9/24/2018 D ISCLOSURES Long-Term Intermittent Administration of - - PDF document

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Long-Term Intermittent Administration of SPRMs: New Treatment Options

James H. Liu, MD Arthur H Bill Professor Chair, Depts of Obstetrics and Gynecology and Reproductive Biology Case Western Reserve University, Cleveland, OH 44108

DISCLOSURES

• Ulipristal -North American studies was sponsored by

Allergan plc, Jersey City, NJ

• Dr. Liu: Consultant to Allergan, Ferring Pharmaceuticals,

Therapeutics MD, Lupin, and Bayer. He is also involved in clinical trials funded to the institution by Allergan, AbbVie, Bayer, Femasys, and Medicine 360.

Introduction

• Uterine fibroids (UFs)

– Symptomatic UFs occur in 25-50% of women of reproductive age1 – Associated with excessive and prolonged menstrual bleeding, and increased pelvic pressure2 – Estrogen and progesterone have significant roles in fibroid cell proliferation2

• Ulipristal acetate (UPA)

– Selective progesterone-receptor modulator3,4 – Targets endometrial, pituitary gland, and uterine fibroid tissue progesterone receptors3,4 – Efficacy demonstrated in clinical trials in Europe (Pearl 1-4) and US (Venus 1)

• Non-inferior to leuprolide acetate5 and superior to placebo6 in controlling bleeding

and reducing fibroid size

• Superior to placebo in rate of, and time to, amenorrhea, and improvement in physical

and social activities7

1. Stewart EA et al. Nat Rev Dis Primers 2016 2:16043; 2. Khan AT et al. Int J Womens Health 2014;6:95-114;3. Biglia N et al. Drug Des Devel Ther 2014;8:285-92; 4. Horak P et al. Int J Endocrinol 2012;2012:436174;

• 5. Donnez J et al. N Engl J Med 2012;366:421-32; 6. Donnez J et al. N Engl J Med 2012;366:409-20;
• 7. Simon J et al. Fertil Steril 2016;106(Suppl):e376 (abs O-268)

PROGESTERONE SIGNALING MECHANISM

Co-regulators Transcription Effector Genes

Gi Gi

LH Surge Drowsy Steroid Steroid Hormone Receptor

Ulipristal Ulipristal Secretory Endometrium Secretory Endometrium

Co-repressors

Liu J et al. ASRM, October 2017 Figure adapted from Griekspoor et al. Nuclear Receptor Signaling (2007) 5, e003. HRE, Hormone Response Element; LH, Luteinizing hormone; NCOR, Nuclear Receptor Co-Repressor; SHR, Steroid Hormone Receptors; SRC, Sarcoma Tyrosine Kinase

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– Risk of UFs is 3-times higher in African American women, who tend to have earlier age of onset, with larger (number and size) and more rapidly growing UFs1,2 – Obesity is also a well-established risk factor for UFs, with studies suggesting higher disease burden in overweight and

• bese women compared to ethnicity-matched

counterparts3,4

RISK FACTORS FOR UTERINE FIBROIDS

• 1. Stewart EA et al. J Womens Health (Larchmt) 2013;22:807-16;

2 .Marshall LM et al. Obstet Gynecol 1997;90:967-73;

• 3. Sparic R et al. Int J Fertil Steril 2016;9:424-35;
• 4. Ross RK et al. Br Med J (Clin Res Ed) 1986;293:359-62

Age Race Health status (eg,

• besity,

diet) Genetic factors Delayed pregnancy, parity (protect) Early menarche UF, uterine fibroid

VENUS II Study Design

– Phase III, prospective, randomized, double-blind, double-dummy, placebo-controlled, partially parallel and partially crossover design (NCT02147158)

• To evaluate the efficacy and safety of UPA for the intermittent treatment of

abnormal uterine bleeding associated with UFs

• Power calculations estimated 400 patients required for study

Screening Treatment course 1 Off-treatment Treatment course 2 Off-treatment follow-up

UPA, ulipristal acetate; UF, uterine fibroid

Liu J et al. ASRM, October 2017

UPA 5 mg (Arm 1) Placebo (Arm 1) ≈10-12 weeks 12 weeks 2 menses 12 weeks 12 weeks

≈400 patients randomized in 1:1:2:1:2:1 ratio

Menses UPA 10 mg (Arm 2) UPA 5 mg (Arm 3) UPA 10 mg (Arm 5) Placebo (Arm 4) Placebo (Arm 6) Placebo (Arm 2) UPA 5 mg (Arm 3) UPA 10 mg (Arm 5) UPA 5 mg (Arm 4) UPA 10 mg (Arm 6) Randomize 1:1:2:1:2:1

VENUS II Study Objectives

Primary efficacy

– Efficacy of UPA 5 mg and 10 mg compared to placebo

• Rate of, and time to, amenorrheaa (treatment course 1)

Secondary efficacy

– Maintenance of effect of UPA 5 mg and 10 mg compared to placebo

• Rate of, and time to, amenorrheaa (treatment course 2)

– Amenorrhea from day 11 through end of treatment (treatment course 1) – UFS-QOL Revised Activities subscale at end of treatment (treatment course 1)

Safety

– AEs (treatment courses 1 and 2)

aAmenorrhea defined as no bleeding (spotting permitted) during last 35 days of treatment

UPA, ulipristal acetate; UFS-QOL, Uterine Fibroid Symptom and Quality of Life questionnaire; AE, adverse event

KEY INCLUSION / EXCLUSION CRITERIA

8

Inclusion

• Pre-menopausal women (follicle-

stimulating hormone ≤20 mIU/mL), aged 18-50 years

• Cyclic (≥22 days and ≤35 days)

heavy / prolonged bleeding in ≥4 of the last 6 menstrual periods

• Menstrual blood loss ≥80 mL by

alkaline hematin method

• ≥1 discrete leiomyoma by

transvaginal ultrasound

• Uterine size ≤20 weeks

Exclusion

• History of endometrial ablation or
• ther uterine surgery
• History or current diagnosis of

confounding medical condition

− Clotting disorder − Uterine, cervical, ovarian,

• r breast cancer

− Abnormal Pap smear − Abnormal liver functions

• Use of hormonal contraceptives
• r intrauterine device
• Prior use of any selective

progesterone-receptor modulator

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RESULTS: DEMOGRAPHIC AND BASELINE CHARACTERISTICS (ITT)

Treatment arm (course 1: course 2)

Placebo: UPA 5 mg n=55 Placebo: UPA 10 mg n=58 UPA 5 mg: UPA 5 mg n=107 UPA 5 mg: placebo n=55 UPA 10 mg: UPA 10 mg n=110 UPA 10 mg: placebo n=47 Total N=432 Mean age, years 40.8 40.7 40.9 41.5 41.0 41.8 41.0 ≥40 years of age, n (%) 32 (58.2) 34 (58.6) 71 (66.4) 37 (67.3) 73 (66.4) 35 (74.5) 282 (65.3) Black, n (%) 38 (69.1) 33 (56.9) 71 (66.4) 43 (78.2) 69 (62.7) 35 (74.5) 289 (66.9) White, n (%) 17 (30.9) 23 (39.7) 32 (29.9) 12 (21.8) 36 (32.7) 11 (23.4) 131 (30.3) Othera, n (%) 0 (0.0) 2 (3.4) 4 (3.7) 0 (0.0) 5 (4.5) 1 (2.1) 12 (2.8) Mean BMI, kg/m2 32.32 31.33 31.91 33.42b 32.75 31.09 32.20 <30 kg/m2, n (%) 22 (40.0) 28 (48.3) 49 (45.8) 19 (34.5) 48 (43.6) 20 (42.6) 186 (43.1) ≥30 kg/m2, n (%) 33 (60.0) 30 (51.7) 58 (54.2) 35 (63.6) 62 (56.4) 27 (57.4) 245 (56.7)

aIncludes Asian, Native Hawaiian or other Pacific Islander, and multiple races; b1 patient did not have a BMI assessment available

ITT, intent to treat; UPA, ulipristal acetate; BMI, body mass index

Total randomized N=432 Course 1 completion n=384 1st off-treatment completion n=327 Entered course 2 n=327 Course 2 completion n=309 Off-treatment follow-up completion n=274

Co-Primary End Point: Amenorrhea Rate

Amenorrhea rate during the last 35 consecutive days of treatment (ITT) spotting permitted

**p<0.0001 vs placebo; n1, number of patients who entered treatment course 2 ITT, intent to treat; CI, confidence interval; UPA, ulipristal acetate 10 20 30 40 50 60 70 80 UPA: placebo (n1=75) UPA 5 mg: UPA 5 mg (n1=84) UPA 10 mg: UPA 10 mg (n1=82) Amenorrhea rate (%) ± 97.5% CI

** **

40.5 57.3 8.0 10 20 30 40 50 60 70 80 Placebo (n=113) UPA 5 mg (n=162) UPA 10 mg (n=157) Amenorrhea rate (%) ± 97.5% CI

** **

42.0 54.8

Treatment course 2 Treatment course 1

Results: Primary End Point

• Time to amenorrhea in treatment course 1 and 2 in race and BMI subgroups

was consistent with amenorrhea rate in the corresponding treatment courses

**p<0.0001 vs placebo. Significance testing was not conducted for the subgroups BMI, body mass index; CI, confidence interval; ITT, intent-to-treat; UPA, ulipristal acetate

Amenorrhea rate during last 35 consecutive days before end of treatment (ITT)

** **

Treatment course 1

0.0 0.0 0.0 0.0 0.0 42.0 54.8 34.8 48.6 59.6 68.0 47.3 58.4 33.8 50.0 50 68 68 63 93 89 41 47 50 72 115 107 n = 113 161 157 10 20 30 40 50 60 70 80 90 100 Overall population (n=432) Black subgroup (n=294) Non-black subgroup (n=138) Obese (BMI ≥30) subgroup (n=245) Non-obese (BMI <30) subgroup (n=186)

Amenorrhea rate (%) ± 97.5% CI

Placebo UPA 5 mg UPA 10 mg 31 35 32 43 49 50 55 54 55 20 30 27 75 84 82 n1 =

Results: Secondary End Points

• Amenorrhea rate during last 35 consecutive days before

end of treatment (ITT)

12 **p<0.0001 vs placebo. Significance testing was not conducted for the subgroups, BMI, body mass index; CI, confidence interval; ITT, intent-to- treat; n1, number of patients who entered treatment course 2; UPA, ulipristal acetate

** **

8.0 7.3 10.0 7.0 9.7 40.5 57.3 27.8 49.1 63.3 74.1 40.8 62.0 40.0 50.0

Treatment course 2

10 20 30 40 50 60 70 80 90 100 Overall population (n1=241) Black subgroup (n1=164) Non-black subgroup (n1=77) Obese (BMI ≥30) subgroup (n1=142) Non-obese (BMI <30) subgroup (n1=98)

Amenorrhea rate (%) ± 97.5% CI

UPA: Placebo UPA 5 mg: UPA 5 mg UPA 10 mg: UPA 10 mg

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Co-Primary End Point: Time to Amenorrhea

• Kaplan-Meier curves for time to amenorrhea (ITT)

**p<0.0001 vs placebo; n1, number of patients who entered treatment course 2 ITT, intent to treat; UPA, ulipristal acetate

** ** ** **

Proportion of patients achieving amenorrhea Time (days) to amenorrhea from 1st dose date 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 Proportion of patients achieving amenorrhea Time (days) to amenorrhea from 1st dose date 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 Placebo (n=113) UPA 10 mg (n=157) UPA 5 mg (n=162) Censored observations

Treatment course 2 Treatment course 1

UPA: placebo (n1=75) UPA 10 mg: UPA 10 mg (n1=82) UPA 5 mg: UPA 5 mg (n1=84) Censored observations

Other Efficacy End Points: Controlled Bleeding

• Controlled bleeding (ITT)

10 20 30 40 50 60 70 80 90 100 UPA: placebo (n1=67) UPA 5 mg: UPA 5 mg (n1=67) UPA 10 mg: UPA 10 mg (n1=58) Controlled bleeding (%) ± 97.5% CI

** **

62.7 86.2 10.4 10 20 30 40 50 60 70 80 90 100 Placebo (n1=98) UPA 5 mg (n1=133) UPA 10 mg (n1=118) Controlled bleeding (%) ± 97.5% CI

** **

3.1 59.4 76.3

Treatment course 2 Treatment course 1

**p<0.0001

50 68 68 63 93 89 72 115 107 41 47 50 113 162 157 n =

Results: Secondary End Points

• Rate of amenorrhea from Day 11 through end of

treatment (ITT)

**p<0.0001 vs placebo. Significance testing was not conducted for the subgroups BMI, body mass index; CI, confidence interval; ITT, intent-to-treat; UPA, ulipristal acetate

** **

34.6 55.4 25.2 49.5 57.4 68.0 36.6 59.6 30.9 50.0

Treatment course 1

10 20 30 40 50 60 70 80 90 100 Overall population (n=432) Black subgroup (n=294) Non-black subgroup (n=138) Obese (BMI ≥30) subgroup (n=245) Non-obese (BMI <30) subgroup (n=186)

Amenorrhea rate (%) ± 97.5% CI

Placebo UPA 5 mg UPA 10 mg 0.0 0.0 0.0 0.0 0.0 37 61 56 58 84 76 62 103 91 33 43 41 n = 95 146 132

• Change from baseline to end of treatment in

UFS-QOL Revised Activities subscale score (ITT)

**p<0.0001 vs placebo. Significance testing was not conducted for the subgroups BMI, body mass index; ITT, intent-to-treat; LS, least squares; N, number of patients with baseline and end-point values; SE, standard error; UFS-QOL, Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire; UPA, ulipristal acetate 2017 ASRM Soper D, et al. (October 2017)

** **

13.0 14.0 10.8 12.3 13.6 48.3 56.7 47.7 53.1 50.4 63.1 51.1 53.7 43.9 60.0

Treatment course 1

10 20 30 40 50 60 70 80 Overall population (n=373) Black subgroup (n=256) Non-black subgroup (n=117) Obese (BMI ≥30) subgroup (n=218) Non-obese (BMI <30) subgroup (n=154)

LS mean change from baseline ± SE

Placebo UPA 5 mg UPA 10 mg

Results: Secondary Endpoints

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Safety: AEs

• Combined course 1 and 1st off-treatment interval (safety population)
• Combined course 2 and 2nd off-treatment interval (safety population)

Event, n (%) Placebo (n=116) UPA 5 mg (n=161) UPA 10 mg (n=155) UPA total (n=316) Patients who died Patients with SAE 2 (1.7) 3 (1.9) 4 (2.6) 7 (2.2) Patients with AE leading to discontinuation 6 (5.2) 4 (2.5) 8 (5.2) 12 (3.8) Treatment arm (course 1: course 2) Event, n (%) Placebo: UPA 5 mg (n1=42) Placebo: UPA 10 mg (n1=44) UPA 5 mg: UPA 5 mg (n1=84) UPA 5 mg: placebo (n1=40) UPA 10 mg: UPA 10 mg (n1=82) UPA 10 mg: placebo (n1=33) Patients who died Patients with SAEa 1 (2.4) 1 (2.3) 2 (2.4) 1 (1.2) 2 (6.1) Patients with AE leading to discontinuation 2 (2.4) 1 (1.2) 4 (12.1)

Safety: Most Common AEs (≥5% in UPA Arms)

• Combined course 1 and 1st off-treatment interval (safety population)
• Combined course 2 and 2nd off-treatment interval (safety population)

Event, n (%) Placebo (n=116) UPA 5 mg (n=161) UPA 10 mg (n=155) UPA total (n=316) Hot flash 2 (1.7) 12 (7.5) 18 (11.6) 30 (9.5) Headache 6 (5.2) 7 (4.3) 16 (10.3) 23 (7.3) Fatigue 5 (4.3) 6 (3.7) 8 (5.2) 14 (4.4) Nausea 5 (4.3) 13 (8.1) 4 (2.6) 17 (5.4) Treatment received in treatment course 2 Event, n (%) Placebo (n1=75) UPA 5 mg (n1=126) UPA 10 mg (n1=126) UPA total (n1=252) Headache 2 (2.7) 8 (6.3) 2 (1.6) 10 (4.0)

Conclusions

UPA efficacy

Both UPA doses were significantly more efficacious than placebo

• Rate of, and time to, amenorrhea (co-primary end points), responses in blacks showed

a trend to be lower than whites, no noticeable impact of BMI

• Efficacy maintained (secondary end points)
• Physical and social activities improvement (UFS-QOL Revised Activities subscale;

secondary end point)

• Modest, reduction in myoma volume of -10-24% over two treatment courses

– Numerically higher response with UPA 10 mg compared to UPA 5 mg

UPA tolerance

– Generally well tolerated – Hot flash and headache were the most common AEs

• Most AEs were mild to moderate in severity. No increased AEs were observed in

treatment course 2

VENUS II confirms results from the VENUS I1 and PEARL2 trials

– UPA is effective and safe in the medical management of symptomatic UFs

• 1. Simon J et al. Fertil Steril 2016;106:e376 (abs O-268);
• 2. Donnez J et al. N Engl J Med 2012;366:421-32

BMI, body mass index; UF, uterine fibroid; UFS-QOL, Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire; UPA, ulipristal acetate

CONCLUSIONS

UPA Safety – Isolated cases of endometrial hyperplasia were observed in all treatment groups including placebo, none exhibited atypical changes, none progress to malignancy and all resolved spontaneously at the end of study. – The incidence of rare liver injury was 8 cases in 765,000

• patients. No evidence for ulipristal induced liver injury was

found in Venus I and II studies. – The European Medicine Agency evaluated the risks and recommended that patients on ulipristal have regular ALT and AST testing at baseline, monthly and at three months during the first two cycles. Ulipristal should not be started on patients with underlying liver disease.

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QUESTIONS?