Corifollitropin alpha
Elonva
P Devroey
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
Meta-analysis of efficacy trials:
probability of live birth
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
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
Oral contraceptive pills in GnRH
antagonist protocol versus long protocol
Ongoing PR
OCP + GnRH
antagonist ( n) (%)
55/115 (48)
Long Protocol (n)
(%)
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
Randomization
Patients received 10.000 IU of hCG
as soon as ≥ 3 follicles of ≥ 17 mm were present in ultrasound
early hCG group, 208 patients
or
2 days later after this criterion was met
late hCG group, 205 patients
Kolibianakis Albano Camus Tournaye Van Steirteghem Devroey FS 2004
Prolongation of the follicular phase in IVF
results in a lower probability of pregnancy
Ongoing pregnancy rate
per OPU (n)
Ongoing pregnancy rate
per ET (n)
Ongoing implantation
rate (n)
Early-hCG group
Late-hCG group
P
35.6%
25%
0.027
(69/194)
(49/196)
39.2%
27.7%
(69/176)
(49/177)
22.6%
15.1%
(87/385)
(58/383)
0.024
0.009
Kolibianakis FS 2004
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 1-2 days
Stimulation with rec-FSH and
GnRH antagonists was started
only if progesterone levels
returned to normal range
Kolibianakis et al HR 2004
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)
Per started cycle % 31.8 (124/390)
(n)
5.0 (1/20)
0.011
26.8 (7.7-33.1)
Per oocyte retrieval 33.8 (124/367)
% (n)
6.3 (1/16)
0.026
27.5 (5.0-34.7)
Ongoing
pregnancy rate
Further research
Initiation of antagonist on day 1?
Kolibianakis HR 2004
Describe the LH concentration during the luteal phase
( post hCG ) in agonist gonadotrophin stimulated cycles
LOW
or
HIGH
Answer : Low
Smitz HR 1988
Is the luteal phase LH concentration ( post
hCG ) in antagonist - gonadotrophin cycles
normal or decreased ?
Answer : decreased
Impact on cycle outcome
Bosch et al HR 2010
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
LH level on day 8
Ongoing
pregnancy rate
per oocyte
retrieval
Ongoing
implantation
rate
Pregnancy loss
after hCG
detection before
12 weeks
% (n)
% (n)
% (n)
mean
min
max
0 - 25th
0.3
0.1
0.5
56.0 (14/25)
39.1 (18/46)
6.7 (1)
25 - 75th
1.0
0.6
1.9
40.3 (25/62)
24.6 (31/126)
7.4 (2)
75 - 100th
3.3
1.9
8.4
24.1 (7/29)
15.7 (8/51)
12.5 (1)
P < 0.010*
P < 0.018*
P < 0.71*
* Exact Chi-square for trend
Kolibianakis HR 2004
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
Definition of OHSS

Iatrogenic complication (!) of
“controlled” (?) ovarian stimulation

Potentially fatal (!)

Risk factor (PCOS)

Triggering mechanism of hCG
Intriguing

Iatrogenic
Who is
responsible?

Ovarian stimulation
How to stimulate?

HCG is the trigger
HCG to be replaced?
Ovarian hyperstimulation syndrome
PubMed ( 01 09 2011)
o
n : 2 275 citations
PubMed ( 30 01 2012)
o
n : 2 333 citations
Pubmed (30 05 2012)
o
n : 2 396 citations
Pubmed (17 03 2015)
o
n: 2 837 citations
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
Maternal death
In IVF in the Netherlands (1984 – 2008)

Death to OHSS : 3 / 100 000 IVF cycles

Respiratory distress (n : 2)

Cerebrovascular thrombosis (n : 1)
Braat HR 2010
Does it mean 30 / 1 000 000 ?
Oocyte donors (GnRHa donors)
Triggering
GnRHa
hCG
Subjects (n)
50
50
Age (y)
25
25
2 300
2 300
17
19
rFSH dose (U)
Eggs retrieved (mean)
OHSS rate
0 / 50
P
8 / 50
0.03
Melo RBMO 2009
GnRH agonist triggering in GnRH
antagonist cycles in OHSS risk

AIM avoiding OHSS

Patients (n = 12)

> 25 follicles

GnRH agonist triggering and 1 500 hCG 35
hours later

COC (n =20)

Ongoing pregnancies 50 % (6/12)

No OHSS
Humaidan RBMO 2009
Oocyte banking (vitrification)
RCT
P
Frozen
Fresh
Ongoing pregnancy
rate / ET
43.7 %
41.7 %
NS
Clinical pregnancy
rate / ET
55.0 %
56.0 %
NS
Implantation rate
40.0 %
41.0 %
NS
Similar results
95 % CI : 0.7 – 1.3
Cobo HR 2010
PubMed Search 18 02 2015
 Keywords:
corifollitropin alfa
 Publications : n=54
Today’s treatment
7-10 days FSH
hCG
1
2
3
4
5
6
7
8
9
10
GnRH antagonist
rFSH
Corifollitropin alfa
1
2
3
4
5
6
7
8
hCG
9
10
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
Comparative pharmacokinetics
FSH activity
Corifollitropin alfa
rFSH
Therapeutic
threshold
1
2
3
4
5
6
7
8
9
10
Stimulation days
Duijkers et al. Hum Reprod. 2002 Devroey et al. J Clin Endocrinol Metab. 2004
Fauser et al. Reprod Biomed Online 2010
Engage and Ensure treatment regimen
Investigational group
Corifollitropin alfa
Placebo rFSH
(daily dose for 7 days)
Reference group
Placebo
Corifollitropin alfa
Daily rFSH
IVF
GnRH antagonist (ganirelix 0.25 mg/d)
day 5 through day of hCG
ICSI
Luteal
phase
support
Daily rFSH
Daily rFSH
(daily dose for 7 days)
Cycle day 2-3 = Stimulation
stimulation day 1
day 5
or
Stimulation
day 8
hCG as soon as 3 follicles
≥17 mm
(or the day thereafter)
Devroey et al. Hum Reprod 2009
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
Risk of OHSS for corifollitropin alfa
OHSS
Corifollitropin alfa
recFSH
71/1023
53/880
3
3.5
Moderate (%)
2.2
1.3
Severe (%)
1.8
1.3
Patients(n)
Mild (%)
Tarlatzis BC et al Reprod Biomed Online 2012
Does hCG administration on or before
day 8 decrease the chance of
pregnancy?
Day when hCG criterion were met
40
40
30
Corifollitropin alfa 150 µg
% of patients
% of patients
Corifollitropin alfa 100 µg
20
10
30
20
10
0
0
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
Pregnancy rates for corifollitropin alfa group:
Meeting criteria for hCG d8 vs. > d8
≤ day 8
> day 8
60
Pregnancy Rate (%)
44.0
50
44,0
38.1
38,1
40
150 microgram
30
20
10
0
Engage
248
485
Does delaying hCG administration by 1
day affect the chance of pregnancy?
Pregnancy rates: hCG delay of 1 day
Engage
100
No
Yes
90
Pregnancy Rate (%)
80
70
60
50
40.3
40,3
38.9
38,9
37.3
37,3
4242
472
244
490
243
40
30
20
10
0
N
Corifollitropin alfa
Puregon
Pregnancy Rates: Oocytes Retrieved
Engage
70
Corifollitropin alfa
Puregon
60
Pregnancy Rate (%)
43,8 44,4
50
35,7
38,2 39,2
40,8
136 171
169 188
163 156
178 133
6-9
10-13
14-18
>18
33,3
37,2
39,9
38,5
40
30
20
10
0
N
84
90
1-5
Oocytes Retrieved
Fatemi HM et al Hum Reprod 2013
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
(Cumulative) ongoing pregnancy rates &
live birth rates in Engage trial
Ongoing PR
per started cycle
per transfer
Live birth rates/
started cycle
Cumulative ongoing
PR/ started cycle
aAdjusted
Corifollitropin alfa
150 µg
n = 756
Puregon®
200 IU/day
n = 750
Estimated
differencea
(95% CI)
38.9%
294/756
38.1%
286/750
0.9% (–3.9 to 5.7)
43.8%
40.6%
3.1% (–2.0 to 8.2)
35.6%
275 in FU
34.4%
266 in FU
47.2%
148 ≥1 FTET
44.9%
147 ≥1 FTET
for age and region. CI, confidence interval; FTET, frozen-thawed embryo transfer.
Boostanfar et al. Hum Reprod 2010
Ongoing PR per started cycle
Engage
Serum LH on Day 8
Treatment group
Serum LH level
IU/L
Ongoing pregnancy rate
N
n
%
95% CI
Corifollitropin alfa
P25≤0.62
<P25
216*
77
35.6 [34.1; 45.2]
P50=0.96
P25-P75
316
125
39.6 [29.3; 42.4]
P75=1.58
>P75
176
68
38.6 [31.4; 46.3]
P25=0.91
<P25
169
60
35.5 [28.3; 43.2]
P50=1.57
P25-P75
340
125
36.8 [31.6; 42.1]
P75=2.66
>P75
169
65
38.5 [31.1; 46.2]
rFSH
*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
Elonva in egg donors with GnRH
agonist triggering
Cycles (n)
Mean age (year)
OHSS risk
MII (mean +/-sd)
Fertilization (%)
ET (mean)
PR/ET (%)
Miscarriage (%)
Implantation rate (%)
223
26.1 ± 4.2
0
11 ± 9
72
1.8
61
13
39
Pellicer A et al personal communication 2013
Evaluation of the degree of satisfaction
(in egg donors)
Corifollitropin alfa
(n=60)
recFSH
(n=60)
Age (y)
23.2
24.4
Weight (kg)
65.6
64.9
10
10
ready at D8
26%
27%
COC
15.1
16.5
MII
85%
77%
-
-
Days of stim(n)
OHSS
Requena et al. RBMOnline 2013
Evaluation of the degree of
satisfaction (in egg donors)
satisfaction
Corifollitropin
(n=60)
recFSH
(n=60)
9.1
9.3
13.5
12.9
75%
25%
(10=completely satisfied)
pain
(VAS 0-100)
preference
(if previous cycle)
Requena et al. RBMOnilne 2013
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%)
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)
Number of singletons
Values are n, mean (SD) unless otherwise stated.
Bonduelle M et al. Hum Reprod 2012
Corifollitropin alfa in combination with
GnRH agonist triggering (Pilot Study)

Corifollitropin alfa
 GnRH agonist triggering
 Egg retrieval
 After 1 hour 1500IU HCG
 After 7 days 1500IU HCG
 Micronized progesteron vaginally
Decleer et al. Facts Views Vision 2014
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
Addition of highly purified HMG
after corifollitropin alfa in POR
• Stimulation protocol
• Elonva + 300 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
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
Number of Oocytes Retrieved
Per attempt
Mean (SD)
Per oocyte pick-up
Mean (SD)
Corifollitropin Alfa
150 µg
rFSH
300 IU/day
n = 694
n = 696
10.7 (7.2)
10.3 (6.8)
n = 675
n = 671
11.0 (7.0)
10.6 (6.7)
Estimated
Difference
ANOVA (95% CI)
0.5 (–0.2 to 1.2)
0.4 (–0.3 to 1.1)
Primary End Point: Ongoing PR*
Pursue
% of patients
ITT Group
23.9%
26.9%
Boostanfar et al. ASRM 2012 San Diego
Congenital malformations with
corifollitropin alfa ( PURSUE study)
Corifollitropin alfa
recFSH
Pregnancies (n)
154
167
Children(n)
183
196
Congenital malformations(n)
9
6
Congenital malformations (%)
4.9
3.1
Stegmann ASRM 2013 Boston
Number of Subjects With OHSS
(All Subjects Treated Group)
Corifollitropin Alfa
150 µg
n = 692
rFSH
300 IU/day
n = 698
0
1 (0.1)
Grade I (mild)
7 (1.0)
1 (0.1)
Grade II (moderate)
5 (0.7)
4 (0.6)
0
6 (0.9)
12 (1.7)
12 (1.7)
OHSS reported as SAE
0
5 (0.7)
Hospitalization
0
2 (0.3)
5 (0.7)
10 (1.4)
Incidence of OHSS, n (%)
Grade unknown
Grade III (severe)
Total
Grade II and/or III
Coda
Yesterday
• GnRH agonist long
Nowadays
• GnRH antagonist
Pro
• Safe and simple
protocol
• Daily rFSH injections • Corifollitropin alfa
• Safe and simple
• hCG for final egg
• GnRH agonist for final egg • Safe
maturation
maturation if needed
• Patient unfriendly
• Patient friendly
• OHSS ± 5%
• OHSS ≈ 0%
• OHSS Free Clinic
• Safe
Acknowledgements to Helena Deryckere