Selective Progesterone modulators the future! Overview of the presentation

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1 Selective Progesterone modulators the future! 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 Kristina Gemzell Danielsson, Kvinnokliniken / WH-center Karolinska Universitetssjukhuset/ Stockholm, Sweden Karolinska Institutet verview of the presentation Background SPRMs - in non pregnant women For contraceptive use ther potential health benefits Conclusions SELECTIVE PRGESTERE RECEPTR MDULATRS(SPRM) Progesterone receptor ligands c an poss ess activ ity ranging from pure antagonis t activity through mixed antagonist/agonist activity to pure agonist activity SPRMs are progesterone receptor ligands with mix ed antagonist/agonist activity H3C RU-486 (Mifepristone) H C C H H H3C Ulipristal acetate (Esmya ) H3C C Me Ac H H J-867 (Asoprisnil) H H CH2 ZK98299 (napristone ) Telapristone acetate (Proellex ) Chabber t - Buf f et, et al. Hum Repr od Updat e 2005; 11: Spit z I M. Cur r pin I nvest ig Dr ugs 2006; 7: Bouchar d P et al. Fer t ilit y and St er ilit y 2011; 96: SPRM : Select ive Pr ogest er one Recept or M odulat or UPA: Ulipr ist al acet at e SPRMS - BTH PRGESTERE AGISTS AD PRGESTERE ATAGISTS, DEPEDIG TARGET TISSUE SPRMs Effects during the cycle and in pregnancy Contragestion Co-activators SPRMs PR PR Progesterone response element PR PR Basal transcription apparatus Transcription activation (progesterone agonism) o transcription activation (progesterone antagonism) Follicular phase Contraception Pregnancy Interruption Co-repressors Ch a b b e rt-bufet,etal. Hum Reprod Update 2005;11: Ma d a u s s KP, et al. Mo l End ocri no l ;2 1: Spitz IM. Curr pin Investig Drugs 2006;7: Bouc hard Petal. Fertility and Sterility 2011;96: PR: Progesterone Rec eptor SPRM: Selective Progesterone Rec eptor Modulator Labour Induction Adjuvant to late Pregnancy termination 1

2 SPRM MDE F ACTI: EFFECT PITUITARY, EDMETRIUM AD VARY Hypothalamus Pituitary vary Endometrial and uterine tissue Ch a b b e rt-bufet,etal. J Clin Endocrinol Metab 2007;92: Do n n e z J, e tal. e w En gl J Me d ;3 66 (5): Do n n e z J, e tal. e w En gl J Me d ;3 66 (5): Esmya SmPC 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 SPRM: Selective Progesterone Receptor Modulator UPA: Ulipristal acetate 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 PRMs for contraceptive use Inhibition of vulation Endometrial Contraception Emergency Contraception Menstrual induction Combination with gestagen Endometrial Contraception Effect of mifepristone on blastocyst implantation in vitro vulation P4, E2 normal plasma levels days 200mg mifepristone Gemzell-Danielsson et al., 1993 Progesterone Mifepristone no implantation seen 2

3 Endometrial Contraception CE-A-MTH TREATMET WITH 200MG MIFEPRISTE DAY LH+2 AS A CTRACEPTIVE METHD SPRMs umber of cycles with an intercourse from 3 days before to 1 day after ovulation Treatment o. of cycles o. of pregnancies Probability of pregnancy Mifepristone one* Post-ovulatory contraception nce-a-week (2.5, 5, 10, 25, 50 mg) Low daily doses (0.1/0.5mg) Inhibition of ovulation ral tablets IUS Vaginal ring *Unprotected intercourse during the time period 3 days before to 1 day after mucus peak day (from WH multicentre study, Fertil Steril 40:773,1993) Endometrial inhibition PRGESTERE RECEPTR MDULATRS (PRMs) Mifepristone SPRM daily oral administration Double-blind RCT of 2 and 5 mg mifepristone/d 120d. Mifepristone continuous low dose Disruption of the follicle maturation on-secretory endometrium Amenorrhea Well tolerated Baird DT, Cameron S et al., Brown et al., JCEM 2002 vulation 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 CDB 2914 IUD induces overall atrophy of the endometrium Wet weight 0.52 g Wet weight 0.06 g SPRMs for intrauterine contraception RCT, 40 women 4-8 weeks before hysterectomy IUS with ZK in 3 doses (1, 4 or 8 mcg/24 h) vs. LG-IUS ZK-IUSs had no effect on bleeding Endometrium was partly suppressed in 9-30% of ZK-IUSs, o proliferative activity in any group. S-levels of ZK not measurable, Myometrial levels in 4 Brenner-PRC Myo Estrogen only Myo Estrogen + CDB K Gemzell 2914 Danielsson IUD Heikinheimo et al.,

4 UPA - CVR Aim; 80% to 90% inhibition of ovulation and amenorrhea ngoing 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 Emergency Contraception Any method used after an unprotected intercourse to prevent an unwanted pregnancy Gemzell-Danielsson et al.,2002 Methods for Emergency Contraception Yuzpe: EE (100 µg) + LG (0.5 mg) repeated 12h later SPRMs - non-contraceptive effects LG: SPRMs: Cu-IUD 0.75 mg repeated 12h later or 1.5 mg single dose UPA 30mg ellane Single dose of 10 mg mifepristone, China Safe, effective (99%), invasive Added health benefits 4

5 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) CLIICAL DEVELPMET - TREATMET F UTERIE FIBRIDS Phase IIa Pre-operative treatment (3 months) Phase IIb Phase III PEARL I Phase III PEARL II Long-term repeated intermittent treatment PEARL III¹ PEARL IV² ¹ PGL4001 Efficacy Assessment in Reduc tion of Symptoms Due to Uterine Leiomy omata (PEARLII-ex te ns io n St u dy) ² PGL4001 Efficacy Assessment in Reduc tion of Symptoms Due to Uterine Leiomy omata (PEARLIV) l i n i cal tri al s.go v EDMETRIAL HISTLGY PAECS (PRM ASSCIATED EDMETRIAL CHAGES) Antiproliferative effect of SPRM in breast tissue Proliferative phase Mid-secretory phase %changeki-67 baseline-endpoint Ki-67 index baseline Ki-67 index posttreatment PAEC: glandular cyst dilatation I m ages pr ovided by Dr Alist air Edinbur gh Wiliams, Univer sit y PAEC: low mitotic activity M edical School PAEC: Pr ogest er one Recept or M odulat or ( PRM ) Associat ed Endom et r ial Changes mifepristone controls Ki-67-index percentual change from baseline to end of 3 months treatment Baseline EoT Engman et al., Hum Reprod, 2008 Prevention of Brca1-mediated mammary tumorigenesis in mice by PRM. SPRMs for treatment of endometriosis 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. Pilot studies; PRMs significantly reduce the pain in endometriosis The effect on the lesions is unclear ngoing studies (incl adenomyosis) Poole et al.,science

6 Conclusions UPA (and mifepristone) - the most effective ECP UPA, 30 mg, approved for EC use (ella/ ellane) 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 6