SELEKTIVE PROGESTERON REZEPTOR MODULATOREN Egarter Ch. Universitätsklinik für Frauenheilkunde Wien

SELEKTIVE PROGESTERON REZEPTOR MODULATOREN Rezeptor Modulatoren sind Substanzen, die sowohl Hormon – agonistische als auch – antagonistische Eigenschaften aufweisen können

STRUKTUR DER ISOFORMEN DES PROGESTERON REZEPTORS Modular domain structure of progesterone receptor A and B isoforms. Schematic representation of progesterone receptor (PR)-A and PR-B isoforms DNA binding domain (DBD) Ligand binding domain (LBD) Activation functions (AFs) 1, 2, and 3 Inhibitory domain (ID), with their amino acid boundaries

PROGESTERON REZEPTOR A UND B IM MYOMETRIUM UND MYOM Immunohistochemical staining of progesterone receptor (PR) on cross-section leiomyomata/myometrium. The illustrations are late secretory phase, but the staining has been studied throughout the cycle (data not shown). M indicates myometrium and F fibroid. A, crosssection leiomyomata/myometrium (3100) stained with an antibody recognizing PR-A and PR-B. B, same cross-section (3100) stained with a PR-B specific antibody. Viville B et al. Human Reprod 1997

VERÄNDERUNG DES PROGESTERON REZEPTORS DURCH LIGANDEN Ligand-induced conformational changes in the ligand binding domain (LBD) that control interaction of coregulatory proteins. In each view, mobile helix 12 is highlighted with stripes. Comparison of LBD structure: (A) In the absence of ligand, helix 12 extends away from the LBD core. (B) Agonist binding induces repositioning of helix 12 to create, together with helices 3, 4, and 5, the activation function (AF)-2 hydrophobic groove that specifically interacts with LXXLL helix motifs of p160 coactivators (indicated in B). (C) Antagonist binding induces an alternate rotation of helix 12 to occupy the coactivator interaction site (compare B and C) and prevents binding of p160 coactivators. (From Bourguet W, Germain P, Gronemeyer H. Nuclear receptor ligand-binding domains: threedimensional structures, molecular interactions and pharmacological implications. Bourguet et al. Trends Pharmacol Sci 2000

VERÄNDERUNG DES PROGESTERON REZEPTORS DURCH SPRM Ligand-induced conformational changes in the ligand binding domain (LBD) that control interaction of coregulatory proteins. In each view, mobile helix 12 is highlighted with stripes. Comparison of LBD structure: (A) In the absence of ligand, helix 12 extends away from the LBD core. (B) Agonist binding induces repositioning of helix 12 to create, together with helices 3, 4, and 5, the activation function (AF)-2 hydrophobic groove that specifically interacts with LXXLL helix motifs of p160 coactivators (indicated in B). (C) Antagonist binding induces an alternate rotation of helix 12 to occupy the coactivator interaction site (compare B and C) and prevents binding of p160 coactivators. (From Bourguet W, Germain P, Gronemeyer H. Nuclear receptor ligand-binding domains: threedimensional structures, molecular interactions and pharmacological implications. Asoprisnil Chwalisz K. et al. Reprod Biol Endocrinol 2006

AKTIVIERUNG DES PROGESTERON REZEPTORS DURCH LIGANDEN Activation of the progesterone receptor (PR) by progesterone receptor ligands. Binding of progesterone to the inactive receptor complex induces a conformational change, which leads to Heat Shock Protein (HSP) dissociation, receptor dimerization, DNA binding, and recruitment of co-activators [e.g. steroid receptor co-activator (SRC) and CBP] to facilitate communication with the basal transcription apparatus RNA POL2 (RNA polymerase). PRE ¼ progesterone response element. Action of progesterone receptor antagonists (PA): PA compete with the agonist for PR binding and promote the activation steps of dimerization and binding to specific PRE of target DNA. However, PA induce an altered conformation in PR that is transcriptionally inactive, resulting in a non-productive interaction of the receptor with DNA. This is caused by PR recruitment of co-repressors (e.g. nuclear receptor co-repressor (NcoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) instead of co-activators. Chabbert-Buffet et al. Human Reprod Upd 2005

AKTIVIERUNG DES PROGESTERON REZEPTORS DURCH LIGANDEN Agonist PR PR PRE Activation of the progesterone receptor (PR) by progesterone receptor ligands. Binding of progesterone to the inactive receptor complex induces a conformational change, which leads to Heat Shock Protein (HSP) dissociation, receptor dimerization, DNA binding, and recruitment of co-activators [e.g. steroid receptor co-activator (SRC) and CBP] to facilitate communication with the basal transcription apparatus RNA POL2 (RNA polymerase). PRE ¼ progesterone response element. Action of progesterone receptor antagonists (PA): PA compete with the agonist for PR binding and promote the activation steps of dimerization and binding to specific PRE of target DNA. However, PA induce an altered conformation in PR that is transcriptionally inactive, resulting in a non-productive interaction of the receptor with DNA. This is caused by PR recruitment of co-repressors (e.g. nuclear receptor co-repressor (NcoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) instead of co-activators. Chabbert-Buffet et al. Human Reprod Upd 2005 8

AKTIVIERUNG DES PROGESTERON REZEPTORS DURCH LIGANDEN Agonist Coactivators Steroid Receptor Co-activator (SCR 1/3) p160 PR PR RNA pol 2 Transcription Activation PRE PR PR Activation of the progesterone receptor (PR) by progesterone receptor ligands. Binding of progesterone to the inactive receptor complex induces a conformational change, which leads to Heat Shock Protein (HSP) dissociation, receptor dimerization, DNA binding, and recruitment of co-activators [e.g. steroid receptor co-activator (SRC) and CBP] to facilitate communication with the basal transcription apparatus RNA POL2 (RNA polymerase). PRE ¼ progesterone response element. Action of progesterone receptor antagonists (PA): PA compete with the agonist for PR binding and promote the activation steps of dimerization and binding to specific PRE of target DNA. However, PA induce an altered conformation in PR that is transcriptionally inactive, resulting in a non-productive interaction of the receptor with DNA. This is caused by PR recruitment of co-repressors (e.g. nuclear receptor co-repressor (NcoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) instead of co-activators. Antagonist Chabbert-Buffet et al. Human Reprod Upd 2005 9

AKTIVIERUNG DES PROGESTERON REZEPTORS DURCH LIGANDEN Agonist Coactivators Steroid Receptor Co-activator (SCR 1/3) p160 SPRMs PR PR RNA pol 2 Transcription Activation PRE No Transcription activation Corepressors Nuclear Receptor Co-repressor (NCoR) Silencing Mediator of Retinoic Acid and Thyroid Hormone (SMRT) PR PR Antagonist Activation of the progesterone receptor (PR) by progesterone receptor ligands. Binding of progesterone to the inactive receptor complex induces a conformational change, which leads to Heat Shock Protein (HSP) dissociation, receptor dimerization, DNA binding, and recruitment of co-activators [e.g. steroid receptor co-activator (SRC) and CBP] to facilitate communication with the basal transcription apparatus RNA POL2 (RNA polymerase). PRE ¼ progesterone response element. Action of progesterone receptor antagonists (PA): PA compete with the agonist for PR binding and promote the activation steps of dimerization and binding to specific PRE of target DNA. However, PA induce an altered conformation in PR that is transcriptionally inactive, resulting in a non-productive interaction of the receptor with DNA. This is caused by PR recruitment of co-repressors (e.g. nuclear receptor co-repressor (NcoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) instead of co-activators. Nucleocytoplasmic shuttling of PR and coregulators Post translational modifications Interaction with signaling pathways cAMP PR P Chabbert-Buffet et al. Human Reprod Upd 2005 10

SELEKTIVE PROGESTERON REZEPTOR MODULATOREN (SPRM) Mifepriston Onapristone Org 33628 The expression of both PR isoforms as well as of their co-regulators has been described in the endometriumPRB is upregulated in the stroma and in the glandular epithelium during the follicular phase, and is down-regulated in both cell compartments during the luteal phase. PRA on the contrary is up-regulated in both cell types in the follicular phase and persists in the stromal compartment during the late luteal phase. The subnuclear localization of PR isoforms has been shown to vary during the menstrual cycle (Arnett-Mansfield et al., 2004). Although the physiological significance of this phenomenon in the endometrium remains to be determined, PR is expressed in an even manner in the nucleus but may also be localized in discrete nuclear foci. In the proliferative phase, homogeneous localization is dominant and PRA and PRB co-localize. In the secretory phase, the focal localization increases and PRB becomes the predominant isoform in the nuclear foci. This focal nuclear localization is believed to correspond to transcriptionfactor-rich storage domains, lacking RNA polymerase II, in which steroid receptors can be active or not depending on the receptor studied (Grande et al., 1997; Arnett-Mansfield et al., 2004). PR co-regulators have been described in the endometrium, as has their regulation during the menstrual cycle (Mote et al., 1999; Gregory et al., 2002). Steroid receptor co-activator (SRC-1) is up-regulated during the follicular phase and downregulated during the luteal phase in the glandular epithelium and in the stroma (Gregory et al., 2002; Vienonen et al., 2004). However, the regulation of the co-repressors NCoR and SMRT is less clear. Immunohistochemical studies (Gregory et al., 2002) suggest that NCoR is up-regulated during the follicular phase and down-regulated during the luteal phase in the glandular epithelium and in the stroma, while SMRT protein levels remain rather low and constant during the cycle. On the other hand another study of NCoR and SMRT mRNA levels has shown the opposite finding. SMRT mRNA appears to be regulated while NCoR mRNA remains stable throughout the cycle (Vienonen et al., 2004). Asoprisnil Ulipristal Chabbert-Buffet et al. Huma Reprod Upd 2005

EINSATZ VON SPRM Gynäkol. Endokrinologie Geburtshilfe Notfallkontrazeption Blutungsstörungen Leiomyome Endometriose Geburtshilfe Schwangerschaftsabbruch Schwangerschaftsbeendigung bei Missed abortion und intrauterinem Fruchttod

SPRM: ULIPRISTAL (Esmya®) Ulipristal (CDB-2914) 19-Norprogesteron

VERÄNDERUNG DER ENDOMETRIUM-HISTOLOGIE DURCH SPRM Ligand-induced conformational changes in the ligand binding domain (LBD) that control interaction of coregulatory proteins. In each view, mobile helix 12 is highlighted with stripes. Comparison of LBD structure: (A) In the absence of ligand, helix 12 extends away from the LBD core. (B) Agonist binding induces repositioning of helix 12 to create, together with helices 3, 4, and 5, the activation function (AF)-2 hydrophobic groove that specifically interacts with LXXLL helix motifs of p160 coactivators (indicated in B). (C) Antagonist binding induces an alternate rotation of helix 12 to occupy the coactivator interaction site (compare B and C) and prevents binding of p160 coactivators. (From Bourguet W, Germain P, Gronemeyer H. Nuclear receptor ligand-binding domains: threedimensional structures, molecular interactions and pharmacological implications. Chwalisz K. et al. Reprod Biol Endocrinol 2006

SPRM UND ENDOMETRIUM CDB-4124 (Telapriston, Proellex®) erhöht Apoptoserate → Atrophie des Endometriums Langzeiteinnahme → Zunahme der Progesteronrezeptoren Vakuolisierung und Dickenzunahme des Endometriums Duration of 12.5mg daily CDB-4124 exposure is associated with endometrial thickness and cyst formation Progesterone receptor modulator-associated endometrial changes (‘PAEC’) after 92 days of 12.5mg daily CDB-4124. Dyssynchronous growth of glands compared with stroma results in scattered cyst formation throughout the endometrial compartment (a). Non-physiologic epithelial changes are characterized by admixture of secretory vacuoles with mitoses (b), or mitoses with apoptotic bodies (c). A similar constellation of effects has been described for other progesterone receptor modulators. Ioffe O. et al. Mod Path 2009

SPRM UND IMPLANTATION IM ENDOMETRIUM L-Selektin Liganden vermehrt exprimiert während der Implantationsphase CDB-2914 (Ulipristal) führt zur verminderten Expression von Addressin (L-Selectin Ligand auf der Oberfläche der Endothelzellen) Stratton P. Fertil Steril 2009

STEROIDHORMON EFFEKTE AUF MYOMETRIUM UND LEIOMYOM Estrogen Progesteron EGF-R EGF IGF-1 TGF1 TGF3 PDGF Wachstumsfaktoren Effects of GADD153 RNA interference on asoprisnil induction of Bcl-2, Bax, and Bak protein contents in cultured leiomyoma cells. Cultured leiomyoma cells were transfected with siControl or GADD153 siRNA for 48 h and then treated with 107 M asoprisnil for 8 h. Inhibition of asoprisnil-induced decrease in Bcl-2 protein content by GADD153 RNA interference (A), and reduced asoprisnil induction of Bax (B) and Bak (C) protein contents by GADD153 RNA interference are shown. *P 0.05 vs. untreated siControl cells or siGADD153 cells. **P 0.01 vs. asoprisnil-treated siControl cells Leiomyom-Zelle Bcl-2 Wild type P53 TNF Apoptose-Faktoren

SPRM UND IGF1 BEIM LEIOMYOM Leiomyoma has significantly higher amounts of epidermal growth factor (EGF) mRNA than myometrium in the secretory phase of the menstrual cycle.6 EGF is shown to increase the uptake of 3Hthymidine and the rate of proliferating cell nuclear antigen (PCNA)-positive nuclei in cultured leiomyoma cells, suggesting that EGF stimulates the proliferative activity of those cells.7 It is now evident that progesterone increases the expression of PCNA,7 EGF and Bcl-2 proteins3 in cultured leiomyoma cells, whereas estradiol increases EGF receptor (EGFR) expression in those cells, but progesterone does not.3 It is conceivable, therefore, that progesterone and estradiol may act in combination to stimulate the proliferative potential of cultured leiomyoma cells through the induction of EGF and EGFR in those cells. Effects of CDB-2914 on proliferating cell nuclear antigen (PCNA) protein content in cultured leiomyoma cells at 48 hours of treatment, as assessed by Western blot analysis. Results represent the meanstandard deviation fold increase over the control value.*, p<0.05 versus PCNA protein content in untreated leiomyoma cells in control cultures;**, p<0.001 versus PCNA protein content in leiomyoma cells treated with progesterone (P4) alone. (Adapted from Xu Q, Takekida S, Ohara N, et al. Progesterone receptor modulator CDB-2914 down-regulates proliferative cell nuclear antigen and Bcl-2 protein expression and up-regulates caspase-3 and poly(adenosine 50-diphosphate-ribose) polymerase expression in cultured human uterine leiomyoma cells. J Clin Endocrinol Metab 2005;90[2]:953–961. CDB-2914 (Ulipristal®) hemmt im Gegensatz zu Progesteron die Expression von PCNA via IGF1 in Leiomyomzellen (antiproliferativer Effekt) Kein Effekt auf Myometriumzellen Yoshida S. et al. Sem Reprod Med 2010

SPRM UND APOPTOSE BEI LEIOMYOM Effects of GADD153 RNA interference on asoprisnil induction of Bcl-2, Bax, and Bak protein contents in cultured leiomyoma cells. Cultured leiomyoma cells were transfected with siControl or GADD153 siRNA for 48 h and then treated with 107 M asoprisnil for 8 h. Inhibition of asoprisnil-induced decrease in Bcl-2 protein content by GADD153 RNA interference (A), and reduced asoprisnil induction of Bax (B) and Bak (C) protein contents by GADD153 RNA interference are shown. *P 0.05 vs. untreated siControl cells or siGADD153 cells. **P 0.01 vs. asoprisnil-treated siControl cells Apoptoserate im Myom wird unter SPRM Asoprisnil durch Downregulation des antiapoptotischen Bcl-2 erhöht → Leiomyom Verkleinerung Xu Q. et al. Am J Physiol Endocr. Metab 2007

SPRM UND APOPTOSE BEI LEIOMYOM Effects of GADD153 RNA interference on asoprisnil induction of Bcl-2, Bax, and Bak protein contents in cultured leiomyoma cells. Cultured leiomyoma cells were transfected with siControl or GADD153 siRNA for 48 h and then treated with 107 M asoprisnil for 8 h. Inhibition of asoprisnil-induced decrease in Bcl-2 protein content by GADD153 RNA interference (A), and reduced asoprisnil induction of Bax (B) and Bak (C) protein contents by GADD153 RNA interference are shown. *P 0.05 vs. untreated siControl cells or siGADD153 cells. **P 0.01 vs. asoprisnil-treated siControl cells Up-Regulation von pro-apoptotischen Faktoren (Caspasen) → Leiomyom Verkleinerung Xu Q. et al. Human Reprod 2006

SPRM UND VEGF BEI LEIOMYOM CDB-2914 (Ulipristal®) hemmt die Expression von VEGF (und Adrenomedullin) in Leiomyomzellen Kein Effekt in Myometrium Zellen Maruo T. et al. Contraception 2007

SPRM UND ETRAZELLULÄRE MATRIX BZW. KOLLAGEN CDB-2914 (Ulipristal®) reduziert die Kollagen Akkumulation im ECM durch Hemmung der Synthese und MMP↑ (TIMP↓) Kein Effekt auf Myometrium Zellen Xu O. et al. Mol Hum Reprod 2008

PEARL I PGL 4001’s (UPA) EFFICACY ASSESSMENT IN REDUCTION OF SYMPTOMS DUE TO UTERINE LEIOMYOMATA

Randomisierte, doppelt-blinde Phase III Studie mit Ulipristal (UPA) vs Randomisierte, doppelt-blinde Phase III Studie mit Ulipristal (UPA) vs. Placebo RANDOMISATION SURGERY 3 Monate 1 x UPA 5 mg tgl. oral + Fe n= 94 1 x UPA 10 mg tgl. oral + Fe n=95 1 x Placebo tgl. oral + Fe n=48 Symptomatische Leiomyome 6 Monate Follow-up Periode ClinicalTrials.gov Identifier: NCT00755755

PEARL I. Einschlusskriterien Prämenopausale Frauen (18–50 a) mit uterinen Myom(en) 1 uterines Myom 3 cm im Durchmesser, aber keines >10 cm im Durchmesser Exzessive uterine Blutung PBAC Score >100 während 1–8 d der Menstruation Anämie Hämoglobin 10.2 g/dL Chirurgischer Eingriff Hysterektomie, Myomektomie, uterine Arterien- Embolisation (UAE) oder Endometrium-Ablation

Pictorial Bleeding Assessment Chart (PBAC) PBAC Score >100 während 1-8 Tag der Menstruation während Screening-Periode

PEARL I Blutungskontrolle (Primärer Endpunkt) Patientinnen mit PBAC<75 Studienende (13. Woche) (ITT Population) * * 92.5% 18.8% Plazebo 5 mg UPA 10 mg UPA *p<0.001 vs Plazebo

PEARL I Dauer bis zur Blutungskontrolle (PBAC < 75) UPA 5mg UPA10mg Placebo UPA Blutungskontrolle innerhalb von 7 Tagen

PEARL I MYOMVOLUMEN (MRI zentralisiert, geblindet) Median Percentage Change from Screening to Week 13 Placebo UPA 5 mg UPA 10 mg Ergebnisse von allen Myom-Messungen mittels MRI 29

PEARL I. Lebensqualität Beschwerden aufgrund der Myome 18 Placebo 16 14 12 10 8 6 4 2 UPA 5 mg UPA 10 mg p<0.001 p=0.001 16.0 14.0 14.1 7 Fragen (0 - 4 )* Blutung Abdominaler Druck Harnmiktionsfrequenz Tägliche Aktivität Schwindel Stimmung Sexuelle Aktivität 14.7 4.0 2.9 UPA verbessert signifikant die Beschwerden bei Myomen 30

PEARL II PGL 4001’s (UPA) EFFICACY ASSESSMENT IN REDUCTION OF SYMPTOMS DUE TO UTERINE LEIOMYOMATA

1 x 3,75 mg Leuprorelin alle 4 Wochen Randomisierte, doppelt-blinde Phase III Studie mit Ulipristal (UPA) vs. GnRH RANDOMISATION SURGERY 3 Monate 1 x UPA 5 mg tgl. oral + Fe n= 93 1 x UPA 10 mg tgl. oral + Fe n=95 1 x 3,75 mg Leuprorelin alle 4 Wochen n=93 Symptomatische Leiomyome 6 Monate Follow-up Periode ClinicalTrials.gov Identifier: NCT00740831

PEARL II. Einschlusskriterien Prämenopausale Frauen (18–50 a) mit uterinen Myom(en) 1 uterines Myom 3 cm im Durchmesser, aber keines >10 cm im Durchmesser Exzessive uterine Blutung PBAC Score >100 während 1–8 d der Menstruation Anämie Nicht erforderlich Chirurgischer Eingriff Hysterektomie, Myomektomie, uterine Arterien- Embolisation (UAE) oder Endometrium-Ablation

PEARL II Blutungskontrolle (Primärer Endpunkt) 100 10 20 30 40 50 60 70 80 90 Patientinnen mit PBAC<75 Studienende (13. Woche) % der Patientinnen mit PBAC < 75 5 mg UPA 10 mg UPA Lupron > 90% zeigen normalisierte Blutungen PBAC < 75

PEARL II Dauer bis zur Blutungskontrolle (PBAC < 75) 7 days UPA 5mg UPA 10mg GnRH Agonist Mit UPA Blutungskontrolle schneller als mit GnRH (7 vs 30 Tage)

PEARL II. Nebenwirkungsprofil Menopausale Symptome Hitzewallungen 13. Woche Estradiol 13. Woche 45 Lupron 40 35 30 25 20 15 10 5 UPA 5 mg UPA 10 mg 70 60 50 40 30 20 10 Median Serum Estradiol (pg/ml) Lupron UPA 5 mg UPA 10 mg Patientinnen mit mittleren bis starken Hitzewallungen (%) UPA im Vergleich zu GnRH günstigeres Profil UPA induziert keine menopausalen Symptome 36

PEARL II. Lebensqualität Beschwerden aufgrund der Myome Median HRQL Ausgangswert – 13. Woche 14.0 Health related Quality of Life (HRQL) Beeinträchtigungen Aktivitäten Energie/Stimmung Kontrolle Selbstbewußtsein Sexuelle Aktivität 2.9 UPA 5 mg UPA 10 mg Lupron Score spezifisch für Myome, kein genereller Score 37

PEARL II. Mediane Volumsverkleinerung (%) Studienende, nach 3 und 6 Monaten Ende 3 Mo 6 Mo Ende 3 Mo 6 Mo Ende 3 Mo 6 Mo - 16.5 Median Change from Screening (%) -43.3 -45.5 - 44.8 -50.0 - 54.8 -55.7 -56.7 -62.5 UPA 5 mg UPA 10 mg Lupron Subgruppe ohne chirurgische Behandlung Veränderung vom Studienende bis 3 bzw. 6 Monate nachher 38

PEARL I. Nebenwirkungen Plazebo (N=48) UPA 5mg (N=95) UPA 10mg (N=94) Patientinnen mit ≥1 NW 8.3% 16.8% 19.4% Brustschmerzen/ Spannung 0.0% 2.1% 5.1% Meno- Metrorrhagia 4.2% Kopfschmerzen 1.1% 3.1% Hyper- cholesterinämie 3.2% 2.0% Hitzewallungen 1.0% 39

PEARL II. Nebenwirkungen UPA (5mg) N=97 UPA (10mg) N=103 Lupron 3.75mg N=101 Patientinnen mit ≥ 1 NW 55.7% 50.5% 70.3% Mittlere, schwere Hitzewallungen 11.3%* 9.7%* 41.6%* Kopfschmerzen 15.5% 5.8% 7.9% Übelkeit 3.1% 3.9% 4.0% Bauchschmerzen 0.0% 2.9% Akne 4.9% 3.0% Hyperhidrose Müdigkeit 4.1% Insomnia 2.1% 1.9% 5.0% Schwindel 1.0% Hyper-cholesterinämie Brustschmerzen/ -spannen 2.0% * p < 0.001 UPA 5 mg v Lupron ; p < 0.001 UPA 10 mg v Lupron * p < 0.001 UPA vs Lupron 40

SPRMS EFFEKTE AUF ENDOMETRIUM Benigne endometriale Veränderungen stellen eine neue morphologische Kategorie dar (PRM Associated Endometrial Change; PAEC) ● Geringe mitotische Aktivität von Drüsen und Stroma ● Subnukleäre Vacuolen ● Apoptose ● Kein Stroma Abbruch und keine Drüsenverdichtung ● Zystisch dilatierte Drüsen mit flachem Epithel ohne nukleäre Pseudostratifizierung Professor A. Williams. Edinburgh University Medical School 41

EXPERTENGRUPPE: PATHOLOGEN PEARL I & II EXPERTENGRUPPE: PATHOLOGEN Endometriumsbiopsien vor Beginn und am Ende (3 Monate), dann nach 6 Monaten ohne Medikation, falls keine Operation Biopsien wurden durch 3 unabhängige, geblindete Experten nach den Kriterien für PAEC begutachtet 42

ENDOMETRIUMDICKE > 16 MM PEARL I. ENDOMETRIUMDICKE > 16 MM 7.0% 5.3% Patientinnen mit Endometriumdicke > 16 mm (%) 3.3% 3.3% 1.8% 0% 0% 0% 43

CONSENSUS DIAGNOSEN BIOPSIEN PEARL I PEARL II   Plazebo UPA 5 mg UPA 10 mg Screening n=48 n=95 n=98 Benigne 48 87 95 Hyperplasie 1 Maligne 13. Woche n=41 n=83 n=81 39 78 38. Woche n=31 n=63 29 60 61 11 Malignane UPA 5 mg UPA 10 mg GnRH n=97 n=103 n=101 88 91 1 n=94 n=98 n=95 85 95 n=63 n=67 n=64 58 62 59 1 complex hyperplasia with atypia

PEARL I & II. ENDOMETRIUM HISTOLOGIE PAEC: PRM-Associated Endometrial Changes Patientinnen PAEC (%) PEARL I PEARL II Placebo UPA 5 mg UPA 10 mg UPA 5 mg GnRH Screening 0.0% 6.5% 1.3% 2.6% 3.8% 2.5% 13. Woche (Studienende) 7.9% 59.7% 56.4% 54.5% 61.3% 13.9% 38. Woche 7.8% 5.1% 6.3% PAEC in ca. 60% nach Behandlung mit UPA über 3 Monate (durch mind. 2 der 3 Patholgen bestätigt) PAEC Veränderungen nach der Behandlung reversibel 45

PEARL I & II Zusammenfassung UPA führt innerhalb von 1 Woche zum Blutungsstopp und normalisiert die Blutungen bei 90-98% der Patientinnen (PBAC < 75) bzw. induziert bei 75% eine Amenorrhoe UPA reduziert das Myomvolumen um 35% bis 42% (UPA 5 mg bzw. 10 mg); dieser Effekt ist zumindest 6 Monate anhaltend UPA erzielt “Quality of Life” Scores wie bei gesunden Frauen Menstruation und Ovulation treten bei den meisten Patientinnen etwa 1 Monat nach Behandlungsende wieder auf 46

PEARL II Zusammenfassung Pearl II: Vergleich von UPA 5 und 10 mg und GnRH: - UPA führt zu einer rascheren Blutungskontrolle als GnRH (7 vs. 30 Tage) - UPA führt zu bleibender Myom-Reduktion zumindest für 6 Monate nach Therapieende (-44.8% und -54.8% für UPA 5 mg und 10 mg vs. -16.5% für GnRH) (Pearl II) - UPA zeigt ein besseres Nebenwirkungsprofil, da Estradiol-Spiegel der frühen follikulären Phase entsprechen 47

ESMYA® II/2012 Wirkstoff: Ulipristalacetat (SPRM) Packungsform: 1x28 Tabletten à 5mg Dosierung: 1Tbl tgl für 3 Monate Seit 1.10. 2012: dunkelgelbe Box Indikation: Patientinnen mit mittelstarken bis sehr starken Symptomen, welche durch Uterusmyome hervorgerufen werden. reproduktionsfähiges Alter präoperativ

Konsensuspapier J Gynäkol Endokrinol 2012; 22 (4)

Zukunft von Ulipristalacetat PEARL III: abgeschlossen 3 Monate Ulipristalacetate 5mg + Placebo/ Progesteron für 10 Tage Randomisiert, doppelblind, multizentrisch, parallele Phase III Studie PEARL III Extension: in der Endphase 4 Zyklen: Ulipristalacetate 5mg für je 90 Tage+ Placebo/ Progesteron für 10 Tage Randomisierte, doppelblinde, multizentrische, parallele Phase III Studie PEARL III Extension Verlängerung: Beginn 10/2012 weitere 4 Zyklen Ulipristalacetat 5mg für je 90 Tage Im Anschluss an die PEARL III Extension