Post on 15-Jan-2016
Corifollitropin alphaElonva
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
Griesinger et al Fertil Steril 2010
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
Oral contraceptive pretreatment
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
Meta-analysis
Griesinger FS 2010
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
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
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
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)
Ongoing pregnancy rate
Per started cycle % (n)
31.8 (124/390) 5.0 (1/20) 0.011 26.8 (7.7-33.1)
Per oocyte retrieval % (n)
33.8 (124/367) 6.3 (1/16) 0.026 27.5 (5.0-34.7)
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
Answer : decreased
Is the luteal phase LH concentration ( post hCG ) in antagonist - gonadotrophin cycles
normal or 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
Ongoing pregnancy rate
per oocyte retrieval
% (n)
Ongoing implantation
rate
% (n)
Pregnancy loss after hCG
detection before 12 weeks
% (n)
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)
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
Cedrin-Durnerin HR 2004
Pill pre-treatment/ 3 day interval, variable starting dose of rec FSH
Single dose antagonist administration by a follicle of 14-16mm
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 syndromePubMed ( 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 deathIn 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 P
Subjects (n) 50 50
Age (y) 25 25
rFSH dose (U) 2 300 2 300
Eggs retrieved (mean)
17 19
OHSS rate 0 / 50 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 results95 % CI : 0.7 – 1.3
Cobo HR 2010
PubMed Search 18 02 2015
Keywords: corifollitropin alfa Publications : n=54
Today’s treatment
GnRH antagonist
1 2 3 4 5 6 7 8 9 10
7-10 days FSHhCG
Corifollitropin alfarFSH
1 2 3 4 5 6 7 8 9 10
hCG
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
Duijkers et al. Hum Reprod. 2002 Devroey et al. J Clin Endocrinol Metab. 2004Fauser et al. Reprod Biomed Online 2010
Comparative pharmacokinetics
10987654321
Stimulation days
FSH
acti
vity
Therapeutic threshold
Corifollitropin alfarFSH
Corifollitropin alfa
PlaceboCorifollitropin alfa
PlaceboCorifollitropin alfa
Engage and Ensure treatment regimen
GnRH antagonist (ganirelix 0.25 mg/d) day 5 through day of hCG
Stimulation day 5
hCG as soon as 3 follicles ≥17 mm
(or the day thereafter)
Stimulation day 8
Cycle day 2-3 =stimulation day 1
Daily rFSH(daily dose for 7 days)
Investigational group
Reference group
Placebo rFSH(daily dose for 7 days)
Placebo rFSH(daily dose for 7 days) Daily rFSH
Daily rFSH
IVF
or
ICSI
Lutealphase
support
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
Patients(n) 71/1023 53/880
Mild (%) 3 3.5
Moderate (%) 2.2 1.3
Severe (%) 1.8 1.3
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
One-third of the patients, regardless of the corifollitropin alfa dose, met the criteria for hCG injection before or on stimulation day 8
0
10
20
30
40
5 6 7 8 9 1011 12 13 141516 1718
Day of hCG criteria
% o
f p
atie
nts
Corifollitropin alfa 100 µg
0
10
20
30
40
5 6 7 8 9 1011 1213141516 1718
Day of hCG criteria
% o
f p
atie
nts
Corifollitropin alfa 150 µg
44,0
38,1
0
10
20
30
40
50
60
Pre
gn
ancy
Rat
e (%
)
248 485
Engage
150 microgram
≤ day 8
> day 844.0
38.1
Pregnancy rates for corifollitropin alfa group: Meeting criteria for hCG d8 vs. > d8
Does delaying hCG administration by 1 day affect the chance of pregnancy?
37,340,342
38,9
0
10
20
30
40
50
60
70
80
90
100
No
Yes
Pregnancy rates: hCG delay of 1 dayPr
egna
ncy
Rate
(%)
472 244 490 243N
Corifollitropin alfa Puregon
Engage
40.3 38.9 37.3 42
Pregnancy Rates: Oocytes Retrieved
Engage
Fatemi HM et al Hum Reprod 2013
43,8
39,940,838,235,7
44,4
38,537,239,233,3
0
10
20
30
40
50
60
70 Corifollitropin alfa
Puregon
Preg
nanc
y Ra
te (%
)
84 16990 171 156N 136 178163188 133
1-5 6-9 10-13 14-18 >18Oocytes Retrieved
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
Corifollitropin alfa150 µgn = 756
Puregon®
200 IU/dayn = 750
Estimateddifferencea
(95% CI)
Ongoing PR per started cycle
per transfer
38.9%294/756
43.8%
38.1%286/750
40.6%
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
Boostanfar et al. Hum Reprod 2010
aAdjusted for age and region. CI, confidence interval; FTET, frozen-thawed embryo transfer.
Ongoing PR per started cycle
*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
Serum LH on Day 8 Engage
Treatment groupSerum LH level
IU/L
Ongoing pregnancy rateN n % 95% CI
Corifollitropin alfa P25≤0.62P50=0.96P75=1.58
<P25P25-P75
>P75
216*316176
7712568
35.639.6 38.6
[34.1; 45.2][29.3; 42.4][31.4; 46.3]
rFSHP25=0.91P50=1.57P75=2.66
<P25P25-P75
>P75
169340169
6012565
35.536.838.5
[28.3; 43.2][31.6; 42.1][31.1; 46.2]
Cycles (n) 223
Mean age (year) 26.1 ± 4.2
OHSS risk 0
MII (mean +/-sd) 11 ± 9
Fertilization (%) 72
ET (mean) 1.8
PR/ET (%) 61
Miscarriage (%) 13
Implantation rate (%) 39
Elonva in egg donors with GnRH agonist triggering
Pellicer A et al personal communication 2013
Requena et al. RBMOnline 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
Days of stim(n) 10 10
ready at D8 26% 27%
COC 15.1 16.5
MII 85% 77%
OHSS - -
Evaluation of the degree of satisfaction (in egg donors)
Requena et al. RBMOnilne 2013
Corifollitropin(n=60)
recFSH(n=60)
satisfaction(10=completely satisfied)
9.1 9.3
pain(VAS 0-100)
13.5 12.9
preference(if previous cycle)
75% 25%
Corifollitropin AlfaN = 424
rFSHN = 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)
Characteristics of live born infants
Care
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
Corifollitropin Alfa 150 µg
rFSH300 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
Mean (SD)
n = 675
11.0 (7.0)
n = 671
10.6 (6.7) 0.4 (–0.3 to 1.1)
Primary End Point: Ongoing PR* %
of
pat
ien
ts
Pursue
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 µgn = 692
rFSH 300 IU/day
n = 698
Incidence of OHSS, n (%)
Grade unknown 0 1 (0.1)
Grade I (mild) 7 (1.0) 1 (0.1)
Grade II (moderate) 5 (0.7) 4 (0.6)
Grade III (severe) 0 6 (0.9)
Total 12 (1.7) 12 (1.7)
OHSS reported as SAE 0 5 (0.7)
Hospitalization 0 2 (0.3)
Grade II and/or III 5 (0.7) 10 (1.4)
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 and simple
• Safe
• Safe
Acknowledgements to Helena Deryckere