This document provides information on ESMYA (ulipristal acetate), a selective progesterone receptor modulator being studied for the treatment of uterine fibroids. It summarizes results from Phase II and Phase III clinical trials that showed ESMYA significantly reduced fibroid size and bleeding compared to placebo. The Phase III PEARL I and PEARL II trials are further evaluating ESMYA's efficacy and safety profile compared to placebo or a gonadotropin-releasing hormone agonist. Additional trials are exploring long-term use of ESMYA and its effects on bleeding patterns, endometrial histology, and potential for uterus-sparing treatments.

1. ESMYA
O
N
CH3
H3C OCH3
OCCH3
O
1.Chabbert-Buffet et al. J Clin Endocrinol Metab 2007;92:3582–3589
Dr. Francisco Vázquez Fernández

2. Introduction to ESMYA
• ESMYA (ulipristal acetate; CDB-2914) is a selective
progesterone receptor modulator (SPRM)
N
CH3
H3C OCH3
OCCH3
• Induces amenorrhoea and inhibits ovulation in normal
women1
O
OCCH3
O
1.Chabbert-Buffet et al. J Clin Endocrinol Metab 2007;92:3582–3589

3. Phase IIa study treatment
Placebo
3 cycles / 90–102 days
B
A
S
E
L
I
H
Y
S
T
E
R
R
A
N
D
ESMYA 10 mg daily
ESMYA 20 mg daily
I
N
E
C
Y
C
L
E
R
E
C
T
O
M
Y
D
O
M
I
S
E

4. Phase IIb study treatment
Patient choice:
• Surgery
Placebo
3 cycles / 90–102 days
B
A
S
E
L
I
R
A
N
D • Surgery
• No surgery
• Further ESMYA
treatment
ESMYA 10 mg daily
ESMYA 20 mg daily
I
N
E
C
Y
C
L
E
D
O
M
I
S
E

5. Endpoints in both studies
• Primary endpoint
– Change in fibroid size, assessed by magnetic
resonance imaging (MRI)
• Secondary endpoints
– Effect on ovulation and folliculogenesis– Effect on ovulation and folliculogenesis
– Change in size of the largest fibroid
– Changes in fibroid-related symptoms
– Effect on quality of life
– Change in adrenal function
– Adverse events

6. ESMYA reduces fibroid size compared
with placebo
7,3
11
0
5
10
15
Changeinfibroidvolume(%)
Placebo
ESMYA 10 mg
Mean percentage change in total fibroid volume from baseline
Phase IIa (n=19) Phase IIb (n=38)
-18,7
-15,5-16,5
-19,1
-20
-15
-10
-5
Changeinfibroidvolume(%)
ESMYA 10 mg
ESMYA 20 mg
p=0.0151
1Combined ESMYA arms vs placebo
p=0.00581
• More patients achieve a reduction in fibroid size with ESMYA than with placebo

7. PEARL I: Randomised, double-blind
Phase III trial of ESMYA vs placebo
R
A
N
D
S
U
RPatients with
3 months
Once-daily oral ESMYA 5 mg
+ concomitant iron
D
O
M
I
S
E
R
G
E
R
Y
Patients with
uterine fibroids
http://www.clinicaltrials.gov/ct2/show/NCT00755755?term=NCT00755755&rank=1
Once-daily oral ESMYA 10 mg
+ concomitant iron
Placebo
+ concomitant iron
ClinicalTrials.gov Identifier: NCT00755755

8. PEARL I: Study objectives
Primary objectives
• Demonstrate superior efficacy of ESMYA + iron versus placebo + iron for:
– Reducing excessive uterine bleeding prior to surgery
– Reducing total fibroid volume prior to surgery
• Assess overall safety of ESMYA in subjects with uterine fibroids
Secondary objectives
• Demonstrate superior efficacy of ESMYA + iron versus placebo + iron at
correcting anaemia caused by uterine fibroidscorrecting anaemia caused by uterine fibroids
• Demonstrate improvements in fibroid-related symptoms, such as pain
• Assess the capacity of ESMYA to decrease uterine volume
Exploratory objectives
• Proportion of subjects switched to less invasive surgery or for whom surgery is
cancelled due to improved condition at treatment completion
• Proportion of subjects undergoing blood transfusion, the number of transfusions
and volume transfused per subject

9. PEARL II: Randomised, double-blind
Phase III trial of ESMYA vs GnRHa
R
A
N
D
S
U
RPatients with
3 months
Once-daily oral ESMYA 5 mg
http://www.clinicaltrials.gov/ct2/show/NCT007408
31?term=NCT00740831&rank=1GnRHa, gonadotrophin-releasing hormone agonist
D
O
M
I
S
E
R
G
E
R
Y
Patients with
uterine fibroids Once-daily oral ESMYA 10 mg
Intramuscular leuprorelin
3.75 mg once every 4 weeks
ClinicalTrials.gov Identifier: NCT00740831

10. PEARL II: Study objectives
Primary objective
• Demonstrate non-inferior efficacy of ESMYA versus GnRHa for reducing
excessive uterine bleeding prior to surgery
• Demonstrate superior safety and tolerability of ESMYA versus GnRHa for
castration-related symptoms and their consequences
Secondary objectives
• Demonstrate improvements in fibroid-related symptoms, such as QOL and pain• Demonstrate improvements in fibroid-related symptoms, such as QOL and pain
• Assess the capacity of ESMYA to:
– Decrease uterine volume
– Decrease the volume of the 3 largest fibroids
Exploratory objectives
• Proportion of subjects switched to less invasive surgery or for whom surgery is
cancelled due to improved condition at treatment completion
• Proportion of subjects undergoing blood transfusion, the number of transfusions
and volume transfused per subject
GnRHa, gonadotrophin-releasing hormone agonist; QOL, quality of life

11. PEARL II: Patients screened and
randomised, by country
157
126
100
125
150
175
Numbersubjects
Screened Randomised
36
51
21
33
93
28
41
20
71
9 7 12
0
25
50
75
100
Austria Belgium Germany Israel Italy Poland Spain
Numbersubjects

12. PEARL II Study - Spanish Participants
20
25
30
35
40
Treatment completed
Early termination
2
4
19
14
8
5
2
6
3
8
0
5
10
15

13. 3 months ESMYA (open-label) followed by 10 days progestin (Primolut Nor®
10mg) or placebo (double blind)
EFFICACY
• To investigate the efficacy of ESMYA on
– Uterine bleeding
– Myoma size
– Pain
– Quality of life
PEARL III: Study objectives
– Quality of life
SAFETY
• To assess safety of ESMYA
• To extend the existing safety database
EXPLORATORY
• Uterine bleeding characteristics upon return of menses
• Histology of the endometrium
• Time to return of menstruation after ESMYA treatment
EXTENSION
• Investigate efficacy and safety of long-term on-off use up to a total of 4
times 3 months ESMYA

14. Esmya
Primolut
Nor
Menstruation
Day14
Hysterec
-tomy
End of study
Follow-up
visit
50%
N=200
Uterus-
PEARL III: Design
Esmya
10 mg
3 months
Nor
10mg
Placebo
10d
Menstruation
Day14–Biopsy
No
surgery
PGL09-027
Extension
50%
Double blindOpen label Optional
extension
sparing
surgery

15. PEARL III: Design
PGL 4001´S EFFICACY ASSESMENT IN REDUCTION
OF SYMPTOMS DUE TO UTERINE LEIOMYOMATA
PEARL III VisitA–Extensionstart
VisitB
VisitC
VisitE
VisitF–F-up
(VE+3mths)
VisitD–EndofESMYA
TA TB TC
ESMYA ESMYA ESMYAESMYA
PEARL III Extension
Visit1-Screening
Visit2-Baseline
Visit6–end.Biopsy
Visit4–OpenLabel
Visit3-Open-label
Visit5–EndofESMYA
Visit7a–Followup
ESMYA ESMYA open-label treatment
Progestin/placebo double-blind treatment
Menses
Telephone call from investigator
Visit7b–Followupif
noextension