ESMYAO

NCH3

H3C OCH3

OCCH3O

1.Chabbert-Buffet et al. J Clin Endocrinol Metab 2007;92:3582–3589

Dr. Francisco Vázquez Fernández

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

Phase IIa study treatment

Placebo

3 cycles / 90–102 days

BASELI

HYSTER

RAND

ESMYA 10 mg daily

ESMYA 20 mg daily

INE

CYCLE

RECTOMY

DOMISE

Phase IIb study treatment

Patient choice:

• Surgery

Placebo

3 cycles / 90–102 days

BASELI

RAND

• Surgery• No surgery• Further ESMYA

treatment

ESMYA 10 mg daily

ESMYA 20 mg daily

INE

CYCLE

DOMISE

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

ESMYA reduces fibroid size compared with placebo

7,311

0

5

10

15

Cha

nge

in fi

broi

d vo

lum

e (%

)

PlaceboESMYA 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

Cha

nge

in fi

broi

d vo

lum

e (%

)

ESMYA 10 mgESMYA 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

PEARL I: Randomised, double -blind Phase III trial of ESMYA vs placebo

RAND

SURPatients with

3 months

Once-daily oral ESMYA 5 mg+ concomitant iron

DOMISE

RGERY

Patients withuterine 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

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

PEARL II: Randomised, double -blind Phase III trial of ESMYA vs GnRHa

RAND

SURPatients with

3 months

Once-daily oral ESMYA 5 mg

http://www.clinicaltrials.gov/ct2/show/NCT00740831?term=NCT00740831&rank=1GnRHa, gonadotrophin-releasing hormone agonist

DOMISE

RGERY

Patients withuterine fibroids Once-daily oral ESMYA 10 mg

Intramuscular leuprorelin3.75 mg once every 4 weeks

ClinicalTrials.gov Identifier: NCT00740831

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

PEARL II: Patients screened and randomised, by country

157

126100

125

150

175

Num

ber

subj

ects

Screened Randomised

3651

2133

93

2841

20

71

9 7 12

0

25

50

75

100

Austria Belgium Germany Israel Italy Poland Spain

Num

ber

subj

ects

PEARL II Study - Spanish Participants

20

25

30

35

40

Treatment completed

Early termination

24

19

14

85

2

63

8

0

5

10

15

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 treatmentEXTENSION• Investigate efficacy and safety of long-term on-off use up to a total of 4

times 3 months ESMYA

EsmyaPrimolut

Nor

Menstruation

Day 14

Hysterec-tomy

End of study Follow-up

visit 50%

N=200

Uterus-

PEARL III: Design

Esmya10 mg3 months

Nor 10mg

Placebo10d

Menstruation

Day 14 –

Biopsy No

surgery

PGL09-027Extension

50%

Double blindOpen label Optional extension

sparing surgery

PEARL III: DesignPGL 4001´S EFFICACY ASSESMENT IN REDUCTION

OF SYMPTOMS DUE TO UTERINE LEIOMYOMATA

PEARL IIIV

isit

A –

Ext

ensi

on s

tart

Vis

itB

Vis

itC

Vis

itE

Vis

itF

–F

-up

(VE

+3m

ths)

Vis

itD

–E

nd o

f ES

MY

A

TA TB TC

ESMYA ESMYA ESMYAESMYA

PEARL III ExtensionVisit1

-S

creening

Visit2 -

Baseline

Visit6 –

end. Biopsy

Visit4 –

Open Label

V isit3 -

Open-label

V isit5 –

End of E

SM

YA

Visit7a –

Follow

up

ESMYA ESMYA open-label treatment

Progestin/placebo double-blind treatment

Menses

Telephone call from investigator

Visit7b –

Follow

up if no extension