Ulipristal Acetat- Effekt på myomrelaterad blödninguterine myoma(s) 1 uterine myoma of 3 cm...
Transcript of Ulipristal Acetat- Effekt på myomrelaterad blödninguterine myoma(s) 1 uterine myoma of 3 cm...
Ulipristal Acetat- Effekt på myomrelaterad blödning
Professor Kristina Gemzell-Danielsson
Karolinska Institutet
Stockholm
ESMYA (UPA) – A SELECTIVE PROGESTERONE RECEPTOR
MODULATOR (SPRM)
● Progesterone receptor ligands can possess activity ranging from pure antagonist
activity through mixed antagonist/agonist activity to pure agonist activity
● SPRMs are progesterone receptor ligands with mixed antagonist/agonist activity
O
CH3 N
CH3
H3C
C
OH
C CH3
RU-486 (Mifepristone)
O
H
H
H
N
OCH3
HO
CH2OCH3
J-867 (Asoprisnil)
O
N
CH3
H3C OCH3
OCCH3
O
Ulipristal acetate (Esmya®)
O
O
OMe
N
OAc
CH3
H3C
Telapristone acetate (Proellex®)
N
O
OH OH
ZK98299 (Onapristone)
Chabbert-Buffet N, et al. Hum Reprod Update 2005;11:293–307
Spitz IM. Curr Opin Investig Drugs 2006;7:882–90
Bouchard P et al. Fertility and Sterility 2011;96:1175-89
SPRM: Selective Progesterone Receptor Modulator
UPA: Ulipristal acetate
SPRM MODE OF ACTION:
EFFECT ON PITUITARY AND ENDOMETRIUM
• Ulipristal Acetate (UPA) - ESMYA:
● Inhibits ovulation (progesterone levels maintained low)
● Reduces LH and FSH secretion while maintaining mid follicular estrogen levels
● Direct effect on the endometrium:
● Fast reduction of bleedings
● PAEC (~60% of patients, benign, reversible)
● Endometrial thickness ( 10-15% of patients, reversible)
● Direct effect on fibroids, reducing fibroid volume
● Inhibition of cell proliferation
● Induction of apoptosis
Hypothalamus
Pituitary
Endometrial
and
uterine
tissue
• Chabbert-Buffet N, et al. J Clin Endocrinol Metab 2007;92:3582–3589
• Donnez J, et al. New Engl J Med 2012;366(5):409–420.
1. Donnez J, et al. New Engl J Med 2012;366(5):421–432.
2. Esmya SmPC
SPRM: Selective Progesterone Receptor Modulator
UPA: Ulipristal acetate
PEARL I:
BASELINE CHARACTERISTICS*
1PBAC: Pictorial Bleeding Assessment Chart *ITT Population
Baseline Medical
Status
Placebo (N=48) UPA 5 mg (N=95) UPA 10 mg (N=94)
Mean PBAC 460
(119–1284)
487
(118–1645)
411
(102–1570)
Mean Hemoglobin 9.55 g/dL 9.32 g/dL 9.46 g/dL
Mean hematocrit 32.5% 32.1% 32.4%
Premenopausal women (aged 18–50 years) with
uterine myoma(s) ● 1 uterine myoma of 3 cm diameter but no
myoma >10 cm diameter
Excessive uterine bleeding ● PBAC score >100 during Days 1–8 of menstruation
Anaemia required (Hg < 10.2 mg/dl)
Eligible for surgical procedure ● Hysterectomy, myomectomy, uterine artery
embolisation or endometrial ablation
Design Inclusion Criteria
PEARL I
Donnez J, et al. N Engl J Med 2012;366:409−20 (PEARL I)
PEARL I:
BLEEDING CONTROL IN MORE THAN 90%
OF WOMEN TREATED WITH UPA (PRIMARY ENDPOINT)
Patients with
PBAC <75
at the End Of
Treatment
(EOT), week
13; ITT
18,40%
91,35% 92,43%
0%
20%
40%
60%
80%
100%
WEEK 13 *p<0.001 vs. placebo
Placebo UPA 5 mg UPA 10 mg
*
PEARL I
*
Patients
Donnez J, et al. N Engl J Med 2012;366:409−20 (PEARL I)
PEARL I:
TIME TO CONTROL OF BLEEDING
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80 90 100
Time (days)
Patients
(%
)
7 days
PBAC <75
PEARL I
UPA 10 mg
UPA 5 mg
Placebo
Bleeding was controlled 7 days from treatment initiation, in
● 75.9% of UPA 5 mg patients and
● 82.7% of patients in the UPA 10 mg group
Donnez J, et al. N Engl J Med 2012;366:409−20 (PEARL I)
UPA: Ulipristal acetate
PEARL II:
BASELINE CHARACTERISTICS*
1PBAC: Pictorial Bleeding Assessment Chart *ITT Population
Baseline Medical
Status
UPA 5mg (N=93) UPA 10 mg (N=95) Lupron 3,75 mg
(N=93)
Mean PBAC 379
(109–1984)
328
(120–1809)
404
(102–2104)
Premenopausal women (aged 18–50 years) with
uterine myoma(s) ● 1 uterine myoma of 3 cm diameter but no
myoma >10 cm diameter
Excessive uterine bleeding ● PBAC score >100 during Days 1–8 of menstruation
Anaemia not required
Eligible for surgical procedure ● Hysterectomy, myomectomy, uterine artery
embolisation or endometrial ablation
Design Inclusion Criteria
PEARL II
Donnez J, et al. N Engl J Med 2012;366:409−20 (PEARL I)
PEARL II:
TIME TO CONTROL OF BLEEDING
PBAC<75
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80 90 100
Time (days)
Patients
(%
)
UPA 5 mg
UPA 10 mg
Lupron 3.75 mg
7 days
PEARL II
30 days
UPA normalised bleeding faster
than GnRHa (7 days vs 30 days)
Donnez J, et al. N Engl J Med 2012;366:421−32 (PEARL II)
UPA: Ulipristal acetate
UPA 5 mg
UPA 10 mg
PEARL II:
UPA STOPS BLEEDING FASTER AND MORE
CONSISTENTLY VS GnRHa (INDIVIDUAL PATIENT DATA)
Daily
PB
AC
sco
re
Da
ily P
BA
C s
co
re
Daily
PB
AC
sco
re
Planned timepoint (days) 7 days
7 days Planned timepoint (days)
PEARL II
28 days
GnRHa
After first menstruation, most UPA
patients are in amenorrhoea, while
many GnRHa patients have further
bleeds during the next 3 weeks due to
flare-up effect
Donnez J, et al. N Engl J Med 2012;366:421−32 (PEARL II)
UPA: Ulipristal acetate
PEARL I (POST HOC ANALYSIS):
INDIVIDUAL BLEEDING EXPERIENCE
OBJECTIVES
● To analyse the Individual Bleeding Pattern of patients treated with
UPA for 90 days:
• During the period from 1st menstruation, at which UPA is started, until
the treatment is completed
• In the presence of sub-mucosal fibroids vs. no fibroids protruding in the
uterine cavity
• In the presence of PAEC vs. no PAEC
METHODOLOGY
● Post-hoc sub-analysis of PEARL I data
Data on file. PEARL I Post hoc analysis on menstrual bleeding experience in PEARL I clinical study
PGL4001's (ulipristal acetate) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata
UPA: Ulipristal acetate
UPA 5 mg (n=95)
UPA 10 mg (n=94)
Placebo (n=48)
Bleeding Control at the EOT:
● UPA 5 mg PBAC < 75: 91.5%
● UPA 10 mg PBAC <75: 92.3%
PEARL I:
BLEEDING RESULTS SUMMARY
Time to control of bleeding Time to persistant amenorrhea
Amenorrhea at EOT:
● UPA 5 mg PBAC < 2: 73.4%
● UPA 10 mg PBAC<2: 81.3%
7 days 8 days
Donnez J, et al. N Engl J Med 2012;366:409−20 (PEARL I)
EOT: End of Treatment
UPA: Ulipristal acetate
Time to persist amenorrhea
PEARL I (POST HOC ANALYSIS)
What was the individual bleeding pattern of women over the
13 week treatment course?
There are established descriptions of bleeding patterns in the
literature that permit classification of experience
Can these better illuminate the data in terms of individual
experience?
Data on file. PEARL I Post hoc analysis on menstrual bleeding experience in PEARL I clinical study
PGL4001's (ulipristal acetate) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata
Adapted from WHO Belsey System of Bleeding Pattern
Placebo UPA 5 mg UPA 10 mg
No Bleeding No bleeding or PBAC <12 over 90 days 2.1% 63.9% 71.3%
This system establishes criteria for defining clinically important bleeding patterns during a 90-day reference period.
Placebo UPA 5 mg UPA 10 mg
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
PEARL I (POST HOC ANALYSIS)
NO BLEEDING OR PBAC<12 OVER 90 DAYS
63.9% 71.3%
2.1%
Data on file. PEARL I Post hoc analysis on menstrual bleeding experience in PEARL I clinical study
PGL4001's (ulipristal acetate) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata
UPA: Ulipristal acetate
Adapted WHO Belsey System of Bleeding Pattern
Placebo UPA 5 mg UPA 10 mg
No Bleeding No bleeding or PBAC <12 over 90 days 2.1% 63.9% 71.3%
Infrequent Bleeding 1 or 2 bleeding-spotting episodes 6.3% 17.9% 12.8%
This system establishes criteria for defining clinically important bleeding patterns during a 90-day reference period.
Placebo UPA 5 mg UPA 10 mg
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
PEARL I (POST HOC ANALYSIS)
BLEEDING CONTROL (NO BLEEDING + INFREQUENT BLEEDING)
81.8% 84.1%
8.4%
Data on file. PEARL I Post hoc analysis on menstrual bleeding experience in PEARL I clinical study
PGL4001's (ulipristal acetate) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata
UPA: Ulipristal acetate
PEARL I (POST HOC ANALYSIS)
SUBMUCOUS FIBROIDS AND BLEEDING
PATTERNS IN PEARL I
Pe
rce
nta
ge
of
Pa
tie
nts
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Placebo n=48 UPA Group n=189
Women with sub-mucous fibroids are more likely to have 1 of the 3 “Other
bleeding patterns” (irregular, frequent or prolonged)
29.7%
12.0%
84%
70.3%
Presence of Submucous fibroids
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Placebo n=48 UPA Group n=189
Non Presence of Submucous fibroids
95.6%
3.3% 4.5%
81.8%
Bleeding Control
Regular Bleeding
Other Bleeding Pattern
13.5%
Data on file. PEARL I Post hoc analysis on menstrual bleeding experience in PEARL I clinical study
PGL4001's (ulipristal acetate) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata
UPA: Ulipristal acetate
PAEC: glandular cyst dilatation PAEC: low mitotic activity
Data on file. PEARL I Post hoc analysis on menstrual bleeding experience in PEARL I clinical study
PGL4001's (ulipristal acetate) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata
PEARL I (POST HOC ANALYSIS)
What was the experience of individual women
over the 13 week treatment phase?
Were women who experienced the “other” bleeding patterns
(i.e. Irregular, Prolonged or Frequent Bleeding) more likely to
have PAEC?
PEARL I (POST HOC ANALYSIS)
INFLUENCE OF PAEC ON BLEEDING
PATTERN
Pe
rce
nta
ge
of
Pa
tie
nts
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Women with PAEC does not seem to influence the ability of UPA to control
the bleeding
20%
80%
Presence of PAEC
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Non Presence of PAEC
12.5%
87.5
Bleeding Control
Regular Bleeding
Other Bleeding Pattern
UPA group (n=115) UPA group (n=40)
Pe
rce
nta
ge
of
Pa
tie
nts
Data on file. PEARL I Post hoc analysis on menstrual bleeding experience in PEARL I clinical study
PGL4001's (ulipristal acetate) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata
UPA: Ulipristal acetate
CONCLUSIONS ON BLEEDING CONTROL
PEARL I & PEARL II
•UPA treatment rapidly stops excessive bleeding
● Bleeding control (defined as PBAC < 75) in > 90% by EOT
● Bleeding control obtained within 10 days of treatment
● Induces amenorrhoea (defined as PBAC < 2) in > 70% by EOT
● Stops heavy bleeding faster than GnRHa
Donnez J, et al. New Engl J Med 2012;366(5):409–420.
Donnez J, et al. New Engl J Med 2012;366(5):421–432.
UPA: Ulipristal acetate
CONCLUSIONS PEARL I (POST HOC ANALYSIS)
• Bleeding control:
● The predominant bleeding pattern in women treated with UPA is ”No bleeding”
(defined as ”no bleeding” or PBAC < 12 in a 90 days period)
63,9% with UPA 5mg and 71,3% with UPA 10mg
Submucosal fibroids:
● Women with submucosal fibroids are more likely to experience prolonged, irregular
and frequent bleeding,
● The vast majority of women with submucosal fibroids experienced no bleeding
PAEC:
● Was not a factor in the bleeding patterns and did not influence the ability of UPA to
control bleeding
Data on file. PEARL I Post hoc analysis on menstrual bleeding experience in PEARL I clinical study
PGL4001's (ulipristal acetate) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata
UPA: Ulipristal acetate