1045_SPRM - contraception

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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

PR: Progesterone Rec eptorSPRM: Selective Progesterone Rec eptor Modulator


SPRMsEffects during the cycle and in pregnancy

Contraception

Contragestion

Pregnancy Interruption

Adjuvant to late Pregnancy terminationLabour Induction

Follicular phase

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SPRM MODE OF ACTION:EFFECT ON PITUITARY, ENDOMETRIUM AND OVARY

•

● Inhibits ovulation (progesterone levels maintained low)

● 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


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


Endometrial Contraception

7 21 28

P4, E2 normal plasma levels

Ovulation

200mg mifepristone

days

Gemzell-Danielsso n et al., 1993


Effect of mifepristone on blastocyst implantation in vitro

Progesterone Mifepristone – no implantation seen

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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)

SPRMs

Post-ovulatory contraception

Once-a-week (2.5, 5, 10, 25, 50 mg)Low daily doses (0.1/0.5mg)

Inhibition of ovulation

Oral tabletsIUSVaginal ring

Endometrial inhibitionK Gemzell Danielsson


PROGESTERONE RECEPTOR MODULATORS (PRMs)

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 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


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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 .

•


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


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


SPRMs -non-contraceptive effects

”Added health benefits”

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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

Proliferative phase

Mid-secretoryphase

PAEC: glandular cyst dilatation

PAEC: low mitotic activity

ENDOMETRIAL HISTOLOGYPAECS (PRM ASSOCIATED ENDOMETRIAL CHANGES)

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


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


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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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

• Potential protective effect on the breast

1045_SPRM - contraception

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