Corifollitropin Alfa Clinical Trial Experience

1
Corifollitropin Alfa (Elonva®
):
Clinical trial experience
Keith Gordon, Ph.D.
Medical Affairs Director & Strategy Lead
Fertility, US Medical Affairs
Kiev, 2014

2
1923 The founding of Organon by Dr. Saal van Zwanenberg
1930’s Gonadotrophins from animal material
1932 Gonadotrophins extracted from urine of postmenopausal women (hMG)
and from pregnant women (hCG) women: Pregnyl®
1963 Human Menopausal Gonadotropin: Humegon®
1996 Biotechnology results in recombinant FSH: Puregon®
1999 GnRH antagonist: Antagon®,
Orgalutran®
,ganirelix acetate
2006 One million children born following treatment with Puregon®
2010 EU Approval corifollitropin alfa: Elonva®
A Proud History of Innovation R&D in Fertility

3
Corifollitropin alfa: Timeline
 First publication: Fares et al., 1992 PNAS 89; 4304-8
 US Patent 5,338,835 Aug 16, 1994 I. Boime (Washington
University, St. Louis, MO) CTP-extended form of FSH
 First Human Exposure (Phase I): Bouloux et al., 2001
Human Reproduction; 16: 1592-7.
 First Live birth published: Beckers et al., 2003; Fertil Steril
79(3): 621-3.
 First Approval, Centralized procedure European Union, 25
Jan 2010 (International birth date).
 First markets to launch: Germany and UK, Jan 2010.

4
Molecular Structure of Corifollitropin alfa
 A recombinant fusion molecule of
FSH and the CTP of the hCGβ-
subunit
 The first of a new class of
gonadotropins with different
pharmacokinetic properties but
similar pharmacologic features as
rFSH
 Interacts only with the FSH
receptor and not with the
LH receptor
FSH
CTP
FSH, follicle-stimulating hormone; CTP, carboxy-terminal peptide; hCG, human chorionic gonadotropin;
LH, luteinizing hormone; rFSH, recombinant FSH.
Fares FA, et al. Proc Natl Acad Sci U S A. 1992;89:4304-4308.

5
Fauser et al, Hum Reprod Update, 2009;15:309-321
Treatment regimen of corifollitropin alfa in
comparison to daily rFSH
10987654321
Stimulation Days
FSHActivity
Therapeutic
threshold
Corifollitropin alfa
rFSH

6
Clinical development program
corifollitropin alfa
23 completed trials
21 trials reported
24 clinical trials
Controlled Ovarian
Stimulation
Ovulation
Induction
GnRH antagonist GnRH agonist
Phase IIPhase I Phase III Phase II Phase II
38801
38802
38803
3882305909
38807
38826
Engage
Ensure
Trust
Pursue
Realize 38805
107010
Pregnancy and infant follow-up trials Frozen Thawed Embryo Transfer trials

7
Study sites
Phase III Trial Program of reported trials

8
Corifollitropin alfa: clinical development program
 In total 24 trials: 23 trials completed
 Ongoing trials: FTET cycles of Pursue trial
Subjects exposed to corifollitropin alfa in reported trials
 142 healthy volunteers in the Phase I trials
 415 patients in Phase II trials exposed to 7.5 to 240 µg
 1705 patients in Phase III trials exposed to 100 or 150 µg
 677 pregnant patients exposed to corifollitropin alfa in pregnancy follow-up
 806 infants evaluated in neonatal follow-up

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Phase III efficacy and safety data

10
Corifollitropin alfaCorifollitropin alfa
Placebo
Placebo
Engage and Ensure Treatment Regimen
GnRH antagonist (ganirelix 0.25 mg/d)
day 5 through day of hCG
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)
Daily rFSH
Investigational group
Reference group
Placebo rFSH
Placebo rFSH
(daily dose for 7 days) Daily rFSHDaily rFSH
Daily rFSHDaily rFSH
IVF
or
ICSI
IVF
or
ICSI
Luteal
phase
support
Luteal
phase
support

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Mean (SD) number of oocytes per started cycle
recFSH
Estimated
difference*
ANOVA (95% CI)
Engage
150 µg
n = 756
13.7 (8.2)
200 IU
n = 750
12.5 (6.7)
1.2 (0.5, 1.9)
Ensure
100 µg
n = 268
13.3 (7.3)
150 IU
n = 128
10.6 (5.9)
2.5 (1.2, 3.9)
*Adjusted for age group and center

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(Cumulative) Ongoing Pregnancy Rates &
Live Birth Rates in Engage trial
150 µg
n = 756
Puregon®
200 IU/day
n = 750
Estimated
differencea
(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 R, et al. Hum Reprod. 2010;25(supple 1):i47 [O-119].
a
Adjusted for age and region. CI, confidence interval; FTET, frozen-thawed embryo transfer.

13
Similar time interval to reach criteria for hCG for
100 μg (≤ 60 kg) and 150 μg (> 60 kg)
Note: Median duration of stimulation was 9 days both in the Engage and Ensure
and in each trial one third of the patients reached the criteria for hCG before or
on Stimulation Day 8.
0%
10%
20%
30%
40%
5 6 7 8 9 10 11 12 13 14 15 16 17 18
Day of hCG criteria
Proportionofsubjects
100 µg corifollitropin alfa
0%
10%
20%
30%
40%
5 6 7 8 9 10 11 12 13 14 15 16 17 18
Day of hCG criteria
Proportionofsubjects
150 µg corifollitropin alfa
Ledger et al RBMonline, 2011

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Distribution of Duration of Stimulation
Engage trial
0
5
10
15
20
25
30
35
40
5 6 7 8 9 10 11 12 13 14 15 16 17 18
Stimulation day
%ofpatients
Corifollitropin alfa 150 µg
rFSH 200 IU/d
One-third of the patients did not require any rFSHOne-third of the patients did not require any rFSH

15
Similar exposure to corifollitropin alfa using
100 µg and 150 µg doses in Phase 3 Trials
0
500
1000
1500
Trial 107012 Trial 38819
AUC(h.ng/mL)
0
2
4
6
8
10
Trial 107012 Trial 38819Cmax(ng/mL)
De Greef et al. 2010 Clin Pharmacol Ther 2010;888:79-87
Data shown for non-Asian subjects, All-Subjects-Pharmacokinetically-Evaluable
AUC = area under the curve; Cmax = maximum concentration

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Trigger with urinary or
recombinant hCG as soon
as 3 follicles ≥ 17 mm
Cycle Day 2-3 =
Stimulation Day 1
Corifollitropin
alfa
150 µg/0.5 mL
GnRH antagonist (0.25 mg/daily)
Day 5 or 6 through day hCG
Stimulation
Day 5 or 6
7 days
Stimulation
Day 8
(rec)FSH/hMG daily
≤ 225 IU
Trust trial: treatment for up to 3 cycles
(rec)hCG
IVF
ICSI
Oocyte
retrieval
ET
(max 3)
Luteal phase support
(vaginal P)

17
Trust trial: main clinical outcome
ITT-group
Trial 38825
Cycle 1
N=682
Cycle 2
N=375
Cycle 3
N=198
Number of oocytes
per started cycle
11.9 (7.2)
0 – 47
11.5 (6.8)
0 – 37
11.3 (7.6)
0 - 56
Total embryos at day 3
for patients with IVF/ICSI
Embryos transferred
for patients with ET
6.4 (4.5)
0-26
1.9 (0.7)
6.5 (4.4)
0-25
2.1 (0.7)
6.6 (4.8)
0-25
2.2 (0.7)
Ongoing PR
per started cycle
22.7% 20.5% 20.7%
Cumulative Ongoing PR
(3 cycles)
61%
Censored for discontinuation
51%
Not censored for discontinuation
Norman et al, Hum Reprod 2011

18
Trust: immunogenicity testing
Cycle
Number of subjects
treated with
Number of
subjects tested
for antibodies
Observed
clinically relevant
immunogenicity incidence
Cycle 1 682 681 0.0
Cycle 2 375 372 0.0
Cycle 3 198 192 0.0
Conclusion: No immunogenicity found
All-subjects-treated group
Norman et al Hum Reprod 2011

19
Ensure and Engage Trust
N=1023
recFSH
N=880
corifollitropin
alfa
N=682
Grade I (mild)
Grade II (moderate)
Grade III (severe)
3.0% (31)
2.2%(22)
1.8%(18)
3.5% (31)
1.3% (11)
1.3% (11)
1.8% (12)
0.9% (6)
0.9% (6)
Any grade 6.9% (71) 6.0% (53) 3.5% (24)
Percentage of Patients With OHSS per Grade
Patients included in Engage and Ensure Trials were ≤ 36 years and patients in the Trust trial ≤ 39 years
Tarlatzis et al RBMonline submitted

20
OHSS incidences
(WHO criteria)
Cycle 1
N=682
Cycle 2
N=375
Cycle 3
N=198
Grade I (mild)
Grade II (moderate)
Grade III (severe)
1.8% (12)
0.9% (6)
0.9% (6)
0.8% (3)
0.5% (2)
0.5% (2)
0.0%
0.0%
0.0%
Any grade 3.5% (24) 1.9% (7) 0.0%
Trust trial: number of subjects with OHSS per grade
All-subjects-treated group

21
PREGNANT SUBJECTS ENROLLED NUMBER OF LIVEBORN INFANTS
TRIALS corifollitropin
alfa recFSH Total corifollitropin
alfa recFSH Total
Phase II 67 21 88 78 23 101
Phase III
107012
38819
342 312 654 424 370 794
Phase III
38825 268 268 304 304
Total 677 333 1010 806 393 1199
Corifollitropin alfa pregnancy and neonatal follow-up

22
Corifollitropin Alfa
N = 424
recFSH
N = 370
Gestational age, weeks 37.8 (3.2) 38.2 (2.8)
Female sex, n, (%) 210 (49.5%) 190 (51.4%)
Number of singletons, n (%) 241 (56.8%) 237 (64.1%)
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
Values are mean (SD) unless otherwise stated.
Combined data of follow-up data Ensure and Engage trial

23
Incidence of Congenital Malformations
Live-born Infants
Corifollitropin alfa recFSH
Combined phase 3 RCTs1
Engage and Ensure
Major
Minor
Any
4.0% (17/424)
12.3% (52/424)
16.3% (69/424)
5.4% (20/370)
11.6% (42/370)
17.0% (63/370)
All phase 2 and 3 trials Major
Minor
Any
4.5% (36/806)
10.0% (81/806)
14.5% (117/806)
Bonduelle M, et al. Hum Reprod. 2010;25(suppl 1):i22 [abstract O-055].

24
Elonva®
SmPC: Adverse Drug Reactions
Common (1%-10%)
 Headache
 Nausea
 Fatigue
 OHSS
 Pelvic pain
 Pelvic discomfort
 Breast complaints
Uncommon (<1%)
 Ovarian torsion
 Dizziness
 Abdominal pain
 Vomiting
 Diarrhea
 Constipation
 Abdominal distension
OHSS = ovarian hyperstimulation syndrome.

25
Elonva®
: Not for (potential) high responders
Additional Contra-indications SmPC:
 A history of OHSS
 A previous COS cycle that resulted in more than 30 follicles
≥11 mm measured by ultrasound examination
 A basal antral follicle count >20

26
Single Injection of Corifollitropin Alfa to Induce
Multifollicular Development for Controlled Ovarian
Stimulation Using Daily Recombinant FSH as a
Reference in Women Aged 35 to 42 Years
(PURSUE)

27
Key Inclusion Criteria
 The subject must fulfill ALL criteria:
– Female ≥35 to ≤42 years of age
– Indication for COS and IVF or ICSI
– Body weight ≥50.0 kg, with a BMI ≥18.0 to ≤32.0 kg/m2
– Regular spontaneous menstrual cycle (cycle length 24 to 35 days)
– Availability of ejaculatory sperm
– Clinical laboratory tests (complete blood count [CBC], blood
chemistries, and urinalysis) within normal limits
– A normal cervical smear result - no atypical or abnormal cells, or in
case of atypical squamous or glandular cells, no signs of malignancy
– Must have results of a physical examination, including blood pressure,
within normal limits
MK-8962 P06029 27Protocol P06029 5/19/2011

28
Key Exclusion Criteria
 Recent history of/or any current endocrine abnormality
 History of ovarian hyper-response (ie, previous COS cycle with more than 30
follicles ≥11 mm on ultrasound) or ovarian hyperstimulation syndrome (OHSS)
 History of/or current polycystic ovary syndrome (PCOS)
 More than 20 basal antral follicles <11 mm (both ovaries combined)
 History of non- or low ovarian response to FSH / Human Menopausal
Gonadotropin (hMG) treatment
 FSH >15.0 IU/L or LH >12.0 IU/L
 History of recurrent miscarriage (3 or more, even when unexplained)
 Less than 2 ovaries or any other ovarian abnormality
 Unilateral or bilateral hydrosalpinx
 Intrauterine fibroids ≥5 cm or any clinically relevant pathology, which could impair
embryo implantation or pregnancy continuationMK-8962 P06029 28Protocol P06029 5/19/2011

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Study Design: Controlled Ovarian
Stimulation (COS) Treatment Cycle
MK-8962 P06029 29
Placebo recFSH (follitropin beta)
(daily dose equivalent to 300 IU for 7 days)
recFSH (follitropin beta)
(daily dose ≤ 300 IU)
(daily dose 300 IU for 7 days)
(daily dose ≤ 300 IU)
Oocyte
retrieval
IVF
ICSI
ET
Luteal phase support
(vaginal progesterone gel 8%:
90 mg once daily)
GnRH antagonist (ganirelix, 0.25 mg/day)
Day 5 through Day of rechCG
rechCG
(250 µg)
Cycle day 2-3 =
Stimulation Day 1
Stimulation
Day 5
Stimulation
Day 8
As soon as 3 follicles ≥ 17 mm
(or the day thereafter)
Investigational group:
Reference group:
150 µg
Placebo
The maximum duration of stimulation is 19 days; recFSH should not be administered on the day of rechCG.
Protocol P06029 5/19/2011

30
Vital Pregnancy Rate
Full Analysis Set
Primary Endpoint
∆= -3.0 (-7.4; 1.4)*
∆ (95% CI)
30MK-8962 P06029
*Non-inferiority margin: lower bound of the 95% CI above -8%

31
Number of Oocytes Retrieved
Full Analysis SetOocytesRetrieved(Mean)
∆=0.5 ( -0.2, 1.2)*
694 696
∆ (95% CI)
31
MK-8962 P06029
*Non-inferiority margin: Lower bound of the 95% CI of -3 oocytes

32
Live-Birth Rate
corifollitropin alfa P06029 32
Full Analysis Set
∆= -2.3 (-6.5; 1.9)
∆ (95% CI)
Live-birthRateperAttempt(%)

33
Adverse Event Summary
MK-8962 P06029 33
All-Subjects-Treated, Intervention
150 µg
(N=692)
recFSH 300 IU
(N=698)
n (%) n (%)
Subjects with AEs 395 (57.1) 403 (57.7)
Subjects with drug-related AEs 142 (20.5) 129 (18.5)
Subjects with SAEs 3 (0.4) 19 (2.7)
Subjects with drug-related SAEs 0 (0.0) 4 (0.6)
Deaths 0 (0.0) 0 (0.0)
Subjects who discontinued due to AEs 5 (0.7) 6 (0.9)
Subjects with AEs of known severe intensity 16 (2.3) 27 (3.9)
CSR 03/18/13

34
Drug-related AE >1% of Subjects in Either
Treatment Group
MK-8962 P06029 34
All-Subjects-Treated, Intervention
150 µg
n=692
recFSH
300 IU/day
n=698
Headache 42 (6.1) 39 (5.6)
Pelvic discomfort 40 (5.8) 41 (5.9)
Nausea 27 (3.9) 17 (2.4)
Breast tenderness 18 (2.6) 8 (1.1)
Fatigue 13 (1.9) 14 (2.0)
OHSS 12 (1.7) 10 (1.4)
Pelvic pain 11 (1.6) 11 (1.6)
Injection site pain 8 (1.2) 4 (0.6)
Dizziness 4 (0.6) 8 (1.1)
CSR 03/18/13

35
Ovarian Hyperstimulation Syndrome
(OHSS)
MK-8962 P06029 35
All Subjects as Treated—based on the treatment actually received*
150 µg
n = 692
recFSH
300 IU/day
n = 698
n (%) n (%)
Grade unknown 0 (0.0) 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 (0.0) 6 (0.9)
Total 12 (1.7) 12 (1.7)
OHSS reported as SAE 0 (0.0) 5 (0.7)
Hospitalization 0 (0.0) 2 (0.3)
Grade II and/or III 5 (0.7) 10 (1.4)
*Two subjects randomized to corifollitropin alfa actually received recFSH

36
Conclusions from PURSUE
 Non-inferiority margin met for primary study endpoint of vital
pregnancy rate and key secondary endpoint of number of oocytes
retrieved and live birth rate
 Corifollitropin alfa was generally well tolerated and had a safety
profile comparable to recFSH
– Number, type, intensity and drug-relationship of adverse experiences
– Incidence, severity and grading of OHSS episodes
– Incidence of hypersensitivity reactions
– Incidence of congenital malformations
 No evidence of clinically meaningful immunogenicity was observed
 Safety evaluation of 321 ongoing pregnancies with 394 fetuses does
not suggest a clinically meaningful safety concern for either
pregnant subjects or their offspring.
36
MK-8962 P06029

37
Indication, benefits and contra-indications
Indication:
Controlled Ovarian Stimulation in combination with a GnRH antagonist for
development of multiple follicles in women participating in an ART program
Benefits: one injection replaces 7 daily injections
simplified treatment
easier to understand, less worry
lower potential for medication errors

38
Prefilled syringe
 Corifollitropin alfa 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
EMEA PI. November 2009.

39
Treatment Protocols in ART
Protocol
IVF/ICSI
OI/IUI
Responder Status
Poor Normal High
Antagonist
Agonist
PuregonELONVA (corifollitropin alfa)
 


 
 


40
Treatment Protocol with corifollitropin alfa
ELONVA™ rFSH
1 2 3 4 5 6 7 8 9 10
hCG
GnRH Antagonist
Posology:
• Flexibility at the start of stimulation and at the day of hCG (plus or minus one day).
• Start ganirelix day 5 as FSH activity is high during the first days of stimulation
• Daily 150 IU rFSH is enough to finish the cycle in normal responders
• Coasting is possible for up to three days in high responders
• No need for rFSH on the day of hCG
• High responders may receive GnRH agonist instead of hCG

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Notes de l'éditeur