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
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
