Disclosures Ef Effects of of Sin Single le Capsu Capsule 17 17 - PDF document

9/19/2018 Disclosures Ef Effects of of Sin Single le ‐ Capsu Capsule 17 17 β‐ Es Estr tradiol/P adiol/Prog oges esterone ne (TX (TX ‐ 001 001HR) HR) on on • Consultant : Multiple pharmaceutical companies including but not limited Metabo Met bolic lic Pa Para rameters rs and and Car Cardio iovasc scular to TherapeuticsMD Outcom Out omes in in Menop Menopausal usal Wo Women of of the the • Stock options: TherapeuticsMD REPLENIS REPLEN ISH Tr Trial Rogerio A Lobo, MD 1 ; James Liu, MD 2 ; Andrew M Kaunitz, MD 3 ; Brian Bernick, MD 4 ; Shelli Graham, PhD 4 ; Ginger D Constantine, MD 5 ; Sebastian Mirkin, MD 4 1 Columbia University Medical Center, New York, NY 2 University Hospital Cleveland Medical Center, Cleveland, OH 3 University of Florida College of Medicine ‐ Jacksonville , Jacksonville, FL 4 TherapeuticsMD, Boca Raton, FL; 5EndoRheum Consultants, LLC, Malvern, PA Background REPLENISH Trial • Randomized, double ‐ blind, placebo ‐ controlled, multicenter, phase 3 trial of • Menopausal vasomotor symptoms (VMS) can be effectively treated with TX ‐ 001HR in menopausal women with an intact uterus (NCT01942668) hormone therapy (HT), which reduces hot flush frequency and severity 1 • However, HT can be associated with an increased risk of adverse events, such as • 1 ‐ year endometrial and general safety study venous thromboembolism (VTE), cardiovascular disease, and cerebrovascular • 12 ‐ week efficacy substudy for the treatment of VMS disease 2 ‐ 4 • Additional safety endpoints • Evidence suggests that progesterone use in HT may not negatively affect VTE risk or cardiovascular outcomes, as with synthetic progestins 5 ‐ 7 • Metabolic parameters • TX ‐ 001HR (TherapeuticsMD, Boca Raton, FL) is an investigational combination of • Cardiovascular outcomes 17 β‐ estradiol and progesterone in a single, oral, softgel capsule 8 1. NAMS. Menopause. 2017;24:728 ‐ 753. 2. Henderson VW and Lobo, RA. Climacteric. 2012;15:229 ‐ 234. 3. Renoux C, et al. J Thromb Haemost. 2010;8:979 ‐ 986. 4. Hale GE and Shufelt CL. Trends Cardiovasc Med. 2015;25:540 ‐ 549. 5. Mirkin S. Climacteric. 2018;21:346 ‐ 354. 6. Canonico M, et al. Arterioscler Thromb Vasc Biol 2010;30:340 ‐ 345. Lobo RA et al. Obstet Gynecol 2018;132:161 ‐ 170. 7. Canonico M, et al. Stroke 2016;47:1734 ‐ 1741. 8. Lobo RA et al. Obstet Gynecol 2018;132:161 ‐ 170. 1

9/19/2018 Study Design: Randomization Disposition and Demographics • 69% completed at 52 weeks Subjects screened for eligibility Treatment Groups n=5020 VMS substudy (12 wks) General study (12 mos)  1 mg E2/100 mg P4 • Mean age of 55 years (40–66) Screen failures • ≥ 7/day or ≥ 50/week • Did not qualify for n=3175  0.5 mg E2/100 mg P4 • Mean BMI of 27 kg/m 2 Randomized to treatment moderate ‐ to ‐ severe  VMS substudy n=1845 0.5 mg E2/50 mg P4 • 65% were white, 32% African American Did not take 1 capsule  hot flushes 0.25 mg E2/50 mg P4 • Randomized 1:1:1:1 n=10  • Randomized 1:1:1:1:1 Placebo 1 mg E2/ 0.5 mg E2/ 0.5 mg E2/ 0.25 mg E2/ Placebo 100 mg P4 100 mg P4 50 mg P4 50 mg P4 Population, n (%) • TX ‐ 001HR was taken daily for up to 12 months (VMS substudy was 12 weeks) Safety 415 424 421 424 151 Completed at 52 weeks 284 (68.4) 305 (71.9) 312 (74.1) 281 (66.3) 93 (61.6) • All participants were assessed for general and endometrial safety Discontinued 131 (31.6) 119 (28.1) 109 (25.9) 143 (33.7) 58 (38.4) Adverse event 46 (11.1) 33 (7.8) 34 (8.1) 41 (9.7) 10 (6.6) • All women completed a daily diary on the frequency and severity of their VMS Lost to follow ‐ up 27 (6.5) 30 (7.1) 26 (6.2) 38 (9.0) 17 (11.3) Subject withdrawal 36 (8.7) 42 (9.9) 29 (6.9) 31 (7.3) 13 (8.6) through week 12 Other* 22 (5.3) 14 (3.3) 20 (4.8) 33 (7.8) 18 (11.9) VMS substudy 141 149 147 154 135 *Other included investigator decision, lack of efficacy, protocol deviation and other. Lobo RA et al. Obstet Gynecol 2018;132:161 ‐ 170. Lobo RA et al. Obstet Gynecol 2018;132:161 ‐ 170. Cholesterol Parameters VMS Frequency and Severity Substudy • Most TX ‐ 001HR doses significantly reduced the frequency and severity of moderate to severe VMS • No clinically significant changes in cholesterol levels observed with TX ‐ 001HR or over 12 weeks; statistically significant reductions occurred as early as 4 weeks with the higher doses placebo Weekly Reduction in VMS Frequency Weekly Improvement in VMS Severity 1 mg E2/100 mg P4* 1 mg E2/100 mg P4* Cholesterol HDL ‐ Cholesterol LDL ‐ Cholesterol Baseline † 0.5 mg E2/100 mg P4 0.5 mg E2/100 mg P4* Mean Concentration (SD), 0 ‡ 0.0 Mean reduction from baseline † Month 12 Mean reduction from baseline 0.5 mg E2/50 mg P4 0.5 mg E2/50 mg P4 250 100 200 ‡ 0.25 mg E2/50 mg P4 0.25 mg E2/50 mg P4* ‐ 10 ‐ 0.2 Placebo Placebo 200 75 150 ‐ 20 ‐ 0.4 150 mg/dL 50 100 ‐ 30 ‐ 0.6 100 ‡ 25 ‐ 40 ‐ 0.8 † 50 50 * ‐ 50 ‡ ‐ 1.0 0 0 * 0 † * * 1/ 0.5/ 0.5/ 0.25/ Placebo 1/ 0.5/ 0.5/ 0.25/ Placebo 1/ 0.5/ 0.5/ 0.25/ Placebo ‐ 1.2 ‐ 60 100 100 50 50 100 100 50 50 100 100 50 50 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 E2/P4 (mg/mg) E2/P4 (mg/mg) E2/P4 (mg/mg) Week Week P <0.05 from *Weeks 3–12; †Weeks 7, 9–12; ‡Weeks 6, 7, 9 vs placebo. P <0.05 from *Weeks 3–12; †Weeks 4–12; ‡Weeks 6 ‐ 12 vs placebo. Lobo RA et al. Obstet Gynecol 2018;132:161 ‐ 170. 2

9/19/2018 Cholesterol Triglyceride and Glucose Parameters • 36 of 1269 women (2.8%) had potentially clinically important cholesterol • No clinically significant changes in triglycerides and glucose levels observed with increases ( ≥ 50 mg/dL or above normal levels) at 12 months TX ‐ 001HR or placebo • Comparable between TX ‐ 001HR (2.8%) and placebo (3.3%) groups Glucose Triglycerides Cholesterol Increase Mean Concentration (SD), 200 125 Change from Baseline (%) 15 100 150 Week 12 75 mg/dL 100 10 Month 12 50 Baseline 50 25 Month 12 4.3 5 3.0 2.9 3.3 2.1 0 1.9 0 1.3 0.9 1.1 0.9 1/ 0.5/ 0.5/ 0.25/ Placebo 1/ 0.5/ 0.5/ 0.25/ Placebo 0 100 100 50 50 100 100 50 50 1/ 0.5/ 0.5/ 0.25/ Placebo E2/P4 (mg/mg) E2/P4 (mg/mg) 100 100 50 50 E2/P4 (mg/mg) Triglycerides Coagulation Parameters • 111 of 1269 women (8.7%) had potentially clinically important triglycerides • No clinically significant changes in antithrombin activity, factor XIV and protein S increases ( ≥ 50 mg/dL or above normal levels) at 12 months were observed with TX ‐ 001HR compared with placebo • Comparable between TX ‐ 001HR (8.9%) and placebo (6.6%) groups Triglycerides Increase Factor XIV Protein S Antithrombin Activity Baseline Change from Baseline (%) Month 12 15 150 175 125 150 11 125 10 Week 12 100 9 Percent (SD) 9 125 9 100 10 8 8 Month 12 75 100 7 6 75 6 75 50 50 5 50 25 25 25 0 0 0 0 1/ 0.5/ 0.5/ 0.25/ Placebo 1/ 0.5/ 0.5/ 0.25/ Placebo 1/ 0.5/ 0.5/ 0.25/ Placebo 1/ 0.5/ 0.5/ 0.25/ Placebo 100 100 50 50 100 100 50 50 100 100 50 50 100 100 50 50 E2/P4 (mg/mg) E2/P4 (mg/mg) E2/P4 (mg/mg) E2/P4 (mg/mg) Lobo RA et al. Obstet Gynecol 2018;132:161 ‐ 170. 3

9/19/2018 Coagulation Parameters Vascular Disease Outcomes • Cardiovascular disease • Fibrinogen levels, time for activated partial thromboplastin and prothrombin, and • Two women experienced “coronary heart disease” adverse events considered prothrombin INR (ratio of 1) remained similar to baseline at 12 months not related to treatment • Unstable angina (0.5 mg E2/50 mg P4) Activated Partial Thromboplastin Prothrombin Fibrinogen Baseline • Angina and coronary artery disease (1 mg E2/100 mg P4) Month 12 14 50 15 • Observed CHD event rate of 2/1684 was less than the expected annual rate of 2 ‐ 3/1000 in Mean Concentration 12 women of this age 1 Mean Time (s) Mean Time (s) 40 10 10 • There were no stroke events (Umol/L) 30 8 • Venous thromboembolism (VTE) 6 20 5 4 • One case of deep vein thrombosis (DVT) with 0.5 mg E2/50 mg P4, deemed possibly 10 2 related to treatment, occurred in a woman with a family history of DVT 0 0 0 1/ 0.5/ 0.5/ 0.25/ Placebo 1/ 0.5/ 0.5/ 0.25/ Placebo 1/ 0.5/ 0.5/ 0.25/ Placebo • Observed VTE event rate of 1/1684 was less than the expected annual rate of 1.7/1000 in 100 100 50 50 100 100 50 50 100 100 50 50 women of this age 2 E2/P4 (mg/mg) E2/P4 (mg/mg) E2/P4 (mg/mg) 1. Lobo RA et al. Arch Intern Med 2004;164:482 ‐ 484. 2. Cushman M, et al. JAMA 2004;292:1573 ‐ 1580. INR: international normalized ratio. Conclusions • After 12 months of treatment with TX ‐ 001HR, no clinically meaningful effects on lipid, glucose, or coagulation parameters were observed compared with placebo • Observed changes in triglyceride levels, antithrombin activity, factor XIV, and protein S were consistent with oral estrogen therapy • Although this trial lacked statistical power to assess these outcomes, VTE, cardiovascular disease, and cerebrovascular events were as expected for a menopausal population • If approved, TX ‐ 001HR may provide the first oral E2/P4 combination for the treatment of VMS in menopausal women with a uterus 4