1 Selective Progesterone modulators – the future ! Kristina Gemzell Danielsson, Kvinnoklinike n / WHO-center Karolinska Universitetssjukh uset/ Karolinska Institutet Stockholm, Sweden Disclosures of Financial Relationships Gemzell-Danielsson has received honorarium as an advisory board member and/or invited speaker at Merck (MSD), Bayer, Exelgyne, Actavis, Gedeon Richter, Exeltis, and HRA-Pharma K Gemzell Danielsson Overview of the presentation • Background • SPRMs - in non pregnant women – For contraceptive use – Other potential health benefits • Conclusions SELECTIVE PROGESTERONE RECEPTOR MODULATORS(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 ac tiv ity O CH3 N CH3 H3C C OH C CH3 RU-486 (Mifepristone) O H H H N O CH3 HO CH2O CH3 J-867 (Asoprisnil) O N CH3 H3C O CH3 O CCH3 O Ulipristal acetate (E smya®) O O OMe N O Ac CH3 H3C Telapristone acetate (P roellex®) N O OH OH ZK 98299 (Onapristone ) Chabbert -Buf f et N, et al . Hum Repr od Updat e 2005; 11: 293–307 Spi tz I M . Cur r O pi n I nvest i g Drugs 2006; 7: 882–90 Bouchar d P et al . Fer t i l i ty and St eri l i ty 2011; 96: 1175- 89 SPRM : Sel ect i ve Pr ogest er one Recept or M odul at or UPA: Ul i pr i st al acet at e SPRMS - BOTH PROGESTERONE AGONISTS AND PROGESTERONE ANTAGONISTS, DEPENDING ON TARGET TISSUE SPR Ms Basal transcription apparatus Transcription activation (progesterone agonism) No transcription activation (progesterone antagonism) PR PR PR PR Co-activators Co-repressors Progesterone response element Chabbert- Bufet N,eta l. Hu m Re pro d Upda te 20 05 ; 1 1:29 3– 307 Ma d a u s s KP,et a l. Mo l End ocri no l 20 07 ; 2 1:1 066 –8 1 Spitz IM. CurrOpi n I nves t i g Drug s 20 06;7 : 8 82 –90 Bo u c h a rd Pe ta l. Fertil it y and Steri l i ty 201 1;96 :11 75-8 9 PR: Pro g e stero ne Rec ep t or SPRM: Se l e cti ve Proge stero ne Rec ep t o rMo du l at or K Gemzell Danielsson SPRMs Effects during the cycle and in pregnancy Contraception Contragestion Pregnancy Interruption Adjuvant to late Pregnancy termination Labour Induction Follicular phase
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1
Selective Progesterone modulators– the future !
Kristina Gemzell Danielsson,Kvinnokliniken / WHO-centerKarolinska Universitetssjukhuset/ Karolinska InstitutetStockholm, Sweden
Disclosures of Financial Relationships
Gemzell-Danielsson has received honorarium as an
advisory board member and/or invited speaker at
Merck (MSD), Bayer, Exelgyne, Actavis, Gedeon
Richter, Exeltis, and HRA-Pharma
K Gemzell Danielsson
Overview of the presentation
• Background• SPRMs - in non pregnant women
– For contraceptive use– Other potential health benefits
• Conclusions
SELECTIVE PROGESTERONE RECEPTOR MODULATORS(SPRM)
● Progesterone receptor ligands can possess activ ity ranging from pure antagonist activ ity through mixed antagonist/agonist activ ity to pure agonist activ ity
● SPRMs are progesterone receptor ligands with mixed antagonist/agonist activ ity
O
CH3N
CH3
H3C
C
O H
C CH3
RU-486 (Mifepristone)
OH
H
H
N
O CH3
HO
CH2O CH3
J-867 (Asoprisnil)
O
N
CH3
H3C O CH3
O CCH3
O
Ulipristal acetate (Esmya®)
O
O
O M e
N
O Ac
CH3
H3C
Telapristone acetate (Proellex®)
N
O
O HO H
ZK98299 (Onapristone )
Chabber t - Buf f et N, et al. Hum Repr od Updat e 2005; 11: 293–307 Spit z I M . Cur r O pin I nvest ig Dr ugs 2006; 7: 882–90Bouchar d P et al. Fer t ilit y and St er ilit y 2011; 96: 1175- 89
SPRM : Select ive Pr ogest er one Recept or M odulat orUPA: Ulipr ist al acet at e
SPRMS - BOTH PROGESTERONE AGONISTS AND PROGESTERONE ANTAGONISTS, DEPENDING ON
TARGET TISSUE
SPRMs
Basaltranscriptionapparatus
Transcriptionactivation
(progesterone agonism)
No transcriptionactivation
(progesterone antagonism)
PR PR
PR PR
Co-activators
Co-repressors
Progesterone response element
Chabbert-Buffet N, e t al . Hum Reprod Update 2005;11:293–307 Madaus s KP, et al . Mol Endocrino l 2007;21:1066–81 Spi tz IM. Curr Opin Inves tig Drugs 2006;7:882–90Bouc hard P et al . Ferti li ty and Steri li ty 2011;96:1175-89
● Reduces LH and FSH secretion while maintaining mid follicular estrogen levels
● Inhibits folllicular development● Direct effect on the endometrium:● Direct effect on fibroids, reducing fibroid volume
● Inhibition of cell proliferation
● Induction of apoptosis
Hypothalamus
Pituitary
OvaryEndometrial
and
uterine tissue
• Chabbert-Buffet N, e t al . J Cl in Endocrinol Metab 2007;92:3582–3589 • Donnez J, e t a l. New Engl J Med 2012;366(5):409–420.1 .Donnez J, e t a l. New Engl J Med 2012;366(5):421–432.2 .Es my a SmPC
SPRM: Selec tiv e Proges terone Receptor ModulatorUPA: Ul ipris ta l ac etate
K Gemzell Danielsson
Effects on the non-pregnant uterus
•Effects on the cervix Ben-Chetrit et al., 2004, Gupta et al., 2001
•Effects on follicular development after selection of the dominant follicle
•Delays or inhibits ovulation•Complex effects on the endometrium•Affects PR expression in the Fallopian tube
K Gemzell Danielsson K Gemzell Danielsson
PRMs for contraceptive use
• Inhibition of Ovulation
• Endometrial Contraception
• Emergency Contraception
• ”Menstrual induction”
• Combination with gestagen
K Gemzell Danielsson
Endometrial Contraception
7 21 28
P4, E2 normal plasma levels
Ovulation
200mg mifepristone
days
Gemzell-Danielsso n et al., 1993
K Gemzell Danielsson
Effect of mifepristone on blastocyst implantation in vitro
Progesterone Mifepristone – no implantation seen
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K Gemzell Danielsson
Endometrial Contraception
ONCE-A-MONTH TREATMENT WITH 200MG MIFEPRISTONE ON DAY LH+2 AS A CONTRACEPTIVE METHOD
Number of cycles with an intercourse from 3 days before to 1 day after ovulation
Treatment No. of cycles No. of pregnancies Probability of pregnancy
Mifepristone 124 1 0.008
None* 72 35 0.486
*Unprotected intercourse during the time period 3 days before to 1 dayafter mucus peak day (from WHO multicentre study, Fertil Steril 40:773,1993)
Mifepristone continuous low dose• Disruption of the follicle maturation• Non-secretory endometrium• Amenorrhea• Well tolerated
Baird DT, Cameron S et al.,
SPRM – daily oral administrationMifepristone
• Double-blind RCT of 2 and 5 mg mifepristone/d 120d.
Brown et al., JCEM 2002
• Ovulation suppressed in over 90% of the cycles, and
amenorrhea was observed in 65% to 90% of the cycles
• Highly effective contraceptive method
UPA
• Effects of UPA in a continuous low dose on the hypothalamic–pituitary–ovarian axis and endometrium RCT
Chabbert-Buffet et al.,. JCEM 2007
K Gemzell Danielsson
K Gemzell DanielssonEstrogen only Estrogen + CDB 2914 IUD
Myo Myo
Wet weight0.52 g
Wet weight0.06 g
CDB –2914 IUD induces overall atrophy of the endometrium
Brenner-ONPRC
SPRMs for intrauterine contraception
• RCT, 40 women 4-8 weeks before hysterectomy
• IUS with ZK230211 in 3 doses (1, 4 or 8 mcg/24 h) vs. LNG-IUS
• ZK-IUSs had no effect on bleeding
• Endometrium was partly suppressed in 9-30% of ZK-IUSs,
• No proliferative activity in any group.
• S-levels of ZK not measurable, Myometrial levels in 4
Heikinheimo et al., 2007
K Gemzell Danielsson
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K Gemzell Danielsson
UPA - CVR
• Aim; 80% to 90% inhibition of ovulation and amenorrhea
• Ongoing studies at Population Council of a CVR
releasing UPA
• A correlation was observed between serum UPA and
degree of inhibition of ovarian activity.
• no evidence of hyperplasia of endometrium, but PAEC
frequently observed .
•
K Gemzell Danielsson
Effects on dysfunctional bleeding Improved cycle control of gestagen methods
Percentage of women with bleeding or spotting
Gemzell-Danielsso n et al.,2002
Emergency Contraception
Any method used after an unprotectedintercourse to prevent an unwanted pregnancy
K Gemzell Danielsson
Methods for Emergency ContraceptionYuzpe: EE (100 µg) + LNG (0.5 mg)
repeated 12h later
LNG: 0.75 mg repeated 12h later or1.5 mg single dose
SPRMs: UPA 30mg ellaOneSingle dose of ≥ 10 mg mifepristone, China
Cu-IUD Safe, effective (99%), invasive
K Gemzell Danielsson
SPRMs -non-contraceptive effects
”Added health benefits”
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K Gemzell Danielsson
Treatment of leiomyomas
• Two previous studies on PRMs placebo controlled (Asoprisnil, UPA)
• Mifepristone 50 mg or placebo every 2nd day for 3 months, pre surgery (Engman et al., 2009)
ULIPRISTAL ACETATE (UPA) CLINICAL DEVELOPMENT - TREATMENT OF UTERINE FIBROIDS
2005 2006 2007 2008 2009 2010 2011 2012 2013
Pre-operativetreatment (3 months)
Long-term repeatedintermittent treatment
Phase IIa
Phase IIb
Phase III PEARL I
Phase III PEARL II
PEARL III¹
PEARL IV²
¹ PGL4001 Efficacy Assessment in Reduc tion of Symptoms Due to Uterine Leiomy omata (PEARLIII-ex tens ion Study)² PGL4001 Efficacy Assessment in Reduc tion of Symptoms Due to Uterine Leiomy omata (PEARLIV) www.c l in ical trials.gov
I m ages pr ovidedby Dr Alist air William s, Edinbur gh Univer sit y M edical School PAEC: Pr ogest er one Recept or M odulat or ( PRM ) Associat ed Endom et r ial Changes
-300
-200
-100
0
100
200
300
400
500
%ch
ange
Ki-6
7 ba
selin
e-en
dpoi
nt
1 2
Ki-67-index percentual change from baseline to end of 3 months treatment
mifepristone controls
Antiproliferative effect of SPRM in breast tissue
-2
0
2
4
6
8
10
12
Ki-67 index baseline Ki-67 index posttreatment
Baseline EoT
Engman et al., Hum Reprod, 2008
K Gemzell Danielsson
Prevention of Brca1-mediated mammary tumorigenesis in mice by PRM.
• Women with mutations in the breast cancer susceptibility gene BRCA1 are predisposed to breast and ovarian cancers.
• Progesterone receptors, but not estrogen receptors, are overexpressed in the mutant mammary epithelial cells because of a defect in their degradation by the proteasome pathway.
• Treatment of Brca1/p53-deficient mice with mifepristone (RU 486) prevented mammary tumorigenesis.
Poole et al.,Science. 2006
K Gemzell Danielsson
SPRMs for treatment of endometriosis
• Pilot studies;
• PRMs significantly reduce the pain in endometriosis
• The effect on the lesions is unclear
• Ongoing studies (incl adenomyosis)
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K Gemzell Danielsson
Conclusions
• UPA (and mifepristone) - the most effective ECP
• UPA, 30 mg, approved for EC use (ella/ ellaOne)
• SPRMs hold the potential to be developed for contraceptive use
• UPA, 5mg, approved for pre surgical treatment of uterine
leiomyoma (Esmya)
• SPRMs also hold the potential for development on other non
contraceptive indications
• More data needed re PAEC and long term endometrial effects