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