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

9/24/2018 D ISCLOSURES Long-Term Intermittent Administration of SPRMs: New Treatment Options • 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, James H. Liu, MD Arthur H Bill Professor AbbVie, Bayer, Femasys, and Medicine 360. Chair, Depts of Obstetrics and Gynecology and Reproductive Biology Case Western Reserve University, Cleveland, OH 44108 P ROGESTERONE S IGNALING M ECHANISM Introduction • Uterine fibroids (UFs) – Symptomatic UFs occur in 25-50% of women of reproductive age 1 Steroid – Associated with excessive and prolonged menstrual bleeding, and increased pelvic pressure 2 G i G i – Estrogen and progesterone have significant roles in fibroid cell proliferation 2 Steroid Hormone Receptor • Ulipristal acetate (UPA) LH Drowsy Surge – Selective progesterone-receptor modulator 3,4 Secretory Secretory – Targets endometrial, pituitary gland, and uterine fibroid tissue progesterone Ulipristal Ulipristal Endometrium Endometrium receptors 3,4 – Efficacy demonstrated in clinical trials in Europe (Pearl 1-4) and US (Venus 1) Co-repressors Non-inferior to leuprolide acetate 5 and superior to placebo 6 in controlling bleeding • and reducing fibroid size Co-regulators • Superior to placebo in rate of, and time to, amenorrhea, and improvement in physical and social activities 7 Transcription 1. Stewart EA et al. Nat Rev Dis Primers 2016 Effector Genes 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) 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 Liu J et al. ASRM, October 2017 1

9/24/2018 R ISK F ACTORS FOR U TERINE F IBROIDS VENUS II Study Design – Phase III, prospective, randomized, double-blind, double-dummy, placebo-controlled, partially parallel and partially crossover design (NCT02147158) – Risk of UFs is 3-times higher in African American • To evaluate the efficacy and safety of UPA for the intermittent treatment of women, who tend to have earlier age of onset, abnormal uterine bleeding associated with UFs with larger (number and size) and more rapidly Race Age • Power calculations estimated 400 patients required for study growing UFs 1,2 ≈ 400 patients randomized in 1:1:2:1:2:1 ratio Health Treatment Treatment Off-treatment – Obesity is also a well-established risk factor Screening Off-treatment status course 1 course 2 follow-up Genetic (eg, for UFs, with studies suggesting higher factors Menses obesity, diet) disease burden in overweight and Placebo (Arm 1) UPA 5 mg (Arm 1) obese women compared to ethnicity-matched Randomize 1:1:2:1:2:1 Delayed Placebo (Arm 2) UPA 10 mg (Arm 2) Early pregnancy, counterparts 3,4 menarche parity (protect) UPA 5 mg (Arm 3) UPA 5 mg (Arm 3) UPA 5 mg (Arm 4) Placebo (Arm 4) UPA 10 mg (Arm 5) UPA 10 mg (Arm 5) 1. Stewart EA et al. J Womens Health (Larchmt) 2013;22:807-16; 2 .Marshall LM et al. Obstet Gynecol 1997;90:967-73; UPA 10 mg (Arm 6) Placebo (Arm 6) 3. Sparic R et al. Int J Fertil Steril 2016;9:424-35; ≈ 10-12 12 2 12 12 4. Ross RK et al. Br Med J (Clin Res Ed) 1986;293:359-62 weeks weeks menses weeks weeks UPA, ulipristal acetate; UF, uterine fibroid UF, uterine fibroid Liu J et al. ASRM, October 2017 K EY I NCLUSION / E XCLUSION C RITERIA VENUS II Study Objectives Primary efficacy Inclusion Exclusion – Efficacy of UPA 5 mg and 10 mg compared to placebo • Rate of, and time to, amenorrhea a (treatment course 1) • Pre-menopausal women (follicle- • History of endometrial ablation or stimulating hormone ≤ 20 mIU/mL), other uterine surgery Secondary efficacy aged 18-50 years • History or current diagnosis of • Cyclic ( ≥ 22 days and ≤ 35 days) confounding medical condition – Maintenance of effect of UPA 5 mg and 10 mg compared to placebo heavy / prolonged bleeding in ≥ 4 of • Rate of, and time to, amenorrhea a (treatment course 2) − Clotting disorder the last 6 menstrual periods − Uterine, cervical, ovarian, – Amenorrhea from day 11 through end of treatment (treatment course 1) • Menstrual blood loss ≥ 80 mL by or breast cancer alkaline hematin method – UFS-QOL Revised Activities subscale at end of treatment (treatment − Abnormal Pap smear course 1) • ≥ 1 discrete leiomyoma by − Abnormal liver functions transvaginal ultrasound Safety • Use of hormonal contraceptives • Uterine size ≤ 20 weeks or intrauterine device – AEs (treatment courses 1 and 2) • Prior use of any selective a Amenorrhea defined as no bleeding (spotting permitted) during last 35 days of treatment progesterone-receptor modulator UPA, ulipristal acetate; UFS-QOL, Uterine Fibroid Symptom and Quality of Life questionnaire; AE, adverse event 8 2

9/24/2018 R ESULTS : D EMOGRAPHIC AND B ASELINE Co-Primary End Point: Amenorrhea Rate C HARACTERISTICS (ITT) 1st off-treatment Total randomized Course 1 completion completion Amenorrhea rate during the last 35 consecutive days of treatment (ITT) spotting N=432 n=384 n=327 permitted Off-treatment follow-up Treatment course 1 Entered course 2 Course 2 completion Treatment course 2 completion 80 n=327 n=309 80 n=274 ** Amenorrhea rate (%) ± 97.5% CI Amenorrhea rate (%) ± 97.5% CI 70 70 ** Treatment arm (course 1: course 2) 60 60 ** ** Placebo: Placebo: UPA 5 mg: UPA 5 mg: UPA 10 mg: UPA 10 mg: Total UPA 5 mg UPA 10 mg UPA 5 mg placebo UPA 10 mg placebo 50 50 N=432 n=55 n=58 n=107 n=55 n=110 n=47 40 Mean age, years 40.8 40.7 40.9 41.5 41.0 41.8 41.0 40 54.8 57.3 ≥ 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) 30 30 Black, n (%) 38 (69.1) 33 (56.9) 71 (66.4) 43 (78.2) 69 (62.7) 35 (74.5) 289 (66.9) 42.0 8.0 20 20 40.5 White, n (%) 17 (30.9) 23 (39.7) 32 (29.9) 12 (21.8) 36 (32.7) 11 (23.4) 131 (30.3) 10 Other a , n (%) 0 (0.0) 2 (3.4) 4 (3.7) 0 (0.0) 5 (4.5) 1 (2.1) 12 (2.8) 10 0 Mean BMI, kg/m 2 32.32 31.33 31.91 33.42 b 32.75 31.09 32.20 0 0 UPA: UPA 5 mg: UPA 10 mg: <30 kg/m 2 , n (%) 22 (40.0) 28 (48.3) 49 (45.8) 19 (34.5) 48 (43.6) 20 (42.6) 186 (43.1) Placebo UPA 5 mg UPA 10 mg placebo UPA 5 mg UPA 10 mg (n=113) (n=162) (n=157) ≥ 30 kg/m 2 , n (%) 33 (60.0) 30 (51.7) 58 (54.2) 35 (63.6) 62 (56.4) 27 (57.4) 245 (56.7) (n1=75) (n1=84) (n1=82) **p<0.0001 vs placebo; n1, number of patients who entered treatment course 2 ITT, intent to treat; CI, confidence interval; UPA, ulipristal acetate a Includes Asian, Native Hawaiian or other Pacific Islander, and multiple races; b 1 patient did not have a BMI assessment available ITT, intent to treat; UPA, ulipristal acetate; BMI, body mass index Results: Primary End Point Results: Secondary End Points Amenorrhea rate during last 35 consecutive days • Amenorrhea rate during last 35 consecutive days before before end of treatment (ITT) end of treatment (ITT) • Time to amenorrhea in treatment course 1 and 2 in race and BMI subgroups was consistent with amenorrhea rate in the corresponding treatment courses Treatment course 1 Treatment course 2 Placebo 100 UPA: Placebo 100 74.1 UPA 5 mg UPA 5 mg: UPA 5 mg 90 68.0 Amenorrhea rate (%) ± 97.5% CI UPA 10 mg 90 63.3 UPA 10 mg: UPA 10 mg Amenorrhea rate (%) 59.6 80 ** ** 62.0 58.4 80 57.3 50.0 70 54.8 50.0 ** 48.6 47.3 49.1 ± 97.5% CI 70 ** 60 40.0 42.0 40.8 33.8 34.8 40.5 50 60 40 27.8 50 30 10.0 40 9.7 20 0.0 0.0 0.0 30 0.0 7.0 10 0.0 7.3 8.0 20 0 n = 113 161 157 72 115 107 41 47 50 63 93 89 50 68 68 10 Overall Black Non-black Non-obese (BMI <30) Obese (BMI ≥ 30) population subgroup subgroup subgroup subgroup 0 n1 = 75 84 82 55 54 55 20 30 27 43 49 50 31 35 32 (n=432) (n=294) (n=138) (n=245) (n=186) Overall Black Non-black Obese (BMI ≥ 30) Non-obese (BMI <30) population subgroup subgroup subgroup subgroup **p<0.0001 vs placebo. Significance testing was not conducted for the subgroups (n1=241) (n1=164) (n1=77) (n1=142) (n1=98) BMI, body mass index; CI, confidence interval; ITT, intent-to-treat; UPA, ulipristal acetate **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 12 3