was following the single injection of ELONVA; no daily rFSH was needed in these patients.
Median duration of stimulation (days), from stimulation day 1 up to and including day of hCG for both groups = 9 days.2
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.
hCG = human chorionic gonadotropin; rFSH = recombinant follicle-stimulating hormone.
1. Fauser BC et al. Reprod Biomed Online. 2010;21:593‒601.
2. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

26. Number and Size of Follicles During Stimulation1
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 14
Day 8 6 12 2 3 10 3 4
Mean Number of Follicles 3 8 3 8 6
Day 5 6 6 5 4
The number of follicles ≥11 mm was similar between the 2 treatments.1
Both groups had an increase in the number of follicles of this size over the course of controlled ovarian stimulation.
A slightly greater (but nonsignificant) number of follicles ≥11 mm was seen in ELONVA™ (corifollitropin alfa)–treated subjects on day 8 of stimulation and on the day of hCG compared with the rFSH group.1
This graph depicts the number and size distribution of follicles on stimulation day 5 and day 8 (all patients in the all-subjects-treated group) as well as on the day of hCG (among patients who received hCG).1
These groups were comparable, although the mean numbers were higher in the ELONVA group on the day of hCG. 2
ELONVA™ (corifollitropin alfa)
Daily
rFSH
ELONVA
Daily
rFSH
ELONVA
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.
rFSH = recombinant FSH; hCG = human chorionic gonadotropin.
1. Fauser BC et al. Reprod Biomed Online. 2010;21:593‒601.

27. Serum Estradiol (E2) Levels1
Engage
Serum Estradiol (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
Estradiol (E2) measurements between groups were comparable.1
If you currently monitor E2, there should be no difference between patients treated with ELONVA™ (corifollitropin alfa) and rFSH.
If you do not currently monitor, there is no need to change your practice. 5 8
hCG
Stimulation Days
E2 = estradiol; rFSH = recombinant follicle-stimulating hormone.
1. Fauser BC et al. Reprod Biomed Online. 2010;21:593‒601.
rFSH = recombinant follicle-stimulating hormone.
1. Fauser BC et al. Reprod Biomed Online. 2010;21:593‒601.

28. Engage
Live Birth Rate1
Live birth rates were comparable between ELONVA™ (corifollitropin alfa) and rFSH
Patients, %a
ITT Group
Study design1
Prospective pregnancy follow-up study to the phase 3, double-blind, multicenter, randomized controlled Engage trial
Objective: To compare live birth rates and cumulative ongoing pregnancy rates after one treatment cycle with ELONVA™ (corifollitropin alfa) or rFSH
Patients who became pregnant after fresh ET in the Engage trial
Primary efficacy end point: live birth rate after fresh ET after a single treatment cycle
Patients who did not become pregnant after fresh ET in the Engage trial, but who had at least 1 cryopreserved embryo used in a subsequent FTET cycle
Primary efficacy end point: cumulative ongoing pregnancy rate after 1 or more FTET cycles
The live-birth rates in the intent-to-treat population were 35.6% for the ELONVA™ (corifollitropin alfa) group and 34.4% in the rFSH group.1
ELONVA group: 269 out of 756 patients had at least 1 liveborn infant
rFSH group: 258 out of 750 patients had at least 1 liveborn infant
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.
rFSH = recombinant follicle-stimulating hormone.
1. Boostanfar R et al. Fertil Steril. 2012;97:1351–1358.

29. 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
When frozen-thawed embryo transfers are included, one can see that from a single controlled ovarian stimulation cycle, the cumulative pregnancy rate is nearly 50% in the ELONVA™ (corifollitropin alfa) arm.1
There were 168 patients in the ELONVA arm and 176 in the rFSH arm with embryos cryopreserved.1
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. Fertil Steril. 2012;97:1351–1358.
rFSH = recombinant follicle-stimulating hormone.
1. Boostanfar R et al. Fertil Steril. 2012;97:1351–1358.

30. Association Between Endogenous LH and Pregnancy Outcomes
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
This retrospective investigation evaluated the impact of endogenous LH levels on ongoing pregnancy rate as part of the Engage trial.1
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 ;23:449– Devroey P et al. Hum Reprod. 2009;24:3063–3072.
LH = luteinizing hormone.
1. Doody KJ et al. Reprod Biomed Online ;23:449–456. .

31. Serum LH Measurements1 LH measured on stimulation days 1, 5, and 8
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
LH was measured by a central laboratory on stimulation days 1, 5, and 8. It is important to recognize that these results were not made available to physician investigators. Therefore, stimulations were not modified in response to these values. Patients were grouped by LH levels into 3 categories: the lowest quartile (P<25), the highest quartile (P>75), and the middle half (P25–P75). A comparison of ongoing pregnancy rates was made by category.1
DELFIA = dissociation-enhanced lanthanide fluorescent immunoassay; LH = luteinizing hormone; P = progesterone.
1. Doody KJ et al. Reprod Biomed Online ;23:449–456.
LH = luteinizing hormone; P = progesterone.
1. Doody KJ et al. Reprod Biomed Online ;23:449–456.

32. ELONVA™ (corifollitropin alfa) Ongoing Pregnancy Rate, %
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
35.6
35.5
36.8
Ongoing pregnancy rates per started cycle varied little across the 3 groups of serum LH on day 8.1
N = 216a
N =
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.
LH = luteinizing hormone.
1. Doody KJ et al. Reprod Biomed Online ;23:449–456.

33. ELONVA™ (corifollitropin alfa) Ongoing Pregnancy Rate, %
Engage
Comparable Ongoing Pregnancy Rates per Started Cycle Regardless of Serum LH on Day of hCG1
ELONVA™ (corifollitropin alfa)
rFSH
Ongoing Pregnancy Rate, %
41.0
42.9
42.5
36.1
36.0
37.5
Ongoing pregnancy rates per started cycle varied little across the 3 groups of serum LH on the day of hCG.1
N = 208a
N =
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.
LH = luteinizing hormone; hCG = human chorionic gonadotropin.
1. Doody KJ et al. Reprod Biomed Online ;23:449–456.

34. 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
Endogenous LH concentrations of patients treated with a standardized GnRH antagonist protocol do not impact success rates.1
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 In press. 2. Doody K et al. Reprod Biomed Online. 2010;20:565‒567.
LH = luteinizing hormone; GnRH = gonadotropin-releasing hormone.
1. Doody KJ et al. Reprod Biomed Online ;23:449–456.

35. Subjects with SAEs, AEs, and OHSS1
Engage
Subjects with SAEs, AEs, and OHSS1
SAEs were similar with ELONVA vs 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)
1.2 (9)
AEs, Procedural Pain
Pregnancy-related Events
Pelvic Pain
Pelvic Discomfort
Headache
22.3
13.8
12.1
11.5
10.5
20.1
11.2
12.3
11.6
15.2
OHSS, overall
OHSS, moderate/severe
7.0 (53)
4.1 (31)
6.3 (47)
2.7 (20)
The rates of SAEs reported for the 2 groups were equal. The most frequently reported SAEs were OHSS [14 patients (1.9%) treated with corifollitropin alfa and 9 patients (1.2%) treated with rFSH] and ruptured ectopic pregnancy.1
The majority of cases of OHSS were mild in both groups.1
Although the incidence of OHSS may be slightly increased with ELONVA™ (corifollitropin alfa), the range is within those of current care using various GnRH analogue regimens.
Overall, results from Engage show that ELONVA results in outcomes comparable with daily rFSH but has the advantage of a single injection, replacing the 7 daily injections of rFSH.
Pelvic discomfort and pelvic pain were frequently reported AEs, but the rates were comparable.
The incidences of pelvic discomfort and pelvic pain that were considered drug-related were also comparable.
Let’s now look at the other, smaller trial: Ensure.
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.
SAE = serious adverse event; OHSS = ovarian hyperstimulation syndrome; GnRH = gonadotropin-releasing hormone; rFSH = recombinant follicle-stimulating hormone; AE = adverse event.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

36. 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 RCT
1 cycle
Patients (n)
1,506
396
Primary end point Coprimary end point
Ongoing PR/cycle
Number of oocytes retrieved
Safety evaluations
AEs/SAEs, including OHSS
Local tolerance
Anti–corifollitropin alfa antibodies
Sites
Europe 20, North America 14
Europe 14, Asia 5
The Engage and Ensure trials are the 2 pivotal clinical trials in which the 2 different doses of ELONVA™ (corifollitropin alfa) were tested in 2 patient populations with different body weights but otherwise comparable demographics.
Let’s focus on the Engage trial, the larger trial that was powered for the co-primary end points of ongoing pregnancy rate and number of oocytes retrieved.1
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‒ Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.

37. Ensure Trial: Treatment Regimen1
ELONVA™
(corifollitropin alfa)
(100 µg) (n=268)
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)
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 dose ≤200 IU)
IVF or
ICSI
Luteal
phase
support
The Ensure trial design1
Phase 3 (pivotal efficacy and safety trial)
Active-controlled (vs daily rFSH), equivalence
Double-blind, double-dummy
Randomization in a 2:1 ratio by center and stratification by age (<32 vs ≥32 years)
Planned number of subjects: ≥440 at 19 sites (14 in Europe, 5 in Asia)
This slide depicts the treatment regimen used in the Ensure trial.1
Patients were randomized to receive1:
A single 0.5-mL injection of ELONVA™ (corifollitropin alfa) (100 µg) on cycle day 2 or 3 (stimulation day 1) and daily rFSH placebo injections (equivalent to 150 IU) for 7 days, or
An injection of placebo ELONVA (0.5 mL) on cycle day 2 or 3 and daily rFSH (150 IU per day) for 7 days.
Daily rFSH was administered only when required in the opinion of the investigator, and a reduced or increased dose of rFSH could be administered from stimulation day 6 onwards if a high response was observed.
Both groups received daily GnRH antagonist (GANIRELIX® 0.25 mg/d) from stimulation day 5 through the day of hCG.1
Both groups received daily rFSH (≤200 IU) from stimulation day 8 through the day of hCG.1
On the day that 3 follicles were ≥17 mm (or the day thereafter), final oocyte maturation was induced with hCG (10,000 or 5,000 IU), and oocytes were collected.1
Patients underwent IVF or ICSI.1
Luteal phase support was given in the form of micronized progesterone (≥600 mg/d vaginally or ≥50 mg/d intramuscularly).1
Initiated on the day of oocyte collection and continued for at least 6 weeks or until either menses or negative pregnancy test performed at least 14 days after embryo transfer
Safety evaluations: AEs/SAEs including OHSS, local tolerance, anti–corifollitropin alfa antibodies
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.
COS = controlled ovarian stimulation; rFSH = recombinant follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; hCG = human chorionic gonadotropin.
1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

38. Main Inclusion and Exclusion Criteria1
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
This trial is similar to the Engage trial, with enrolled patient body weight the only main difference between the trials. In addition to European sites, this trial also included Asian clinics, rather than North American clinics like in the Engage trial.1
Main inclusion criteria1
Females of couples with an indication for COS and IVF/ICSI and a normal menstrual cycle length (24–35 days)
≥18 and ≤36 years of age at time of signing informed consent form
Body weight ≤60 kg, and body mass index ≥18 and ≤32 kg/m2
Main exclusion criteria1
History of or any current (treated) endocrine abnormality
History of ovarian hyperresponse or ovarian hyperstimulation syndrome (modified World Health Organization criteria)
History of or current polycystic ovary syndrome (Rotterdam criteria)
More than 20 basal antral follicles <11 mm (both ovaries combined)
History of low or no ovarian response to FSH/human menopausal gonadotropin treatment
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.
COS = controlled ovarian stimulation; FSH = follicle-stimulating hormone; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection.
1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

39. Key Patient Characteristics at Screening1
Ensure
Key Patient Characteristics at Screening1
ELONVA™ (corifollitropin alfa)
100 μg
(n=268)
rFSH 150 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)
This slide shows that the demographics of the intent-to-treat groups at screening were similar between treatments.1
Distribution of races was comparable between groups; the majority of patients in the trial were Caucasian or Asian.1
rFSH = recombinant follicle-stimulating hormone; SD = standard deviation.
1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.
1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

40. Primary End Point: Number of Oocytes Retrieved1
Ensure
Primary End Point: Number of Oocytes Retrieved1
ELONVA™
(corifollitropin alfa)
100 μg
(n=268)
rFSH 150 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
The primary objective was to show that the ELONVA™ (corifollitropin alfa) regimen, in terms of the number of cumulus-oocyte complexes retrieved, was equivalent to the reference treatment (predefined equivalence range: -3 to +5 oocytes).1
This table shows that the mean number of oocytes retrieved was significantly higher (P<0.001) in patients treated with ELONVA compared with the patients who received rFSH.1
The estimated difference between treatments (using a 95% confidence interval) was 2.5 oocytes more in the ELONVA treatment group.1
The percentage of MII oocytes was comparable between treatments, indicating that the quality of the oocytes retrieved was similar.1
The mean percentage of MII oocytes for the ELONVA treatment group was 82.5%; for the rFSH treatment group, it was 79.1%.
A total of 137 patients in the ELONVA treatment group and 72 patients in the rFSH treatment group received ICSI.1
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.
rFSH = recombinant follicle-stimulating hormone; ICSI = intracytoplasmic sperm injection.
1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

41. Serum E2 levels were comparable between ELONVA and rFSH
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
As in the Engage trial, the E2 measurements were comparable between groups.1
If you currently monitor E2, there should be no difference between patients treated with ELONVA™ (corifollitropin alfa) and rFSH.
If you do not currently monitor, there is no need to change your practice. 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.
E2 = estradiol; rFSH = recombinant follicle-stimulating hormone.
1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

42. Serum LH Levels in Patients With hCG Injection1
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
At the start of stimulation, the median serum LH levels were 4.5 IU/L and 4.1 IU/L for the ELONVA™ (corifollitropin alfa) and rFSH treatment groups, respectively.1
On day 3, median serum LH levels had rapidly declined for both groups. From day 3 to day 5, the median serum LH levels increased in the ELONVA group, while the levels remained similar in the rFSH group.1
From day 5 to day 8, the median LH levels decreased again in the ELONVA group, whereas the median LH values in the rFSH group did not change until day 8.1
At the day of embryo transfer, the median LH levels were similar for the 2 treatment groups.1 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.
LH = luteinizing hormone; rFSH = recombinant follicle-stimulating hormone.
1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

43. Implantation Rate (Mean %) per started Cycle1
Ensure
Implantation Rate (Mean %) per started Cycle1
Implantation rates were comparable between ELONVA and rFSH
ITT Group
Patients, % (SD)
This slide shows the implantation rate per started cycle (as a mean percentage of patients).
Implantation rate was defined as 100 times the maximum number of gestational sacs, as assessed by any ultrasound scan after embryo transfer, divided by the number of embryos transferred (per patient), maximized to 100%.1
For all of the measured end points, rates were comparable between ELONVA™ (corifollitropin alfa) and daily rFSH.1
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.
rFSH = recombinant follicle-stimulating hormone.
1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

44. Ongoing Pregnancy Rate per Started Cycle1
Ensure
Ongoing Pregnancy Rate per Started Cycle1
ITT Group
Patients, %
34.4
This slide shows the ongoing pregnancy rates per started cycle (as a percentage of patients).
Ongoing pregnancy: vital fetus at least 10 weeks after embryo transfer or live birth
For all of the measured end points, rates were comparable between ELONVA™ (corifollitropin alfa) and daily rFSH.1
This study was not powered to measure the difference in pregnancy rates.1
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.
rFSH = recombinant follicle-stimulating hormone.
1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

45. Ensure: Percentage of Patients With AEs/SAEs1
AST Group
ELONVA™ (corifollitropin alfa)
100 μg (n=268)
rFSH 150 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, %
OHSS, %
Moderate or severe OHSS, %
6.7
3.4
4.7
1.6
SAEs occurred in 7.5% of patients in the ELONVA™ (corifollitropin alfa) group and 6.2% of patients in the rFSH group.1
Discontinuation due to AEs or SAEs did not occur in the ELONVA group or in the rFSH group.1
The most frequently reported SAE was ectopic pregnancy (3.0% with ELONVA vs 3.1% with rFSH)
The most frequently reported AEs in the ELONVA and rFSH groups, respectively, were pelvic discomfort (10.1% vs 14.7%), pelvic pain (10.4% vs 10.9%), antepartum hemorrhage (6.0% vs 12.4%) and headache (8.2% vs 8.5%)
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.
SAE = serious adverse event; rFSH = recombinant follicle-stimulating hormone; AE = adverse event; OHSS = ovarian hyperstimulation syndrome.
1. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒76.

46. 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
The Trust trial was a phase 3, multicenter, uncontrolled trial in patients >60 kg who underwent up to 3 cycles of COS for IVF or ICSI with ELONVA™ (corifollitropin alfa) 150 µg.1
The primary outcomes were the formation of antibodies against corifollitropin alfa, hypersensitivity reactions, local tolerance, and occurrence of serious adverse events (including ovarian hyperstimulation syndrome).1
Clinical outcomes were recorded, but were not a primary end point.1
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.
COS = controlled ovarian stimulation; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection.
1. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.

47. Trust: Treatment for up to 3 Cycles1
ELONVA™ (corifollitropin alfa) 150 µg
hCG
7 days
FSH daily ≤225 IU
GnRH antagonist (0.25 mg/d)
day 5 or 6 through day of hCG
IVF
ICSI
Oocyte retrieval ET
(max 3)
Luteal phase support (vaginal P)
This slide depicts the treatment regimen used in the Trust trial.1
All subjects started their controlled ovarian stimulation cycle on cycle day 2 or 3 with ELONVA™ (corifollitropin alfa)150 µg. Daily FSH or menotropins were started on stimulation day 8. The maximum FSH dose was 225 IU/day, but could be reduced as appropriate.1
GnRH antagonist treatment with GANIRELIX® or cetrorelix, 0.25 mg/d, was started on cycle day 5 or 6 and continued up to and including the day of hCG.1
A maximum of 3 embryos could be transferred 3 or 5 days after oocyte retrieval. Progesterone, ≥600 mg/d vaginally, was started on the day of oocyte retrieval for luteal phase support.1
Cycle day 2–3 =
stimulation day 1
Stimulation
day 5 or 6
Stimulation
day 8
hCG as soon as 3 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.
rFSH = recombinant follicle-stimulating hormone; hCG = human chorionic gonadotropin.
1. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.

48. Immunogenicity Testing in Exposed Patients1
Trust
Immunogenicity Testing in Exposed Patients1
Number of Subjects Treated With ELONVA™ (corifollitropin alfa)
Number of Subjects Tested for Antibodies
Observed Clinically Relevant Immunogenicity Incidence
Cycle 1
682
681
0.0
Cycle 2
375
372
Cycle 3
198
192
Immunogenicity was determined by monitoring the development of potential anti–corifollitropin alfa antibodies. Pretreatment and posttreatment samples were obtained from each subject after each treatment cycle, 2 weeks after embryo transfer, or 2 to 3 weeks after cycle discontinuation.1
All posttreatment samples were negative, except for a single sample after cycle 2. However, the sample showed no neutralizing activity and did not interfere with the bioactivity of corifollitropin alfa. Therefore, the result was not considered to be clinically relevant.1
1. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.
1. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.

49. 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
Ovarian hyperstimulation syndrome (OHSS) was reported in 24 patients (3.5%) in their first cycle of controlled ovarian stimulation and 7 patients (1.9%) in the second cycle. No cases of OHSS occurred during the third treatment cycle.1
In total, 15 cases of OHSS were considered mild, 8 cases were considered moderate, and 8 cases were reported as severe.1
OHSS = ovarian hyperstimulation syndrome.
1. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.
1. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.

50. 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
Tarlatzis et al. assessed OHSS rates in the Engage, Ensure, and TRUST studies of ELONVA™ (corifollitropin alfa). In addition, the data were pooled to provide a reliable estimate of severe OHSS incidence, given its relative rarity.1
Overall, 5.6% (95/1705) of the patients treated with ELONVA experienced signs or symptoms of OHSS (mild, moderate, or severe). In the pooled analysis, the incidence of severe OHSS was 1.8% for ELONVA and 1.3% for rFSH. The difference was small and not significant.1
OHSS = ovarian hyperstimulation syndrome.
1. Tarlatzis BC et al. Reprod Biomed Online. 2012;24:410–419.
OHSS = ovarian hyperstimulation syndrome; rFSH = recombinant follicle-stimulating hormone.
1. Tarlatzis BC et al. Reprod Biomed Online. 2012;24:410–419.

51. Subjects With AEs/SAEs
Trust
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)
In the Trust trial a total of 63 SAEs were reported in 47 patients; among the most common were ectopic pregnancy (n=8) and missed abortion (n=3).1
15 SAEs were considered related to the use of with ELONVA™ (corifollitropin alfa) , Including all 10 cases of OHSS.1
The most common AEs were procedural pain related to oocyte retrieval (17.7%), headache (9.1%), and pelvic pain (7.6%).1
No drug-related hypersensitivity reactions occurred, and all local injection-site reactions were mild in severity.1
SAE = serious adverse event; AE = adverse event; OHSS = ovarian hyperstimulation syndrome.
1. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.
SAE = serious adverse event; AE = adverse event; OHSS = ovarian hyperstimulation syndrome.
1. Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.

52. 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
In the pivotal trials of ELONVA (Engage and Ensure)1,2:
A single injection of ELONVA™ (corifollitropin alfa) resulted in similar ongoing pregnancy rates as daily rFSH.
This new regimen achieves outcomes comparable with the currently available protocols with fewer injections.
This reduced treatment burden is an important part of the patient-centered approach.
As shown in the Trust trial, there are no clinically relevant immune antibody responses with ELONVA; thus, there is no concern for immunogenicity.3
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– Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.
rFSH = recombinant follicle-stimulating hormone; IVF = in vitro fertilization.
1. Devroey P et al. Hum Reprod. 2009;24:3063‒3072.
2. Corifollitropin alfa Ensure Study Group. Reprod Biomed Online. 2010;21:66‒ Norman RJ et al. Hum Reprod. 2011;26:2200‒2208.

53. Conclusion
ELONVA™ (corifollitropin alfa) in combination with a GnRH antagonist may be an option for anticipated normal responders entering an IVF/ICSI program
IVF/ICSI
Responder Status
Poor
Normal
High
OI/IUI
GnRH1–4
antagonist
ELONVA
rFSH
If needed from day 8
GnRH5,6
agonist
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, 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.
GnRH = gonadotropin-releasing hormone; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection.

54. ELONVA™ (corifollitropin alfa)1
Align to local label
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.