AGENDA. Mode of action and application of SPRMs in the treatment of uterine fibroids N. Chabbert Buffet

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2 WELCOM E

3 AGENDA Mode of action and application of SPRMs in the treatment of uterine fibroids N. Chabbert Buffet Efficacy and safety of Ulipristal Acetate: Clinical evidence from PEARL l I, II & III trials H.R. Tinneberg Real world data on Ulipristal Acetate: an update on the PREMYA study H. Fernandez Repeated intermittent use of Ulipristal Acetate: new phase III data from the PEARL IV part 1 trial E. Loumaye

4 Please turn off your cell phone (and other electronic devices) or turn it to silent (not vibrate) mode, prior to the start of the symposium. Photos and video are not permitted at the symposium. Please refrain from recording or taking photographs. Question cards During the scientific presentation, please write down your questions on the lecture on the question cards you received. The hostesses will collect them from you after the lecture and hand them over to me.

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6 Mode of Action and application of SPRMs* in the treatment of uterine fibroids Professor Nathalie Chabbert-Buffet, MD, PhD Obstetrics, Gynecology and Reproductive Medicine Department Hospital Tenon AP-HP P and M Curie University Paris *SPRMs, Selective Progesterone Receptor Modulators

7 Progesterone receptors ligands have pleiotropic actions Bouchard P. et al. Fertil. Steril

8 SPRM : Selective Progesterone Receptor Modulators PR, steroid or non steroid, ligands Modulate (enhance or decrease) specific target genes transcription Tissue specific activities Chabbert-Buffet N. et al.. Human Reprod updates

9 Chemical structure of SPRMs Chabbert-Buffet N. et al.. Mol Cell Endocrinol. 2012

10 Chemical structure of SPRMs Chabbert-Buffet N. et al.. Mol Cell Endocrinol. 2012

11 Progesterone induced transciptional activity Progesterone Progesterone PR PR Co-activators Basal transcriptional machinery PRE Transcription Activation PR : progestreone receptor PRE : Progesterone Response Element Chabbert-Buffet N. et al.. Mol Cell Endocrinol. 2012

12 SPRMs can exert agonist or antagonist activity Co-activators Basal transcriptional machinery Transcription activation (agonist effect) SPRM PR PR PR PR PRE No transcription activation (antagonist effect) Co-repressors Chabbert-Buffet N. et al.. Mol Cell Endocrinol. 2012

13 SPRMs molecular MoA UPA Specific contacts PR LBD /SMRT UPA bound structure Petit Topin et al 2014

14 Activity of PR ligands Mifepristone Asoprisnil Ulipristal acetate Progesterone Antagonists SPRM Agonists Spitz I.M. Current Opinion Invest Drugs 2006

15 MoA of Ulipristal acetate (UPA) Selective, partial agonist, PR -mediated effect, in specific tissues Pituitary Myomas Endometrium Endome trium Pituitary UPA Myoma

16 UPA effects on the Pituitary a 18 Inhibition of ovulation in most ,5 mg/d 12 5 mg/d 400 patients for daily doses > 5mg (progesterone levels below 0.3 ng/ml) partial suppression of FSH levels c progesterone (ng/ml) persistence 12 of physiological 5 E2 levels LH(IU/l) D 3 D 7 D 11 D 14 D 18 D 21 D 24 D 28 10mg/d b estradiol (pmol/l) d FSH (IU/L)) D3 D7 D14 D18 D21 D24 D28 D 3 D 7 D 11 D 14 D 18 D 21 0 D 24 D 28 D 3 D 7 D 11 D 14 D 18 D 21 0 D 24 D 28 Chabbert-Buffet et al JCEM 2007

17 UPA 5mg/d inhibits ovulation in 81,8 % women % anovulation E2 levels * 81,8 % (n = 11) (n = 10) * p < 0,001 vs placebo Chabbert-Buffet et al.. J Clin Endocrinol Metab 2007

18 UPA : Action on myomas Reduced tumor volume Inhibition of cell proliferation & Apoptosis induction

19 Effects of UPA in myomas : in vitro data Angiogenic factors VEGF- A, VEGF-B and Adrenomedullin (ADM) are implied in myomas angiogenesis Progesterone induces angiogenic factors expression in myoma cells and normal cells (VEGF- A, VEGF-B and d ADM) 10-6 M ulipristal acetate reduces angiogenic factors expression in myoma cells but not in normal cells Xu Q. Human Reprod 2006

20 UPA induces apoptosis in myomas in vivo Preop treatment Ulipristal acetate GnRH analog N Control 10 Mean AI (SD) 158,9 (±193,2) 27,5 (±62,3) 2,0 (±2,1) Apoptotic index (AI) AI median range N with AI > 10 (%) 9 (81,8 %) 4 (23,5 %) Patients from the PEARL 2 study Horak P. Int J Endocrinol 2012;

21 Direct endometrial action (1/2) Reduced menstrual bleeding Amenorrhea in most patients Reversible effect, menses return within 4 weeks after treatment discontinuation

22 Endometrial microvascularization vwf+ / αsma- vwf+ / αsma+ Relative percentage of vessels (%) Basal Cycle LNG Short Term LNG Long Term Basal Cycle 2,5 mg/j 5 mg/j 10 mg/j Treatment VA-2914 S. Ravet, Human Rep, 2007 S. Ravet, Human Rep.2009,

23 Endometrial collagen fibrillar network control Ulipristal Contrôle menstrual LNG-IUD Ravet, Human Rep.2009,

24 Mutter et al Modern Pathol 2008 Direct action in the endometrium (2/2) Class -specific histological changes called PAECs* (PRM associated endometrial changes ) role in amenorrhea?

25 Endometrial aspects in SPRMs users Mifepristone 5 mg/j Lakha, F. et al. Hum. Reprod. 2007

26 Endometrial aspects in SPRMs users PAECs Mutter Modern

27 Vascular modifications Mutter Modern Pathol 2008

28 Conclusion Antiovulatory effect +/- direct tissular (myoma and endometrium) effect : Amenorrhea/ bleeding control Reduced cell proliferation and increased cell apoptosis : Persistent reduction in myoma volume No E2 blunting: Good clinical tolerance (vs GnRH analogs)

29 THANK YOU

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31 Efficacy and Safety of Ulipristal Acetate: Clinical Evidence from PEARL* I, II & III trials Professor Hans-Rudolf Tinneberg *PEARL, PGL4001's (ulipristal acetate) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata

32 PEARL I PEARL I PEARL II PEARL II PGL 4001 s (UPA s) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata

33 PEARL I PEARL II Time to control of bleeding Patients with PBAC <75 (ITT) UPA 10 mg UPA 5 mg 100 Placebo 100 UPA 5 mg UPA 10 mg GnRHa depot 3.75 mg Patients (%) days Time (days) 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 7 days 30 days Time (days) UPA normalised bleeding faster than GnRHa (7 days vs 30 days)

34 PEARL I Higher number of patients with corrected anaemia in UPA groups Anaemia correction at week 13 (ITT) (all patients had Hb 10.2 g/dl at screening) 100 Hb >12.0 g/dl Patients (%) % 85.3% 89.4% INTERPRETATION: Preoperative anaemia, even to a mild degree, is independently associated with an increased risk of 30-day morbidity and mortality in patients undergoing major non-cardiac surgery 50 Placebo UPA 5 mg UPA 10 mg + iron + iron + iron Donnez J, et al. N Engl J Med 2012;366: Hb, haemoglobin; ITT, intent-to-treat; UPA, ulipristal acetate

35 PEARL II Effect on fibroid volume reduction Percentage change from baseline at Week 13 (PP population) Median % volume reduction in 3 largest fibroids after end of treatment (EOT) 0 UPA 5 mg UPA 10 mg GnRHa depot 0 Follow-up Follow-up Follow-up EOT 3-mo 6-mo EOT 3-mo 6-mo EOT 3-mo 6-mo Median % volume reduction in the largest fibroids No significant difference between GnRHa and UPA GnRHa, gonadotrophin-releasing hormone agonist; PP, per protocol; UPA, ulipristal acetate -70 Change from EOT (week 13) to 6-mo follow up for UPA 5 mg and UPA 10 mg vs GnRHa depot : p<0.05 Donnez J, et al. N Engl J Med 2012;366:421 32

36 PEARL I Ratio* of volume at EOT vs baseline Individual fibroid volume changes by baseline volume (UPA 5 and 10 mg) Ratio of EOT volume to baseline volume vs Baseline volume UPA 5 mg 21% 19% UPA 10 mg 65% 49% Plotted symbols are for individual fibroids* (patients may have had more than one fibroid) * Ratio: 1 = No change, < 1 = Reduction, > 1 = Increase EOT, end of treatment; UPA, ulipristal acetate Baseline volume (cm 3 )

37 PEARL II UPA has a superior safety profile to GnRHa Safety, Week Median serum oestradiol (pg/ml) Oestradiol 300 Median CTX (µg/mmol Cr) UPA 5 mg UPA 10 mg Lupron 9.7 Screening Week 9 Week GnRHa, gonadotrophin-releasing hormone agonist; UPA, ulipristal acetate Donnez J, et al. N Engl J Med 2012;366:421 32

38 PEARL II UPA has a superior safety profile to GnRHa Safety, Week Oestradiol Patients with moderate and severe hot flushes (%) Median serum oestradiol (pg/ml) 60.5 Hot flushes Median CTX (µg/mmol Cr) Bone resorption 39.6 UPA 5 mg UPA 10 mg GnRHa Screening Week 9 Week 13 GnRHa, gonadotrophin-releasing hormone agonist; UPA, ulipristal acetate Donnez J, et al. N Engl J Med 2012;366:421 32

39 PAEC Hysteroscopic view PAEC: glandular cyst dilatation PAEC: low mitotic activity

40 PEARL I PEARL II Endometrium Histology (PAEC) % Patients having PAEC PEARL I PEARL II Placebo UPA 5 mg UPA 10 mg UPA 5 mg UPA 10 mg GnRHa Screening 0.0% 6.5% 1.3% 2.6% 3.8% 2.5% Week 13 (end of treatment) 7.9% 59.7% 56.4% 54.5% 61.3% 13.9% Week % 7.8% 5.1% 6.5% 6.3% 6.3% PAEC: PRM-Associated Endometrial Changes Benign and reversible changes in the endometrium, denoted as PAEC, were observed in approximately 60% of patients treated with UPA for 3 months (confirmed by at least 2 out of 3 pathologist) PAEC changes were reversible after treatment cessation PAEC, PRM-associated endometrial change; UPA, ulipristal acetate Donnez J, et al. N Engl J Med 2012;366: (PEARL I) Donnez J, et al. N Engl J Med 2012;366: (PEARL II)

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42 PEARL III & extension PEARL III Extension Clinical Study Results PGL 4001 s (UPA s) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata Donnez J, et al. Fertil Steril 2014;101: UPA, ulipristal acetate

43 PEARL III & extension PEARL III and Extension: Open-label on-off intermittent use of UPA 10 mg Belgium Spain Austria Poland Patients with symptomatic uterine fibroids UPA 10mg: 4 sequential courses of 12 weeks EACH COURSE FOLLOWED BY 10 days of double-blind NETA vs placebo UPA 10 mg UPA 10 mg UPA 10 mg UPA 10 mg PEARL III PEARL III Extension Pictorial bleeding assessment chart (PBAC) UPA 10 mg (open-label) Progestin or placebo (double-blind) Menses NETA, norethindrone acetate; UPA, ulipristal acetate

44 PEARL III & extension Purpose of the study The purpose of this phase III clinical study is to: investigate the clinical efficacy and safety of the long-term intermittent 3-month administration of UPA 10 mg per day for the treatment of symptomatic uterine myoma and to assess the clinical benefit of a 10-day administration of a progestin to reverse the anti-progesterone effect of UPA on the endometrium and its effect on post-treatment menstrual bleeding. NETA, norethindrone acetate; UPA, ulipristal acetate

45 PEARL III & extension Patient flow: All patients UPA + Placebo N=103 PEARL III: 209 included 203* randomised UPA + NETA N=98 UPA + Placebo completed, N=98 UPA + NETA completed, N=92 UPA 10 mg + Placebo Continued in extension PEARL III Extension N=132 UPA 10 mg + NETA Continued in extension N=68 N=67 N=60 N=56 1st UPA course 2nd UPA course 3rd UPA course 4th UPA course N=64 N=64 N=59 N=51 * Two patients were randomised but did not receive treatment NETA, norethindrone acetate; UPA, ulipristal acetate Donnez J, et al. Fertil Steril 2014;101:

46 PEARL III & extension Effects on bleeding control UPA, ulipristal acetate

47 PEARL III & extension Study design: Uterine bleeding assessment PEARL III PEARL III Extension UPA DB UPA DB UPA DB UPA DB Pictorial bleeding assessment chart (PBAC) Simplified bleeding pattern No bleeding Spotting Bleeding Heavy bleeding Menses DB, double-blind (Progestin or placebo); UPA, ulipristal acetate

48 PEARL III & extension Bleeding control: Amenorrhoea (ITT population, all patients) Proportion of patients in amenorrhoea* at the end of each course of UPA 10 mg Proportion of Patients in amenorrhoea 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 79.5% 1st UPA course n= % 2nd UPA course n= % 3rd UPA course n= % 4th UPA Course n=107 Primary efficacy endpoint *Amenorrhoea was defined as the first day for which there was no bleeding for longer than 35 days UPA, ulipristal acetate Donnez J, et al. Fertil Steril 2014;101:

49 PEARL III & extension Time to amenorrhoea (ITT population, all patients) Subjects in amenorrhoea at the end of each course of UPA treatment Proportion of subjects (%) (n=132) th course 3rd course 2nd course 1st course Time (days) Mean (median) time to no bleeding, days (range) 1st UPA course 2 nd UPA course 3rd UPA course 4th UPA course UPA 10 mg N= (4.0) (0 57) 3.3 (2.0) (0 32) 5.3 (3.0) (0 49) 4.2 (3.0) (0 40) After the 1st course of UPA 10 mg, the effect is faster and remains the same each time whether it is the 2nd, 3rd or 4th course of UPA 10 mg UPA, ulipristal acetate Donnez J, et al. Fertil Steril 2014;101:

50 PEARL III & extension Median PBAC a NETA vs Placebo post UPA 10 mg course: Time to next menstruation & intensity of bleeding Median PBAC assessment on intensity of menstrual bleeding of first menstruation after each end of UPA course *** 84 54** 75 28**** Median days Median days to first menstruation after end of each UPA course Ulipristal acetate 10 mg + placebo Ulipristal acetate 10 mg + NETA 55 13* (p<0.001)* Safety population n= st UPA 2nd UPA 3rd UPA 4th UPA course course course course a Median PBAC score. Data were collected from day 1 to 8 after treatment course *p = 0.02; **p = 0.01; ***p = 0.006; ****p < NETA, norethindrone acetate; PBAC, Pictorial Bleeding Assessment Chart; UPA, ulipristal acetate 0 1st UPA course 2nd UPA course 3rd UPA course 4th UPA course * For all statistical comparisons between treatment groups at each treatment course

51 PEARL III & extension Effects on fibroid volume reduction

52 PEARL III & extension Efficacy: Fibroid volume reduction (ITT population, all patients) Patients with clinically significant reduction in fibroid volume * ( 25%) 100% Proportion of Patients with 25% fibroid volume reduction 80% 60% 40% 20% 77,7% 79,8% 78,3% 82.3% 69.8% 72,2% 0% 1st UPA course n=130 2nd UPA course n=119 3rd UPA course n=106 * Volume of 3 largest fibroids. Total percentage reduction 4th UPA course n=96 Follow-up (3 months n=97 after the end of the 4th course) (n=97) ITT, intent-to-treat; UPA, ulipristal acetate Donnez J, et al. Fertil Steril 2014;101:

53 PEARL III & extension Efficacy: Fibroid volume reduction (ITT population, all patients) Patients with clinically significant reduction in fibroid volume * ( 25%) Proportion of Patients with 25% fibroid volume reduction 100% 80% 60% 40% 20% Least responders (no change or <25% change) 77,7% 79,8% 78,3% 82.3% 69.8% 72,2% 80% 0% 1st UPA course n=130 2nd UPA course n=119 3rd UPA course n=106 * Volume of 3 largest fibroids. Total percentage reduction 4th UPA course n=96 Follow-up (3 months n=97 after the end of the 4th course) (n=97) ITT, intent-to-treat; UPA, ulipristal acetate Donnez J, et al. Fertil Steril 2014;101:

54 PEARL III & extension Relationship between reduction in myoma volume and amenorrhoea / only spotting ITT population After 4 courses Myoma volume reduction 25% Amenorrhoea/ only spotting Yes No Yes 80% 2% No 17% 1% After 4 courses: 80% of patients had no bleeding/spotting and reduced fibroid volume 25% 1% still had some bleeding and did not have reduced fibroid volume 25% ITT, intent-to-treat

55 PEARL III & extension Efficacy: Fibroid volume reduction (ITT population, all patients) Patients with clinically significant reduction in fibroid volume * ( 50%) 100% Proportion of Patients with 50% fibroid volume reduction 80% 60% 40% 20% 50,0% 64,7% 62,3% 69.8% 69.8% 57,7% 0% 1st UPA course n=130 2nd UPA course n=119 3rd UPA course n=106 * Volume of 3 largest fibroids. Total percentage reduction 4th UPA course n=96 Follow-up Follow-up (3 months after n=97 the end of the 4th course) (n=97) ITT, intent-to-treat; UPA, ulipristal acetate Donnez J, et al. Fertil Steril 2014;101:

56 PEARL III & extension Efficacy: Reduction in longest diameter of largest myoma (ITT population, All patients) Median change from baseline in longest diameter of the largest myoma UPA course: 1st (n=132) 2nd (n=131) 3rd (n=119) 4 th (n=107) Follow-up (3 months, n=99) 0 Median percentage change from baseline % -28.6% -29.8% -37.1% % -27.5% Reduction in diameter (%) = Reduction in volume (% approx.) Example ITT, intent-to-treat; UPA, ulipristal acetate

57 PEARL III & extension Effects on pain and quality of life (QoL)

58 PEARL III & extension Effect of UPA 10 mg on pain and QoL Mean VAS pain Visual analogue scale All patients Patients with most severe pain UFS-QoL questionnaire 50 ITT population Symptom severity score 1. Bleeding 2. Abdominal pressure 3. Urination frequency 4. Fatigue Baseline 1st UPA course 2nd UPA course 3rd UPA course 4th UPA course UPA significantly improved QOL Symptom severity scores at end of treatment correspond to those of typical healthy subjects UFS-QOL, Uterine Fibroid Symptom and Quality of Life questionnaire; UPA, ulipristal acetate; VAS, visual analogue scale

59 PEARL III & extension Conclusions Bleeding control Vast majority of patients (80%) are in amenorrhoea and the effect is obtained within the first course of treatment Bleeding control is achieved very quickly at the start of each treatment Fibroid volume reduction 80% of patients had a clinically significant reduction in fibroid volume The volume of the 3 largest fibroids was reduced by 72% after 4 courses of UPA Addition of a Progestin showed only limited benefit on intensity and time to bleeding after UPA The results of this study indicate that the use of more than one course maximises the potential benefits of UPA treatment This needs to be confirmed with other clinical data on repeated courses of treatment The current approved duration of treatment is 2 courses of 3 months treatment Repeated courses of UPA did not increase the incidence of PAEC UPA, ulipristal acetate

60 THANK YOU

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62 Real-world data on current prescription patterns and clinical outcomes of ulipristal acetate treatment: Experience from the PREMYA* study Professor Hervé Fernandez France Centre Hospitalier Universitaire de Bicêtre Paris France *PREMYA, A Prospective Multicentre Non-interventional Study of Women Treated with ESMYA (ulipristal acetate) as pre-operative treatment of moderate to severe symptoms of uterine fibroids

63 PREMYA Objectives Primary Goal: Provide real-world data related to the current treatment patterns and clinical outcomes of ulipristal acetate (UPA) treatment for symptomatic uterine fibroids Describe the safety profile of UPA in usual medical care Describe the demographic characteristics of patients treated with UPA Evaluate the frequency of findings of endometrial thickening >16 mm and document any follow-up investigations and treatment in the clinical practice setting Compare the characteristics of patients having gynaecological surgery following UPA treatment with patients who do not progress to gynaecological surgery Evaluate health-related quality of life outcomes in patients with symptomatic uterine fibroids, including characterization of severity and burden of illness prior to and subsequent to UPA treatment UPA, ulipristal acetate

64 PREMYA Non-interventional study design Study Design: Multicentre, prospective, non-interventional study Patients who have been diagnosed with symptomatic uterine fibroids and are initiating treatment with UPA Population Uterine fibroids Initiating treatment with UPA 10 countries EU (n=1500) 12 weeks ESMYA Open-label Primary Endpoint Provide real-world data related to the current treatment patterns UPA, ulipristal acetate

65 PREMYA Main Inclusion criteria Pre-menopausal adult women with a diagnosis of symptomatic uterine fibroids who are initiating treatment with UPA Patient is willing and able to attend scheduled follow-up visits, provide the required medical data, and complete self-administered questionnaires about her uterine fibroids and associated symptoms and HRQoL and functioning Patient has personally signed and dated the informed consent document indicating that she has been informed of all pertinent aspects of the study HRQoL, health-related quality of life; UPA, ulipristal acetate

66 PREMYA Main Exclusion criteria Patient is pregnant or plans to become pregnant in the next 3 months Patient is breastfeeding Patient has genital bleeding not due to uterine fibroids Patient has been diagnosed with uterine, cervical, ovarian or breast cancer Patient is using an investigational drug/therapy or has discontinued the use of an investigational drug/therapy within 30 days prior to study enrolment Patient has hypersensitivity to the active substance of UPA or to one of its excipients Patient has severe hepatic impairment UPA, ulipristal acetate

67 PREMYA Demographics Characteristic Total study population (N=1534) Mean age, years (SD) 42.9 (6.6) Median (range) 43.9 ( ) Age categories, n (%) 20 <30 years 77 (5.0) 30 <40 years 386 (25.2) <50 years 892 (58.1) 50 <60 years 179 (11.6)++ 60 years 1 (0.1) Race/ethnicity, n (%) a Caucasian 1280 (83.4) Black 161 (10.5) Asian 49 (3.2) Other 43 (2.8) Mean body weight, kg (SD) b 70.8 (15.7) Median (range) 68 (40 142) Mean body mass index, kg/m 2 (SD) at baseline b 25.9 (5.6) Median (range) 24.8 ( ) a N=1533, data missing for 1 subjects; b N=1074, data missing for 460 subjects; subjects SD, standard deviation

68 PREMYA Update on recruitment status at present date All countries, number of patients Interim Report until database lock 20 Feb 2015 Study Ongoing Last Patient Last Visit July 2015 Number of patients at baseline: 1534 Visit 1 (up to 3 months) 1243 Visit 2 (up to 6 months) 958 Visit 3 (up to 9 months) 732 Visit 4 (up to 12 months) 583 Visit 5 (up to 15 months) 366 End-of-study visit 775 Unscheduled visit 223 Total study population (N=1534) Number of discontinued patients 249 (16.2%)

69 PREMYA Patient discontinuations Total study population (N=1534) Number of discontinued patients 249 (16.2%) Reason for discontinuation Lost to follow-up 113 (7.4%) Adverse events (AEs) 20 (1.3%) Lack of efficacy 10 (0.7%) Withdrew consent 22 (1.4%) Other 81 (5.3%) Reason not given 3 (0.2%)

70 PREMYA Demographics, All Subjects Characteristic Total study population (N=1534) Mean age, years (SD) 42.9 (6.6) Median (range) 43.9 ( ) Age categories, n (%) 20 <30 years 77 (5.0) 30 <40 years 386 (25.2) 40 <50 years 892 (58.1) 50 <60 years 179 (11.6) 60 years 1 (0.1) Race/ethnicity, n (%) a Caucasian 1280 (83.4) Black 161 (10.5) Asian 49 (3.2) Other 43 (2.8) Mean body weight, kg (SD) b 70.8 (15.7) Median (range) 68 (40 142) Mean body mass index, kg/m 2 (SD) at baseline b 25.9 (5.6) Median (range) 24.8 ( ) a N=1533, data missing for 1 subjects; b N=1074, data missing for 460 subjects; subjects SD, standard deviation

71 PREMYA Demographics Afro-Caribbean Population (AC) Characteristic Non AC origin population (N=1373 (89.5%) AC population (N a =161 (10.5%)) Mean age, years (SD) 43.2 (6.5) 40.3 (6.9) Median (range) 44.2 ( ) ( ) Age categories, n (%) 20 <30 years 62 (4.5) 15 (9.3) 30 <40 years 324 (23.7) 61 (37.9) 40 <50 years 820 (59.7) 72 (44.7) 50 <60 years 166 (12.1) 13 (8.1) 1 (0.1) 60 years 0 (0.0) Mean body weight, kg (SD) b 70.4 (15.2) 74.9 (18.9) Median (range) 68 (40-142) 70 (45 137) Mean body mass index, kg/m 2 (SD) at baseline b 25.7 (5.4) 27.4 (6.6) Median (range) 24.5 ( ) 25.9 ( ) a N=161, data missing for 0 subjects; Not AC: N=1373 data missing for 0 subjects; b N=114, data missing for 47 subjects; Not AC: N=960, data missing for 413 subjects SD, standard deviation

72 PREMYA Interventions for uterine fibroids before UPA treatment at baseline (History) Patients experiencing at least 1 intervention for uterine fibroids, N=215 (14.0% of all patients) Type of intervention a Total Population Non AC Population AC Population N= 215 patients N=168 patients N=47 patients Myomectomy 159 (67.9%) 120 (51.3%) 39 (16.7%) Uterine fibroid/artery embolization 22 (9.4%) 14 (6.0%) 8 (3.4%) Endometrial ablation 20 (8.5%) 19 (8.1%) 1 (0.4%) Focused ultrasound therapy 4 (1.7%) 4 (1.7%) 0 (0.0%) Myolysis or cryomyolysis 0 (0.0%) 0 (0.0%) 0 (0.0%) Other 29 (12.4%) 23 (9.8%) 6 (2.6%) Total Interventions (76.9%) 54 (23.1%) All patients with surgical indication. Less procedures and myomectomies in Afro-Caribbean population a Percentages are based on total number of procedures (N=234) AC: Afro-Caribbean UPA, ulipristal acetate

73 PREMYA Interventions for uterine fibroids after UPA treatment Patients experiencing at least 1 intervention for uterine fibroid, N=503 with 534 Interventions Type of intervention N= 534 Total Population N=503 Non AC Population N=438 AC population Hysterectomy 203 (38.0%) 188 (40.7%) 15(20.8%) Myomectomy Hysteroscopic 96 (18.0%) 77(16.7%) 19(26.4%) All Laparoscopic patients had a surgical indication 93 (17.4%) at enrolment 84(18.2%) 9(12.5%) Until Laparotomic now, procedures performed 70 (13.1%) during follow 52(11.3%) up period 18(25.0%) in Uterine 32.8% fibroid (503/1534) embolization of subjects. 17 Study (3.2%) is ongoing 11(2.4%) 6(8.3%) No surgical complications reported at this time Endometrial Ablation 14 (2.6%) 14(3.0%) 0 (0%) Focused Ultrasound Therapy 4 (0.7%) 3(0.6%) 1(1.4%) N=65 Other (myolysis or cryomyolysis, DIU insertion, endometrial ablation) 37 (6.9%) 33(7.1%) 4(5.6%) AC: Afro-Caribbean

74 PREMYA Time distribution of Interventions for uterine fibroids after UPA treatment Number of interventions for uterine fibroid, All Patients NAC 76 AO 7 70 Number of Interventions NAC 39 AO: NAC 26 AO Month 3 Month 6 Month 9 Month 12 Month Hysterectomy Myomectomy (Hysteroscopic) Myomectomy (Laparoscopic) Myomectomy(Laparotomic) UAE Endometrial Ablation Focused Ultrasound The majority of surgeries occurred during 6 months after treatment African population tend to have lower proportion of surgeries (all types) Number of patients 514, NAO: Non African Origin; AO: African Origin * Other procedures (not shown 24) Total procedures: 532 UPA, ulipristal acetate AC: Afro-Caribbean NAC Non Afro-Caribbean

75 PREMYA Medical Treatment for uterine fibroids after UPA Patients experiencing at least 1 medical treatment for uterine fibroids, N=160 (10.4%) a Type of treatment b N=174 c GnRHa 0 (0%) Oral contraceptive 38 (21.8%) Progestins 23 (13.2%) NSAIDs 10 (5.8%) Iron supplements 35 (20.1%) Other 68 (39.1%) No difference observed between Afro-Caribbean and rest of the study population (not shown) a Percentage based on total number of patients (N=1534) b Percentages are based on total number of treatments (N=174) c Total number of treatments GnRHa, gonadotropin releasing hormone agonist; NSAIDs, non-steroidal anti-inflammatory drugs; UPA, ulipristal acetate

76 PREMYA Study assessments Clinical Global Impression-Improvement Scale (CGI-I) 7-point scale ranging from 1 (very much improved) to 7 (very much worse) Patient Treatment Benefit Scale (PTB) 4-point scale designed to document patient perception of their condition compared to 3 months ago Options are: 1 (greatly improved), 2 (somewhat improved), 3 (no different) and 4 (worse) UFS-QoL Symptom Severity Scale 8 items that contains questions on bleeding and bulk symptoms with a 1-month recall period Pain Assessment A visual analogue scale of 10 cm UFS-QoL, Uterine Fibroid Symptom and Quality of Life questionnaire

77 PREMYA Improvement in symptoms of uterine fibroids: Clinical Global Impression-Improvement Scale (CGI-I) Improvement after UPA in clinical global impression (CGI) a,total study population Patients (%) ,6 *p< between M3 and M6 42,9 42,6 44,1 47,5 Month 3 Month 6 Month 9 Month 12 Month 15 N=1243 N=958 N=732 N=583 N=366 CGI scale 0 - Not assessed 1 - Very much improved Improved uterine fibroids 2 - Much improved symptoms in CGI 3 - Minimally improved 4 - No change 5 - Minimally worse 6 - Much worse 7 - Very much worse a Scored 1, 2 or 3 on the CGI scale QoL, quality of life; UPA, ulipristal acetate

78 PREMYA Improvement in symptoms of uterine fibroids: Clinical Global Impression-Improvement Scale (CGI-I) Improvement after UPA in clinical global impression (CGI) a Afro-Caribbean Population (AC) Patients (%) ,1 *p< between M3 and M6 40,3 45,2 35,3 66,6 Month 3 Month 6 Month 9 Month 12 Month 15 N=115 N=77 N=62 N=34 N=21 CGI scale 0 - Not assessed 1 - Very much improved Improved uterine fibroids 2 - Much improved symptoms in CGI 3 - Minimally improved 4 - No change 5 - Minimally worse 6 - Much worse 7 - Very much worse Difference at Month 15 is an interesting finding a Scored 1, 2 or 3 on the CGI scale QoL, quality of life; UPA, ulipristal acetate

79 PREMYA Improvement in uterine bleeding: Patient Treatment Benefit Scale (PTB) Improvement after UPA in patient treatment benefit scale (PTB) a,total study population Patients (%) ,5 *p< between M3 and M6 65,1 67,1 68,6 68,5 Improved uterine bleeding in PTB PTB scale 1 - Greatly Improved 2 - Somewhat Improved 3 - No Difference 4 - Worse Month 3 Month 6 Month 9 Month 12 Month 15 N=1243 N=958 N=732 N=583 N=366 a Scored 1 or 2 on the PTB scale QoL, quality of life; UPA, ulipristal acetate

80 PREMYA Improvement in uterine bleeding: Patient Treatment Benefit Scale (PTB) Improvement after UPA in patient treatment benefit scale (PTB) a Afro-Caribbean Population (AC) ,4 *p< between M3 and M6 79,4 90,5 Improved uterine bleeding in PTB Patients (%) ,1 66,1 PTB scale 1 - Greatly Improved 2 - Somewhat Improved 3 - No Difference 4 - Worse Month 3 Month 6 Month 9 Month 12 Month 15 N=115 N=77 N=62 N=34 N=21 No significant difference observed between Afro-Caribbean and rest of the study population. a Scored 1 or 2 on the PTB scale QoL, quality of life; UPA, ulipristal acetate

81 PREMYA Symptom improvement by requirement for surgery a Patients with improvement in symptoms (PTB) after UPA b,total study population Percentage of patients No surgery Minimally invasive surgery Invasive surgery Month 3 Month 6 Month 9 Month 12 Month 15 N = a 7 patients who received invasive and noninvasive surgery were excluded b Based on PTBS (score 1 or 2 = improvement) PTBS, Patient treatment benefit scale; UPA, ulipristal acetate PTBS 1 Greatly improved 2 Somewhat improved 3 No difference 4 Worse 60

82 PREMYA Symptom improvement by requirement for surgery a Patients with improvement in symptoms (PTB) after UPA b Afro-Caribbean Population (AC) Percentage of patients No surgery Minimally invasive surgery Invasive surgery Month 3 Month 6 Month 9 Month 12 Month 15 N = a 7 patients who received invasive and noninvasive surgery were excluded b Based on PTBS (score 1 or 2 = improvement) PTBS, Patient treatment benefit scale; UPA, ulipristal acetate PTBS 1 Greatly improved 2 Somewhat improved 3 No difference 4 Worse No significant difference observed between Afro-Caribbean and rest of the study population

83 PREMYA UFS-QoL Symptom Severity Scale Distress due to heavy menstrual bleeding, Total Study Population Patients at study start (i%) Patients distressed by heavy bleeding Patients distressed by Heavy Bleeding 4,9 7,1 5,7 11,9 70,4 Heavy Bleeding at baseline No data Not at all A little bit Somewhat A great deal to a very great deal QoL scale (heavy bleeding during menstrual period) 1 - Not at all 2 - A little bit 3 - Somewhat 4 - A great deal 5 - A very great deal Mth, month; QoL, quality of life; UPA, ulipristal acetate Patients (%) Patients (%) ,4 "A great deal" or "A very great 9 22,6 21,4 15,6 17,2 Enroll Mth 3 Mth 6 Mth 9 Mth 12 Mth 15 UPA 24,7 82,0 64,2 66,4 "Not at all" to 73,7 75,8 Enroll Mth 3 Mth 6 Mth 9 Mth 12 Mth 15 N=1534 UPA N=1243 N=985 N=732 N=583 N=366

84 PREMYA UFS-QoL Symptom Severity Scale Distress about pelvic discomfort (tightness & pressure), Total Study Population Patients distressed by tightness and pressure in pelvic area "A great deal" or "A very great deal" Patients at study start (%) ,2 11,7 16,9 21,8 44,4 Pelvic pressure at baseline No data Not at all A little bit Somewhat A great deal to a very great deal QoL scale (feeling tightness or pressure in pelvic area) 1 - Not at all 2 - A little bit 3 - Somewhat 4 - A great deal 5 - A very great deal Patients (%) Patients (%) ,4 9,4 13,9 12 9,1 9,3 Enroll Mth 3 Mth 6 Mth 9 Mth 12 Mth 15 UPA 50,4 81,4 73,2 75,5 81,3 "Not at all" to "Somewhat" 84,1 Enroll Mth 3 Mth 6 Mth 9 Mth 12 Mth 15 N=1534 N=1243 N=958 N=732 N=583 N=366 Mth, month; QoL, quality of life; UPA, ulipristal acetate UPA

85 PREMYA Effect of UPA on pain, Total Study Population VAS: from 0, no pain, to 100, worst possible pain Median VAS pain score UPA Enrollment (N=1459) Month 3 (N=1135) 7 46 Month 6 (N=842) 12 Month 9 (N=645) 10 Month 12 (N=536) 7,5 Month 15 (N=339) 7 Less pain UPA, ulipristal acetate; VAS, visual analogue scale

86 PREMYA Effect of UPA on pain Afro-Caribbean Population (AC) VAS: from 0, no pain, to 100, worst possible pain Median VAS pain score Enrollment (N=155) 54 UPA Enrollment NAC (1304) 45 Month 3 (N=105) 8 7 AC Month 6 (N=67) NAC Month 9 (N=51) 10 Month 12 (N=32) 15 Month 15 (N=19) 8 Less pain Slightly higher pain levels in African population INAC: Non Afro-Caribbean; AC: Afro-Caribbean Enrolment NAC:had a score of 45 at baseline with N=1304, a score of 7 at Month 3 with N=1030 and a score 12 at Month 6 with N=775), UPA, ulipristal acetate; VAS, visual analogue scale

87 PREMYA Correlation between patients (PTB) and physicians (CGI) assessment of benefit Percentage of patients with change in symptoms after UPA a,total study population PTBS outcome PTB improved PTB improved PTB not improved PTB not improved CGI-I outcome CGI improved CGI not improved CGI improved CGI not improved Month 3 (N=788) No surgery Month 6 (N=576) Month 9 (N=469) Minimally invasive surgery Month 3 (N=208) Month 6 (N=168) Month 9 (N=105) Month 3 (N=225) Invasive surgery Month 6 (N=196) Month 9 (N=144) PTBS 1 Greatly improved 2 Somewhat improved 3 No difference 4 Worse a Based on PTBS (score 1 or 2 = improvement) and CGI-I (score 1, 2 or 3 = improvement) CGI-I, Clinical Global Impression Improvement Scale; PTBS, Patient treatment benefit scale; UPA, ulipristal acetate CGI-I 1 Very much improved 4 No change 2 Much improved 5 Minimally worse 3 Minimally improved 6 Much worse 7 Very much worse No significant difference observed between Afro-Caribbean and rest of the study population.

88 PREMYA Patient-reported outcomes by age group Patients with improvement in symptoms (CGI-I) after UPA a,total study population Percentage of patients <30 years years years 50 years Month 3 Month 6 Month 9 Month 12 Month 15 N = a Based on CGI-I (score 1, 2 or 3 = improvement) CGI-I, Clinical Global Impression Improvement Scale; UPA, ulipristal acetate CGI-I 1 Very much improved 4 No change 2 Much improved 5 Minimally worse 3 Minimally improved 6 Much worse 7 Very much worse

89 PREMYA Endometrial thickening and histology Total study population Time after UPA initiation Month 3 Month 6 Month 9 Month 12 Month 15 N, (N miss) a 1349 (1) 1082 (1) 778 (0) 560 (1) 365 (1) Endometrial thickening, n (%) Endometrial thickening reported Endometrial thickening >16 mm 110 (8.2) 55 (5.1) 25 (3.2) 22 (3.9) 7 (1.9) 35 (2.6) 16 (1.5) 5 (0.6) 5 (0.9) 2 (0.5) Patients with Endometrial thickening, n (%) Baseline to Month 6 After Month 6 to Month 15 N Biopsy performed 11 (7.9) 5 (8.3) PAEC 4 (2.9) 4 (6.7) Endometrial Hyperplasia without Atypical Change 4 (2.9) 1 (1.7) Other b 7 (5.0) 1 (1.7) a Percentages are based on number of patients with non-missing data b Other : 2 Adenocarcinoma, 1 Leiomyosarcoma, 1 Endometrial Polyp, 1 Glandular cyst & 3 unavailable at this time. N, Number of subjects with non-missing assessments; UPA, ulipristal acetate

90 PREMYA But which patients require surgery? Patients with severe bleeding symptoms after UPA a,total study population Percentage of patients No surgery Minimally invasive surgery Invasive surgery Month 3 Month 6 Month 9 Month 12 Month 15 N = a Based on UFS-QoL questionnaire, questions 1 to 4 combined (score 4 or 5 = severe): 1. Heavy bleeding during menstrual period 2. Passing blood clots during menstrual period 3. Variations in the length of menstrual period 4. Variations in the number of days between periods UFS-QoL, Uterine Fibroid Symptom and Quality of Life questionnaire; UPA, ulipristal acetate

91 PREMYA Pain could be a requirement for surgery? Patients with moderate-to-severe pain after UPA a,total study population 25 No surgery Minimally invasive surgery Invasive surgery Percentage of patients Month 3 Month 6 Month 9 Month 12 Month 15 N = a Based on pain VAS, (score 2 or 3, VAS 40) UPA, ulipristal acetate; VAS, visual analogue scale

92 Conclusions (1) Premya presents real world data about the use of Esmya for symptom management related to uterine fibroids during one 3 month course. The majority of surgeries occurred during the first 6 months after UPA treatment with myomectomy being the most frequent Quality of life and pain are highly improved by UPA and tend to remain lower than baseline during 12 months follow up after treatment cessation. Improvement of symptoms (assessed by CGI-I and PTB) is observed up to 6 months after UPA treatment. This improvement was better in patients with no surgery but was not impacted by type of surgery when performed

93 Conclusions (2) At 6 months, 70% of the patients not requiring surgery reported an improvement vs 60% and 57% of those requiring surgery (minimally invasive and invasive respectively) No association between age and severity of symptoms was observed, even for patients <40 years old or > 50 years old Patients of Afro-Caribbean origin tend to be younger, have less surgical procedures and higher levels of pain. No differences in symptoms found. Further comparative studies are required FUTURE: Observational study with UPA 5 mg repeated intermittent use without surgery as inclusion criteria

94 THANK YOU FOR YOUR ATTENTION!

95 Back up

96 PREMYA Interventions for uterine fibroids within 12 months after UPA treatment Patients experiencing at least 1 intervention for uterine fibroid, N=492 with 519 Interventions Type of intervention N= 519 Total Population N=503 Patients with at least 1 intervention at 12 months N= 492 Hysterectomy 203 (38.0%) 197(40.0%) Myomectomy Hysteroscopic 96 (18.0%) 96 (19.5%) Laparoscopic 93 (17.4%) 91 (18.5%) All patients Laparotomic had a surgical indication 70 (13.1%) at enrolment 67 (13.6%) Until 12 Uterine months, fibroid embolization procedures performed 17 (3.2%) during 17 (3.5%) follow up period in 32.1% (492/1534) of subjects. Study is ongoing Endometrial Ablation 14 (2.6%) 14 (2.9%) No surgical Focused complications Ultrasound Therapy reported 4 (0.7%) at this 3 (0.6%) time AC: Afro-Caribbean Other (myolysis or cryomyolysis, DIU insertion, endometrial ablation) 37 (6.9%) 34(6.9%)

97 PREMYA Patient-reported outcomes by age group Patients with improvement in symptoms (PTB) after UPA a,total study population Percentage of patients <30 years years years 50 years Month 3 Month 6 Month 9 Month 12 Month 15 N = a Based on PTBS (score 1 or 2 = improvement) PTBS, Patient treatment benefit scale; UPA, ulipristal acetate 75 PTBS 1 Greatly improved 2 Somewhat improved 3 No difference 4 Worse

98 PREMYA Patient-reported outcomes by age group Patients with severe symptoms after UPA a,total study population Percentage of patients <30 years years years 50 years Month 3 Month 6 Month 9 Month 12 Month 15 N = a Based on UFS-QoL questionnaire, all 8 questions combined (score 4 or 5 = severe): 1. Heavy bleeding during menstrual period 2. Passing blood clots during menstrual period 3. Variations in the length of menstrual period 4. Variations in the number of days between periods 5. Feeling tightness or pressure in pelvic area 6. Frequent urination during daytime 7. Frequent night-time urination 8. Feeling tired UFS-QoL, Uterine Fibroid Symptom and Quality of Life questionnaire; UPA, ulipristal acetate UFS-QoL 1 Not at all 2 A little bit 3 Somewhat 4 A great deal 5 A very great deal

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100 Repeated Intermittent Use of Ulipristal Acetate: New Phase III data from the Pearl IV* Part 1 trial Ernest Loumaye, MD, PhD Former Co-founder and CEO of PregLem SA *PEARL, PGL4001's (ulipristal acetate) Efficacy Assessment in Reduction of symptoms due to uterine Leiomyomata

101 PEARL IV PEARL IV A Phase III, multicentre, randomised, double-blind clinical study, investigating the efficacy and safety of repeated 12-week courses of ulipristal acetate (UPA) 5 mg or 10 mg daily for the long-term management of symptomatic uterine fibroids 2nd pivotal study for the indication of repeated intermittent use of UPA

102 PEARL IV Study design 4 Courses of 12 weeks of UPA Patients with menorrhagia due to uterine fibroids UPA 12 weeks UPA UPA UPA UPA PEARL IV - Part I PEARL IV - Part II UPA 5 mg or 10 mg (double-blind) Menses UPA, ulipristal acetate

103 PEARL IV Key inclusion criteria Premenopausal women Aged years old At least one uterine fibroid Uterine fibroid 3 12 cm diameter Regular menstrual cycles 22 to 35 days duration (FSH <20 miu/ml) Body mass index kg/m 2 Uterus volume Upper limit equivalent to 16 weeks pregnancy Excessive uterine bleeding PBAC >100 FSH, follicle stimulating hormone; PBAC, Pictorial Bleeding Assessment Chart

104 PEARL IV Efficacy study endpoints Primary efficacy endpoint Percentage of subjects who are in amenorrhoea at the end of both treatment courses 1 and 2 Secondary endpoints Percentage of subjects in amenorrhoea in the last 56 days of both treatment courses Median time to amenorrhoea Percentage of subjects with controlled bleeding in the last 56 days of both treatment courses Proportion of days with uterine bleeding/heavy uterine bleeding between visit 2 and visit 8 Change from baseline in the volume of the 3 largest myomas and uterus Change from baseline in quality of life (UFS-QoL and EQ-5D) Change from baseline in pain (VAS) EQ-5D, EuroQol 5-dimensional health status questionnaire; UFS-QoL, Uterine Fibroid Symptom and Quality of Life questionnaire; UPA, ulipristal acetate; VAS, visual analogue scale

105 PEARL IV Countries involved Belgium Czech Republic France Italy 46 sites in total Germany Latvia Lithuania Hungary Romania United Kingdom Ukraine

106 PEARL IV Patient disposition 555 screened (Visit 1) UPA 5 mg N=228 Received treatment N=228 N=219 N=213 Received treatment N=213 N=208 N=194 a 451 randomised Treatment course 1 N=451 Completed course 1 Started course 2 Treatment course 2 N=420 Completed course 2 Follow up UPA 10 mg N=223 Received treatment N=223 N=214 N=207 Received treatment N=207 N=203 N=193 a a 4 subjects (1 UPA 5 mg, 3 UPA 10 mg) with non-missing data at an early termination visit were included in the Visit 8 summaries for uterine and myoma volume assessment. UPA, ulipristal acetate

107 PEARL IV Baseline characteristics Characteristic (Full analysis set) UPA 5 mg/day (N=228) UPA 10 mg/day (N=223) Mean age, years (SD) 41.6 (5.4) 41.1 (5.1) Ethnic origin, n (%): White 211 (92.5) 214 (96.0) Black 12 (5.3) 8 (3.6) Other 4 (1.8) 1 (0.4) Not reported 1 (0.4) 0 Mean weight, kg (SD) 69.2 (12.7) 70.0 (12.8) Mean BMI, kg/m 2 (SD) 25.2 (4.1) 25.3 (4.5) BMI, body mass index; UPA, ulipristal acetate

108 PEARL IV Effects of UPA on bleeding control UPA, ulipristal acetate

109 PEARL IV e-diary design simplified simplified PBAC PBAC PBAC UPA UPA V8 V7 V6 V5 V4 V3 V2 S3 S2 S1 UPA 5 mg or 10 mg (double-blind) Menses Record PBAC Simplified Bleeding Questionnaire Diary: Medication intake Prompts for visits and meds Bleeding: PBAC or simplified PBAC, Pictorial Bleeding Assessment Chart; UPA, ulipristal acetate

110 PEARL IV Efficacy: Amenorrhoea (Full analysis set) Primary efficacy endpoint Proportion of patients in amenorrhoea* at the end of both treatment courses 1 and 2 80 Percentage of patients ,9 10.8% p = ,7 0 UPA 5 mg (N=197) UPA 10 mg (N=187) *Amenorrhoea was defined as no more than one day of spotting within a 35-day interval N, Number of subjects with non-missing amenorrhoea assessments for treatment courses 1 and 2; UPA, ulipristal acetate

111 PEARL IV Efficacy: Controlled bleeding Patients with controlled bleeding a at the end of Treatment courses 1 and 2 (FAS) P = NS Percentage of patients ,1 86, UPA 5 mg (N=185) UPA 10 mg (N=172) a Controlled bleeding was defined as no episodes of heavy bleeding and a maximum of 8 days of bleeding (not including days of spotting) during the last 56 days of a treatment course FAS1, Full analysis set 1; N, number of patients with non-missing controlled bleeding assessments for Treatment courses 1 and 2; UPA, ulipristal acetate

112 PEARL IV PBAC assessment of blood loss Intensity of menstrual bleeding a (PBAC score) [FAS] UPA 5 mg UPA 10 mg Median PBAC score Menses at screening First menses after Treatment course 1 First menses after Treatment course 2 N=218 N=214 N=172 N=156 N=159 N=152 a Only the first 8 days of menses are included in the total PBAC score FAS1, full analysis set 1; PBAC, Pictorial Bleeding Assessment Chart; UPA, ulipristal acetate

113 PEARL IV Effects of UPA on fibroid and uterine volume reduction UPA, ulipristal acetate

114 PEARL IV Efficacy: Fibroid volume reduction Median change from screening in total fibroid volume a (FAS) Median % change from screening After Treatment course 1 End of Treatment course 2-38,0 UPA 5 mg UPA 10 mg -38,2-54,1-58,0 N=207 N=206 N=197 N=200 a Volume of 3 largest fibroids combined FAS, Full analysis set 1; UPA, ulipristal acetate After treatment course was measured at end of treatment plus 1bleed

115 PEARL IV Efficacy: Fibroid volume reduction Patients with clinically significant reduction in fibroid volume a ( 25%) [FAS] 100 Percentage of patients ,3 66,5 80,2 83,0 80% UPA 5 mg UPA 10 mg 0 After Treatment course 1 (Visit 6) End of Treatment course 2 (Visit 7) N=207 N=206 N=197 N=200 a Volume of 3 largest fibroids combined FAS, Full analysis set 1; N, number of patients with non-missing assessments; UPA, ulipristal acetate After treatment course was measured at end of treatment plus 1bleed

116 PEARL IV Efficacy: Uterine volume reduction Patients with clinically significant reduction in uterine volume ( 25%) [FAS] 100 Percentage of patients ,4 31,3 47,8 50,7 UPA 5 mg UPA 10 mg 0 After Treatment course 1 (Visit 6) End of Treatment course 2 (Visit 7) N=214 N=211 N=205 N=203 FAS, Full analysis set 1; N, number of patients with non-missing assessments; UPA, ulipristal acetate After treatment course was measured at end of treatment plus 1bleed

117 PEARL IV Effects of UPA on pain and quality of life UPA, ulipristal acetate

118 PEARL IV Effect of UPA on pain VAS: from 0, no pain, to 100, worst possible pain Median pain score (VAS) for all patients and those with most severe pain (FAS) Less pain Median VAS pain score ,5 64,0 7,0 8,0 41,0 32,0 UPA 5 mg UPA 10 mg UPA 5 mg* UPA 10 mg* 6,0 7,0 *Patients from FAS with most severe pain: VAS >60 at baseline 0 Baseline End of Treatment course 1 Start of Treatment course 2 End of Treatment course 2 UPA 5 mg*: UPA 10 mg*: N=97 N=102 N=82 N=85 N=61 N=73 N=67 N=69 FAS, Full analysis set 1; N(*), number of patients with most severe pain with non-missing assessments; UPA, ulipristal acetate; VAS, visual analogue scale

119 PEARL IV Fewer symptoms Effect of UPA on symptom severity Validated UFS-QoL questionnaire 1 UFS-QoL: Median symptom severity score (FAS) Median symptom severity score UPA 5 mg: UPA 10 mg: 50,0 50,0 Baseline N=202 N=197 15,6 UPA 5 mg 12,5 End of Treatment course 1 N=182 N=173 31,3 31,3 UPA 10 mg Start of Treatment course 2 N=154 N=164 15,6 12,5 End of Treatment course 2 N=165 N=161 Symptom severity score domains: 1. Bleeding 2. Abdominal pressure 3. Urination frequency 4. Fatigue Level reported in UFS-QoL validation study in patients with symptomatic fibroids Level reported in UFS-QoL validation study for healthy subjects 1. Spies JB, et al. Obstet Gynecol 2002;99: FAS, Full analysis set 1; N, number of patients with non-missing assessments; UFS-QoL, Uterine Fibroid Symptom and Quality of Life questionnaire; UPA, ulipristal acetate

120 PEARL IV Better HRQOL Effect of UPA on HRQoL Validated UFS-QoL questionnaire 1 UFS-QoL: Median total HRQoL score (FAS) Median total HRQOL score ,9 55,2 85,8 UPA 5 mg 82,8 74,6 72,4 UPA 10 mg 85,3 80,2 HRQoL score domains: 1. Concern 2. Activities 3. Energy/mood 4. Control 5. Self-consciousness 6. Sexual function Level reported in UFS-QoL validation in healthy subjects Level reported in UFS-QoL validation study in patients with symptomatic fibroids 30 Baseline End of Treatment course 1 Start of Treatment course 2 End of Treatment course 2 UPA 5 mg: UPA 10 mg: N=201 N=198 N=182 N=173 N=154 N=164 N=164 N= Spies JB, et al. Obstet Gynecol 2002;99: FAS, Full analysis set 1; HRQoL, health-related quality of life; N, number of patients with non-missing assessments; UFS-QoL, Uterine Fibroid Symptom and Quality of Life questionnaire; UPA, ulipristal acetate

121 PEARL IV Safety UPA, ulipristal acetate

122 PEARL IV Safety: Treatment-related AEs during UPA treatment AEs occurring in 2.0% patients in total or in a single treatment course (Safety population) Overall Treatment course 1 Treatment course 2 AE, No. of patients (%) Patients with 1 AE UPA 5 mg (N=230) UPA 10 mg (N=221) UPA 5 mg (N=230) UPA 10 mg (N=221) UPA 5 mg (N=215) UPA 10 mg (N=205) 59 (25.7) 53 (24.0) 47 (20.4) 44 (19.9) 28 (13.0) 22 (10.7) Headache 12 (5.2) 10 (4.5) 10 (4.3) 10 (4.5) 6 (2.8) 0 Hot flushes 16 (7.0) 17 (7.7) 12 (5.2) 14 (6.3) 8 (3.7) 6 (2.9) Fatigue 3 (1.3) 5 (2.3) 2 (0.9) 5 (2.3) 2 (0.9) 1 (0.5) Acne 5 (2.2) 4 (1.8) 4 (1.7) 4 (1.8) 2 (0.9) 1 (0.5) AE, adverse event; UPA, ulipristal acetate

123 PEARL IV Safety: TEAEs by severity Patients with most frequent TEAEs by severity (UPA 5 mg and 10 mg combined) a 50 N=451 41,9 Percentage from study patients ,1 23,9 3,5 0,4 Headache Any TEAE ,7 0 7,3 1,1 Hot flush 0,0 a Safety population TEAE, treatment-emergent adverse event; UPA, ulipristal acetate

124 PEARL IV Effects of UPA on endometrium UPA, ulipristal acetate

125 PEARL IV Timing of biopsies 4 Courses of 12 weeks of UPA Patients with menorrhagia due to uterine fibroids UPA 12 weeks UPA UPA UPA UPA PEARL IV - Part I PEARL IV - Part II UPA 5 mg or 10 mg (double-blind) Biopsies Menses UPA, ulipristal acetate

126 PEARL IV Effect of UPA on endometrium thickness Patients with endometrium thickness >16 mm (Safety population) 12 Percentage of patients ,9 5,0 8,7 6,1 6,3 3,5 3,6 3,1 UPA 5 mg UPA 10 mg 0 Screening After Treatment course 1 End of Treatment course 2 After Treatment course 2 N=225 N=220 N=214 N=207 N=207 N=200 N=192 N=193 N, number of patients in whom endometrial thickness was measured UPA, ulipristal acetate

127 PEARL IV Part 1 Endometrium histology Biopsy performed after 1 st menstruation following second treatment course completion (V8) Consensus results from at least 2 of the 3 pathologists (Safety population) UPA 5 mg (N=230) UPA 10 mg (N=221) Histology, n (%) Visit 8 a Visit 8 a Number of diagnoses Benign endometrium 176 (98.9) 180 (98.9) Hyperplasia 1 (0.6) b 2 (1.1) c Malignant neoplasm 1 (0.6) d 0 Polyps (benign) 2 (1.1) 2 (1.1) a Visit 8, after Treatment course 2. b Simple, non-atypical hyperplasia c Simple, non-atypical hyperplasia (n=1) and simple atypical hyperplasia (n=1). d Endometrial adenocarcinoma (pre-existing condition) UPA, ulipristal acetate

128 PEARL IV Part 1 Endometrium histology: PAEC Biopsy performed at screening and after 1 st menstruation following second treatment course completion (V8) Consensus results from at least 2 of the 3 pathologists (Safety population) UPA 5 mg + UPA 10 mg combined results (N=451) Histology, n (%) Screening Visit 8 a Number of patients with adequate biopsies * 422 (93.8%) 360 (93.0%) Non-physiological changes 34 (8.1) a 64 (17.8) b Epithelial changes 31 (7.3) 58 (16.1) a Visit 8, end of Treatment course 2 a 17 biopsies(8%) at screening for the 5- and 10-mg treatment groups, respectively b 29 biopsies(16%) and 35 biopsies (19%) after treatment course 2 for the 5- and 10-mg treatment groups, respectively * % based on number of biopsies performed at visit (Screening = 450, Visit 8 = 387) PAEC, progesterone receptor modulator-associated endometrial change; UPA, ulipristal acetate

129 PEARL IV Efficacy conclusions Bleeding control The majority of patients are in amenorrhoea in both treatment courses (62% for subjects on UPA 5 mg and 73% for subjects on 10 mg, p=0.03 between groups) Bleeding control is achieved quickly after start of treatment (median 5 days) in over 80% of patients and with no difference between 5 mg and 10 mg Fibroid volume reduction For the 3 largest fibroids combined, 54% fibroid volume reduction was achieved with UPA 5 mg, and 58% reduction with 10 mg, after 2 courses of UPA About 80% of patients had a clinically significant reduction ( 25%) in fibroid volume after the second treatment course Pain and quality of life Pain and quality of life are controlled as in previous studies The effect remains present, though diminished, during off-drug interval and equivalent for UPA 5 mg and 10 mg UPA, ulipristal acetate

130 PEARL IV Safety conclusions Safety profile of UPA confirmed on a large scale Decreased incidence of endometrial thickening with repeated courses to be confirmed during PEARL IV part II All evidence so far indicates PAEC is harmless and quickly reversible No current concerns about endometrial hyperplasia or carcinoma The results of this study indicate that the use of more than one course maximises the benefits of UPA treatment This needs to be confirmed with other clinical data on repeated courses of treatment (Under investigation) The current approved duration of treatment is up to 2 courses of 3 months of treatment EOT, end of treatment course 2; PAEC, progesterone receptor modulator associated endometrial changes; UPA, ulipristal acetate

131 Back-Up slides

132 PEARL IV Discontinuations Subject request (n=25):! 8 subjects did not see any improvement! 7 due to safety! 6 due to logistic (visit schedule)! 1 due to wish pregnancy! 1 due to wish hysterectomy Reasons for discontinuation, n UPA 5 mg/day UPA 10 mg/day Total Discontinuation at any time a N=34 N=30 N=64 Not Eligible Lack of Efficacy Adverse event Other UPA related! reason 2 did not (n=12): specify 7 any reason due to no return of menses within 90 days Not UPA related due to logistics (visit schedule, e-diary) Subject request due to hyperplasia at screening (result available day of randomisation) Protocol deviation Lost to follow-up Surgery/procedure for fibroids Other reason a Discontinuations that occurred at any time during treatment course 1 or treatment course 2, prior to visit 8 UPA, ulipristal acetate