1. Corifollitropin alpha Elonva
P Devroey

2. GnRH antagonist Reduced patients’ burden and psychological stress
Patient friendly
Short duration
Similar pregnancy outcome
Meta – analysis
Reduced risk of OHSS correlated with GnRH long protocols
Strategy to erase OHSS with GnRH agonist trigger
Safe
OHSS risk
Zero
Devroey HR 2009

3. Meta-analysis of efficacy trials: probability of live birth

4. Oral Contraceptive Pretreatment Significantly Reduces Ongoing Pregnancy Likelihood in GnRH Antagonist Cycles: A Meta-Analysis
The probability of an ongoing pregnancy per randomized woman was found to be significantly lower in patients who received oral contraceptive pill pre-treatment (RR 0.80, 95% CI: 0.66 to 0.97; p=0.02
Griesinger et al Fertil Steril 2010

5. Oral contraceptive pretreatment
Meta-analysis
Study
OCP (n)
No OCP (n)
Total
670
673
Risk Ratio 0.80 (0.66, 0.97)
In favour of no OCP
1 pregnancy loss/ 20 women treated
Griesinger FS 2010

6. OCP + GnRH antagonist ( n) (%)
Oral contraceptive pills in GnRH antagonist protocol versus long protocol
OCP + GnRH antagonist ( n) (%)
Long Protocol (n) (%)
Ongoing PR
55/115 (48)
61/113 (54)
Multiples
15/55 (27)
18/61 (30)
Implantation Rate
75/207 (36)
80/204 (39)
Live birth rate
51/115 (44)
53/113 (47)
Garcia-Velasquo FS 2011

7. Randomization Patients received 10.000 IU of hCG
as soon as ≥ 3 follicles of ≥ 17 mm were present in ultrasound
early hCG group, patients or
2 days later after this criterion was met
late hCG group, patients
Kolibianakis Albano Camus Tournaye Van Steirteghem Devroey FS 2004

8. Prolongation of the follicular phase in IVF results in a lower probability of pregnancy
Early-hCG group
Late-hCG group P
Ongoing pregnancy rate per OPU (n)
35.6%
(69/194)
25%
(49/196)
0.027
Ongoing pregnancy rate per ET (n)
39.2%
(69/176)
27.7%
(49/177)
0.024
Ongoing implantation rate (n)
22.6%
(87/385)
15.1%
(58/383)
0.009
Kolibianakis FS 2004

9. How to manage patients with elevated progesterone levels at initiation of stimulation ?
Patients with elevated progesterone levels on day two of the cycle were always postponed for days
Stimulation with rec-FSH and GnRH antagonists was started only if progesterone levels returned to normal range
Kolibianakis et al HR 2004

10. Elevated progesterone levels at initiation of stimulation are associated with a significantly lower chance of pregnancy
Normal P group
High P group P
Difference (95% CI)
Ongoing pregnancy rate
Per started cycle % (n)
31.8 (124/390)
5.0 (1/20)
0.011
26.8 ( )
Per oocyte retrieval % (n)
33.8 (124/367)
6.3 (1/16)
0.026
27.5 ( )
Further research Initiation of antagonist on day 1?
Kolibianakis HR 2004

11. Describe the LH concentration during the luteal phase ( post hCG ) in agonist gonadotrophin stimulated cycles
LOW or HIGH
Answer : Low
Smitz HR 1988

12. Is the luteal phase LH concentration ( post hCG ) in antagonist - gonadotrophin cycles normal or decreased ?
Answer : decreased

13. Impact on cycle outcome
Bosch et al HR 2010

14. ONGOING PREGNANCY RATE AND ONGOING IMPLANTATION RATE ACROSS GROUPS OF PATIENTS WITH INCREASING LH LEVELS ACCORDING TO PERCENTILE ANALYSIS
Groups of patients according to LH levels on day 8
Ongoing pregnancy rate per oocyte retrieval
% (n)
Ongoing implantation rate
Pregnancy loss after hCG detection before weeks
LH level on day 8
mean
min
max
0 - 25th
0.3
0.1
0.5
56.0 (14/25)
39.1 (18/46)
6.7 (1) th
1.0
0.6
1.9
40.3 (25/62)
24.6 (31/126)
7.4 (2) th
3.3
8.4
(7/29)
(8/51)
12.5 (1)
P < 0.010*
P < 0.018*
P < 0.71*
* Exact Chi-square for trend
Kolibianakis HR 2004

15. Recombinant LH after antagonist initiation
Pill pre-treatment/ 3 day interval, variable starting dose of rec FSH
Single dose antagonist administration by a follicle of 14-16mm
Cedrin-Durnerin HR 2004

16. Definition of OHSS
Iatrogenic complication (!) of “controlled” (?) ovarian stimulation
Potentially fatal (!)
Risk factor (PCOS)
Triggering mechanism of hCG

17. Intriguing Iatrogenic Who is responsible?
Ovarian stimulation How to stimulate?
HCG is the trigger HCG to be replaced?

18. Ovarian hyperstimulation syndrome
PubMed ( )
n : citations
PubMed ( )
n : citations
Pubmed ( )
n : citations
Pubmed ( )
n: citations

19. Fatal OHSS 25 years old Japanese lady Bilateral chest pain - dyspnoea
Pleural effusion
Fatal after respiratory insufficiency
Autopsy massive pulmonary edema
Semba Patol Int 2000
Fatal

20. Maternal death In IVF in the Netherlands (1984 – 2008)
Death to OHSS : 3 / IVF cycles
Respiratory distress (n : 2)
Cerebrovascular thrombosis (n : 1)
Braat HR 2010
Does it mean 30 / ?

21. Oocyte donors (GnRHa donors)
Triggering
GnRHa
hCG P
Subjects (n) 50
Age (y) 25
rFSH dose (U)
2 300
Eggs retrieved (mean) 17 19
OHSS rate
0 / 50
8 / 50
0.03
Melo RBMO 2009

22. GnRH agonist triggering in GnRH antagonist cycles in OHSS risk
AIM avoiding OHSS
Patients (n = 12)
> 25 follicles
GnRH agonist triggering and hCG 35 hours later
COC (n =20)
Ongoing pregnancies 50 % (6/12)
No OHSS
Humaidan RBMO 2009

23. Oocyte banking (vitrification)
RCT P
Frozen
Fresh
Ongoing pregnancy rate / ET
43.7 %
41.7 % NS
Clinical pregnancy rate / ET
55.0 %
56.0 %
Implantation rate
40.0 %
41.0 %
Similar results
95 % CI : 0.7 – 1.3
Cobo HR 2010

24. PubMed Search 18 02 2015 Keywords: corifollitropin alfa
Publications : n=54

25. Today’s treatment GnRH antagonist 1 2 3 4 5 6 7 8 9 10 7-10 days FSH
hCG
Corifollitropin alfa
rFSH 1 2 3 4 5 6 7 8 9 10
hCG

26. Sustained follicle stimulants
A recombinant fusion molecule of FSH and the carboxy-terminal peptide (CTP) of the human chorionic gonadotropin-beta (hCG) subunit
The first of a proposed new class of gonadotropins (Sustained Follicle Stimulants) with different pharmacokinetic properties but similar pharmacological features as wild-type FSH
Interacts only with the FSH receptor and not with the luteinizing hormone (LH) receptor
Fares et al Proc Natl Acad Sci USA 1992

27. Comparative pharmacokinetics
Corifollitropin alfa
rFSH
FSH activity
Therapeutic threshold 1 2 3 4 5 6 7 8 9 10
Stimulation days
Duijkers et al. Hum Reprod Devroey et al. J Clin Endocrinol Metab. 2004
Fauser et al. Reprod Biomed Online 2010

28. Engage and Ensure treatment regimen
Corifollitropin alfa
Investigational group
Placebo rFSH
(daily dose for 7 days)
Daily rFSH
Placebo
Corifollitropin alfa
IVF or
ICSI
GnRH antagonist (ganirelix 0.25 mg/d)
day 5 through day of hCG
Luteal
phase
support
Reference group
Engage trial design
Phase 3 (pivotal efficacy and safety trial)
Active-controlled (vs. daily rFSH), noninferiority
Double-blind, double-dummy
Randomization by interactive voice response system (IVRS)
Stratified by center and age (<32 vs. ≥32 years) in 1:1 ratio
Planned number of patients: 1400
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 receive
A single 0.5-mL injection of corifollitropin alfa (150 µg) on cycle day 2 or 3 (stimulation day 1) and daily rFSH placebo injections (equivalent of 200 IU) for 7 days, or
An injection of placebo corifollitropin alfa (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.
Both groups received daily rFSH (≤200 IU) from stimulation day 8 through the day of hCG.
On the day that 3 follicles were ≥17 mm (or the day thereafter), final oocyte maturation was induced with hCG (10,000 or 5000 IU), and oocytes were collected.
Patients underwent IVF or ICSI.
Luteal phase support was micronized progesterone (≥600 mg/d vaginally or ≥50 mg/d intramuscularly [IM]).
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
Daily rFSH
(daily dose for 7 days)
Daily rFSH
Cycle day 2-3 =
stimulation day 1
Stimulation
day 5
Stimulation
day 8
hCG as soon as 3 follicles ≥17 mm
(or the day thereafter)
Devroey et al. Hum Reprod 2009 28 28

29. Prediction of OHSS with corifollitropin alfa versus rFSH
Patients at risk
≥ 18 or 19 follicles
Sensitivity and specificity were 74.3% and 75.2%
Preventive measure
Switch from hCG to agonist triggering
Tarlatzis BC et Reprod Biomed Online 2012

30. Risk of OHSS for corifollitropin alfa
recFSH
Patients(n)
71/1023
53/880
Mild (%) 3
3.5
Moderate (%)
2.2
1.3
Severe (%)
1.8
Tarlatzis BC et al Reprod Biomed Online 2012

31. Does hCG administration on or before day 8 decrease the chance of pregnancy?

32. Day when hCG criterion were met40 40
Corifollitropin alfa 100 µg
Corifollitropin alfa 150 µg 30 30
% of patients
% of patients 20 20 10 10 5 6 7 8 9 10 11 12 13 14 15 16 17 18 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Day of hCG criteria
Day of hCG criteria
One-third of the patients, regardless of the corifollitropin alfa dose, met the criteria for hCG injection before or on stimulation day 8

33. Pregnancy rates for corifollitropin alfa group: Meeting criteria for hCG d8 vs. > d8
≤ day 8
44.0
> day 8
38.1
Engage
150 microgram
Pregnancy Rate (%)
248
485

34. Does delaying hCG administration by 1 day affect the chance of pregnancy?

35. Pregnancy rates: hCG delay of 1 day
Engage
Pregnancy Rate (%)
40.3
38.9
37.3 42 N
472
244
490
243
Corifollitropin alfa
Puregon

36. Pregnancy Rates: Oocytes Retrieved
Engage
Pregnancy Rate (%) 84
169 90
171
156 N
136
178
163
188
133
1-5
6-9
10-13
14-18
>18
Oocytes Retrieved
Fatemi HM et al Hum Reprod 2013

37. Corifollitropin alfa on Day 2 versus Day 4
Prospective randomized trial
Study population 52 patients
Total dose of rFSH significantly reduced in CD4 (p=0.01)
Significant reduction of duration in CD4 Number of COS is comparable (12,8 versus 14,7)
Ongoing pregnancy rates in CD2 group 48% versus 41% in CD4 group
Blockeel et al HR 2014

38. Estimated differencea
(Cumulative) ongoing pregnancy rates & live birth rates in Engage trial
Corifollitropin alfa
150 µg
n = 756
Puregon®
200 IU/day
n = 750
Estimated differencea
(95% CI)
Ongoing PR per started cycle
per transfer
38.9% 294/ %
38.1% 286/ %
0.9% (–3.9 to 5.7)
3.1% (–2.0 to 8.2)
Live birth rates/ started cycle
35.6%
275 in FU
34.4%
266 in FU
Cumulative ongoing PR/ started cycle
47.2%
148 ≥1 FTET
44.9%
147 ≥1 FTET
aAdjusted for age and region. CI, confidence interval; FTET, frozen-thawed embryo transfer.
Boostanfar et al. Hum Reprod 2010

39. Ongoing PR per started cycle
Serum LH on Day 8
Engage
Treatment group
Serum LH level
IU/L
Ongoing pregnancy rate N n %
95% CI
Corifollitropin alfa
P25≤0.62
P50=0.96
P75=1.58
<P25
P25-P75
>P75
216*
316
176 77
125 68
35.6
39.6
38.6
[34.1; 45.2]
[29.3; 42.4]
[31.4; 46.3]
rFSH
P25=0.91
P50=1.57
P75=2.66
169
340 60 65
35.5
36.8
38.5
[28.3; 43.2]
[31.6; 42.1]
[31.1; 46.2]
*More than 25% of patients had a value below the LLOQ and were all included in the <P25 group.
Doody KJ et al. Reprod Biomed Online 2011

40. Elonva in egg donors with GnRH agonist triggering
Cycles (n)
223
Mean age (year)
26.1 ± 4.2
OHSS risk
MII (mean +/-sd)
11 ± 9
Fertilization (%) 72
ET (mean)
1.8
PR/ET (%) 61
Miscarriage (%) 13
Implantation rate (%) 39
Pellicer A et al personal communication 2013

41. Evaluation of the degree of satisfaction (in egg donors)
Corifollitropin alfa
(n=60)
recFSH
Age (y)
23.2
24.4
Weight (kg)
65.6
64.9
Days of stim(n) 10
ready at D8
26%
27%
COC
15.1
16.5
MII
85%
77%
OHSS -
One injection of corifollitropin alfa replaces 7 daily injections of rFSH during COS.
The number of injections is reduced by about 70% compared with the long agonist protocol (from 35 to 10).
In combination with the GnRH antagonist, this COS protocol can considerably reduce the treatment burden on patients.
Additional daily rFSH after day 7 is to be determined by physician assessment.
So what exactly is corifollitropin alfa? Let’s take a look at its molecular makeup on the next slide to see how it can perform as a sustained follicle stimulant.
Requena et al. RBMOnline 2013

42. Evaluation of the degree of satisfaction (in egg donors)
Corifollitropin
(n=60)
recFSH
satisfaction
(10=completely satisfied)
9.1
9.3
pain
(VAS 0-100)
13.5
12.9
preference
(if previous cycle)
75%
25%
One injection of corifollitropin alfa replaces 7 daily injections of rFSH during COS.
The number of injections is reduced by about 70% compared with the long agonist protocol (from 35 to 10).
In combination with the GnRH antagonist, this COS protocol can considerably reduce the treatment burden on patients.
Additional daily rFSH after day 7 is to be determined by physician assessment.
So what exactly is corifollitropin alfa? Let’s take a look at its molecular makeup on the next slide to see how it can perform as a sustained follicle stimulant.
Requena et al. RBMOnilne 2013

43. Characteristics of live born infants
Care
Corifollitropin Alfa
N = 424
rFSH
N = 370
Gestational age, weeks
37.8 (3.2)
38.2 (2.8)
Female sex, n, mean (%)
210 (49.5%)
190 (51.4%)
Number of singletons
241
237
Weight at birth—singletons only, g
3297 (534)
3247 (586)
Weight at birth—all, g
2860 (755)
2928 (715)
Length at birth, cm
48.2 (4.1)
48.6 (4.1)
Head circumference, cm
33.6 (2.2)
33.5 (2.6)
Apgar score: 1 min
8.2 (1.5)
8.1 (1.5)
Apgar score: 5 min
9.1 (1.0)
9.1 (0.9)
Values are n, mean (SD) unless otherwise stated. Bonduelle M et al. Hum Reprod 2012 43 43

44. Corifollitropin alfa in combination with GnRH agonist triggering (Pilot Study)
Egg retrieval
After 1 hour 1500IU HCG
After 7 days 1500IU HCG
Micronized progesteron vaginally
Decleer et al. Facts Views Vision 2014

45. Corifollitropin alfa in combination with GnRH agonist triggering (Pilot study)
Patients (n) 11
Age (y) 32
BMI (kg/m²) 24
COC (mean) 10
Pregnancies (n) 4
Decleer et al. Facts Views Vision 2014

46. Addition of highly purified HMG after corifollitropin alfa in POR
Stimulation protocol
Elonva IU Menopur
GnRH antagonist from day 7 of the cycle
Patients < 40 y
Patients ≥ 40 y
Number 29 18
Pregnancy rate
8/29 (28%)
0/18 (0%)
Polyzos NP et al. Hum Reprod 2013

47. Most Important Entry Criteria (PURSUE Study)
Inclusion criteria
Indication for COS and IVF/ICSI
Age ≥ 35 and ≤ 42 years
Body weight ≥ 50 kg, and body mass index ≥ 18 and ≤ 32 kg/m2
Normal menstrual cycle (cycle length 24–35 days)
Availability of ejaculatory sperm 47

48. Number of Oocytes Retrieved
Corifollitropin Alfa
150 µg
rFSH
300 IU/day
Estimated Difference
ANOVA (95% CI)
Per attempt
Mean (SD)
n = 694
10.7 (7.2)
n = 696
10.3 (6.8)
0.5 (–0.2 to 1.2)
Per oocyte pick-up
n = 675
11.0 (7.0)
n = 671
10.6 (6.7)
0.4 (–0.3 to 1.1) 48

49. Primary End Point: Ongoing PR*
Pursue
ITT Group
% of patients
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 corifollitropin alfa and daily rFSH.
The absolute treatment difference slightly favored corifollitropin alfa.
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 USS or Doppler, or confirmed by live birth.
26.9%
23.9%
Boostanfar et al. ASRM 2012 San Diego

50. Congenital malformations with corifollitropin alfa ( PURSUE study)
recFSH
Pregnancies (n)
154
167
Children(n)
183
196
Congenital malformations(n) 9 6
Congenital malformations (%)
4.9
3.1
Stegmann ASRM 2013 Boston

51. Number of Subjects With OHSS (All Subjects Treated Group)
Corifollitropin Alfa µg
n = 692
rFSH
300 IU/day
n = 698
Incidence of OHSS, n (%)
Grade unknown
1 (0.1)
Grade I (mild)
7 (1.0)
Grade II (moderate)
5 (0.7)
4 (0.6)
Grade III (severe)
6 (0.9)
Total
12 (1.7)
OHSS reported as SAE
Hospitalization
2 (0.3)
Grade II and/or III
10 (1.4) 51

52. Coda Yesterday Nowadays Pro GnRH agonist long protocol
Daily rFSH injections
hCG for final egg maturation
Patient unfriendly
OHSS ± 5%
GnRH antagonist
Corifollitropin alfa
GnRH agonist for final egg maturation if needed
Patient friendly
OHSS ≈ 0%
OHSS Free Clinic
Safe and simple
Safe
Acknowledgements to Helena Deryckere