1. A new drug called Elonva (corifollitropin alfa) provides a patient-friendly approach to ovarian stimulation in ART by reducing the complexity and burden of treatment through shorter stimulation cycles and fewer injections compared to traditional gonadotropins. 2. Studies show Elonva individualizes treatment by optimizing ovarian response and risk of OHSS while maintaining or increasing pregnancy rates. 3. Starting gonadotropin stimulation on cycle day 4 reduces the total dose and duration of stimulation compared to day 2 with no difference in outcomes.

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Elonva: A new
patient friendly
approach in ART
Daniel S. Seidman, MD
Department of Ob/Gyn,
Sheba Medical Center,
Sackler School of Medicine,
Tel-Aviv University

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6%
6%
8%
8%
9%
11%
25%
28%
0 5 10 15 20 25 30
Physical or Psychological Treatment Burden
is a Primary Reason for Dropout
Physical or psychological burden of treatment
Unknown
Relational problems/divorce
Ethical objections to ICSI treatment after failed
IVF treatment
Adoption
Poor embryo quality
Poor response/signs of ovarian aging
Other
Among 384 couples undergoing IVF treatment, 65 (17%) dropped out
Reason for Dropout
Percentage
Adapted from Verberg et al. Hum Reprod. 2008;23:2050.

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Reasons couples discontinued
treatments before achieving two live
children at each stage:
Ceased ART for 1st
child (25)
Did not return for
2nd child (13)
Ceased ART for 2nd
child (13)
Stage treatment
discontinued (n)
9 (36%)5 (38.5%)4 (30.8%)Psychological
burden
9 (36%)04 (30.8%)Lost hope of success
4 (16%)01 (7.7%)Medical staff advice
1 (4%)02 (15.4%)Bureaucratic
difficulties
2 (8%)3 (23.1%)1 (7.7%)Divorce
01 (7.7%)1 (7.7%)Major illness
04 (30.8%)0Not ready yet for 2nd
child
12 (48%)8 (61.5%)4 (30.8%)Eventually returned
/ plan to return for
treatments
Lande et al., 2014

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Reasons couples chose to cease ART
treatments before completing all
subsidized cycles
Brandes et al.Olivius et al.Smeenk et al.Lande et al.
15.3%21%20.5%34.3%*Drop-out rate
1-21-21.55.2**Number of
cycles
49%32.3%38.5%39.1%Psychological
burden
33%31%30.8%10.9%Physician
recommendation
9%18.1%08.7%Divorce /
relational
problem
18%1.9%04.3%Health problem
0021.8%8.7%Postpone
treatment
7%0028.3%Lost hope

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1 2 3 4 5 6
ECPR = expected cumulative pregnancy rate; RCPR = real cumulative pregnancy rate.
Schroder et al. RBM Online. 2004;8:600.
Difference between
expected and real
pregnancy rates is caused
by the diminishing size of
the cohort due to dropout
frequency
Dropouts Negatively Impact Real
Cumulative Pregnancy Rates
Data from 4102 IVF cycles in 2130 women
Cycles
0
10
20
30
40
50
60
70
Percent
Dropout rate ECPR RCPR
(n=2130) (n=1087) (n=518) (n=222) (n=74) (n=36)

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Patient-Centered Approach in
IVF
 Increase cumulative live birth rates
 Optimize risk/benefit ratio
–Individualization of management
strategies
– Reduce OHSS and cycle
cancellation
 Reduce complexity and patient
burden
–Shorter treatment cycles
–Fewer overall injections

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The objective of the individualization
of the treatment strategy
To increase the
percentage of patients
with an appropriate
number of retrieved
oocytes, while reducing
the number of women at
high risk of cycle
cancellation due to poor
response or ovarian
hyperstimulation
syndrome (OHSS).

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Elonva:
Individualization
of treatment
10Elonva 100 mg
+ rFSH
± Agonist trigger
Elonva 150
mg
+ pure hMG
Elonva 100 or 150 mg
+rFSH

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33 Injections
Normal
respon
se
patient
s
Hp hMG

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Only 6 Injection
• 24
oocytes
• 10
fertilized
• 2
embryos
Normal
respon
se
patient
s
rFSH/LH

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36 Injections 11 Injections
hMG hMG

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Low response Good
response

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• 9 Oocytes
Fertilized
•5 embryos
transferred
Good response
patients
hMG

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29 oocytes
14 fertilized
3 embryos
transferred
Pregnant
Good response
patients
hMG

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Study Question:
 Is the ovarian response to
controlled ovarian stimulation
(COS) related to the ongoing
pregnancy rate when taking into
account the main covariates
affecting the probabilities of
pregnancy following fresh embryo
transfer?

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Summary answer:
 In patients treated with
corifollitropin alfa or daily
recombinant FSH (rFSH) in a
GnRH-antagonist protocol:
– A high ovarian response did NOT
compromise ongoing pregnancy
rates
– Increased cumulative pregnancy
rates following fresh and frozen-
thawed embryo transfer.

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Corifollitropin alfa (Elonva®)
 Is it safe?

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Comparative incidence of OHSS
following ovarian stimulation with
corifollitropin alfa or recombinant
FSH
 Overall, 1705 patients received
corifollitropin alfa and 5.6%
experienced mild, moderate or severe
OHSS.
 In the randomized controlled trials,
Engage and Ensure, the pooled
incidence of OHSS with corifollitropin
alfa was 6.9% (71/1023 patients)
compared with 6.0% (53/880 patients) in

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Comparative incidence of OHSS
following ovarian stimulation with
corifollitropin alfa or recombinant
FSH
 Adjusted for trial, the odds ratio for
OHSS was 1.18 (95% CI 0.81–1.71)
indicating that the risk of OHSS for
corifollitropin alfa was similar to that
for rFSH.
 Despite a higher ovarian response with
corifollitropin alfa compared with rFSH
for the first 7 days of ovarian
stimulation, the incidence of OHSS was

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Good Response Patient
Small follicles
hMG

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Good Response Patient

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Agonist trigger !
0.2 mg Decapeptyl
Good Response
Patient
Large follicles
hMG

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Poor responders
 Most difficult patients and fastest
growing group
 Difficult to define
 Bologna criteria
–AMA (≥ 40 y)
–previous poor response (≤ 3
oocytes)
–AFC<7 or AMH < 1.1ng/mL

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10 Injections
Poor
response
patients
hMG

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3 oocytes
3 embryos
transferred
Pregnant
Poor
response
patients
hMG

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Poor Response Patient  18 Days
 1 oocyte
hMG

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Poor Response
 12 Days
 3
oocytes
hMG

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Poor
response
patients
HP hMG

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Objective:
 To identify whether women with
poor ovarian response may benefit
from treatment with corifollitropin
alfa in a GnRH antagonist protocol.
 Design: Retrospective pilot study.
 Intervention: Corifollitropin alfa
(150 mg) followed by 300 IU rFSH
in a GnRH antagonist protocol.
Polyzos et al. Fertil Steril 2013

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Conclusions:
 Treatment of poor ovarian
responders, as described by the
Bologna criteria, with
corifollitropin alfa in a GnRH
antagonist protocol results in low
pregnancy rates, similarly to
conventional stimulation with a
short agonist protocol.
Polyzos et al. Fertil Steril 2013

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Study Question:
 Will sequential administration of
highly purified (hp)-HMG after
corifollitropin alfa in a GnRH
antagonist protocol benefit women
with poor ovarian response
according to the Bologna criteria?

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Endocrine profiles during the follicular phase
in women who are poor ovarian responders,
according to age
E2, estradiol. *P . 0.05 for all comparisons between age groups
at Days 2, 7, 9 and day of hCG triggering.

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Summary Answer:
 Corifollitropin alfa followed by hp-
HMG in a GnRH antagonist
protocol results in very promising
pregnancy rates, albeit only in
young (<40 years old) poor ovarian
responders fulfilling the Bologna
criteria.

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Objective:
 To identify predictors of ovarian
response in women undergoing
ovarian stimulation with
corifollitropin alfa in a GnRH
antagonist protocol and determine
specific thresholds for the
prediction of low and excessive
responders.

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Conclusions:
 AMH and AFC are the best
predictors for low and excessive
response in women treated with
corifollitropin alfa in an antagonist
protocol.
 Using AMH and AFC to select
suitable candidates for treatment
with corifollitropin alfa may result
in a safe and convenient

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Corifollitropin alfa (Elonva®)

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Elonva:
Individualization
of treatment
10Elonva 100 mg
+ rFSH
± Agonist trigger
Elonva 150
mg
+ pure hMG
Elonva 100 or 150 mg
+rFSH

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Day When hCG Criterion Was Met
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 rFSH
Engage
Adapted with permission from Fauser BC et al. Reprod Biomed Online. 2010;21:593‒601.

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Corifollitropin alfa daily
rFSH

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Conclusions
 Early responders receiving HCG prior
to or on stimulation day 8 have
advanced follicular development but
the final number and size of
preovulatory follicles is comparable to
those of normal responders.
 A short follicular phase of stimulation
did not affect the number of oocytes
retrieved, the number of good-quality
embryos obtained or the ongoing
pregnancy rates.

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Corifollitropin alpha: donors
Requena et al. RBMOnline 2013
Efficacy
Corifollitropin
(n=60)
recFSH
(n=60)
Age (y) 23.2 24.4
Weight (kg) 65.6 64.9
Days of stim 10 10
ready at D8 26% 27%
COC 15.1 16.5
MII 85% 77%
OHSS - -

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Corifollitropin alpha: donors
Requena et al. RBMOnilne 2013
Patient satisfaction
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%

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Study Conclusions
 No significant differences were found
in any analysed parameters between
treatments.
 However, when donors who had
undergone both treatments chose
which treatment they preferred, the
results clearly showed a positive trend
towards choosing corifollitropin a,
confirming that this protocol may
reduce treatment burden and increase
donor compliance.

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Overall Conclusions
 Corifollitropin alfa offers an attractive
new option for ovarian stimulation.
 Proper patient selection avoids over
response.
 OHSS totally preventable by triggering
with GnRH agonist.
 Corifollitropin alfa may offer an
advantage to young poor response
patients
 Corifollitropin alfa use is associated

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Thanks for listening

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Conclusions
 Treatment flexibility of ovarian stimulation does not
substantially affect the clinical outcome in patients’
treatment following initiation of ovarian stimulation
with either corifollitropin alfa or with daily rFSH in a
gonadotropin-releasing hormone antagonist

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Day 4

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37 years old
Severe OTA

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
 1.Usage of estradiol pretreatment for planning cycles
2. Elevated levels of progesterone at the start of
stimulation, approaches to manage it
3. When (which day) to start gonadotropins (particularly
ELONVA)?
4. Does hCG delay for 1-2 day influence on the chance
of pregnancy?
5. How “quickly” the ovaries will respond to Elonva
stimulation?
6. Trigger agonist
7. Which extra dose of rFSH required on the 8th day, if
not met the criteria for the hCG?

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Results
 The total dose of rFSH at the end of the follicular
phase was significantly reduced in the CD4 group
compared with the CD2.
 A significant reduction of total duration of rFSH
stimulation in the CD4 group was also observed.
 The number of cumulus-oocyte-complexes was
comparable in both treatment groups
 Ongoing pregnancy rates of 48% in the CD2 group
and 41% in the CD4 group were achieved.
 Final oocyte maturation was triggered with GnRH
agonist instead of hCG in two patients in the CD2
group and in eight patients in the CD4 group,
because of an increased risk of ovarian

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Conclusion
 If the approach of starting ovarian
stimulation on Day4 of the cycle
could be implemented in a large
population of infertile patients, it
would result in a significant
reduction of gonadotrophin
consumption.