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Rogerio A Lobo, MD1; James Liu, MD2; Andrew M Kaunitz, MD3; Brian Bernick, MD4; Shelli Graham, PhD4; Ginger D Constantine, MD5; Sebastian Mirkin, MD4

1Columbia University Medical Center, New York, NY 2University Hospital Cleveland Medical Center, Cleveland, OH 3University of Florida College of Medicine‐Jacksonville, Jacksonville, FL 4TherapeuticsMD, Boca Raton, FL; 5EndoRheum Consultants, LLC, Malvern, PA

Disclosures

• Consultant: Multiple pharmaceutical companies including but not limited

to TherapeuticsMD

• Stock options: TherapeuticsMD

Background

• Menopausal vasomotor symptoms (VMS) can be effectively treated with

hormone therapy (HT), which reduces hot flush frequency and severity1

• However, HT can be associated with an increased risk of adverse events, such as

venous thromboembolism (VTE), cardiovascular disease, and cerebrovascular disease2‐4

• Evidence suggests that progesterone use in HT may not negatively affect VTE risk
• r cardiovascular outcomes, as with synthetic progestins5‐7
• TX‐001HR (TherapeuticsMD, Boca Raton, FL) is an investigational combination of

17β‐estradiol and progesterone in a single, oral, softgel capsule8

• 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.

• 7. Canonico M, et al. Stroke 2016;47:1734‐1741. 8. Lobo RA et al. Obstet Gynecol 2018;132:161‐170.

REPLENISH Trial

• Randomized, double‐blind, placebo‐controlled, multicenter, phase 3 trial of

TX‐001HR in menopausal women with an intact uterus (NCT01942668)

• 1‐year endometrial and general safety study
• 12‐week efficacy substudy for the treatment of VMS
• Additional safety endpoints
• Metabolic parameters
• Cardiovascular outcomes

Lobo RA et al. Obstet Gynecol 2018;132:161‐170.

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Study Design: Randomization

• TX‐001HR was taken daily for up to 12 months (VMS substudy was 12 weeks)
• All participants were assessed for general and endometrial safety
• All women completed a daily diary on the frequency and severity of their VMS

through week 12 Treatment Groups

 1 mg E2/100 mg P4  0.5 mg E2/100 mg P4  0.5 mg E2/50 mg P4  0.25 mg E2/50 mg P4  Placebo

VMS substudy (12 wks)

• ≥7/day or ≥50/week

moderate‐to‐severe hot flushes

• Randomized 1:1:1:1:1

General study (12 mos)

• Did not qualify for

VMS substudy

• Randomized 1:1:1:1

Lobo RA et al. Obstet Gynecol 2018;132:161‐170.

Disposition and Demographics

• 69% completed at 52 weeks
• Mean age of 55 years (40–66)
• Mean BMI of 27 kg/m2
• 65% were white, 32% African American

Screen failures n=3175 Randomized to treatment n=1845 Subjects screened for eligibility n=5020 1 mg E2/ 100 mg P4 0.5 mg E2/ 100 mg P4 Placebo 0.5 mg E2/ 50 mg P4 0.25 mg E2/ 50 mg P4 Did not take 1 capsule n=10 *Other included investigator decision, lack of efficacy, protocol deviation and other. Population, n (%) Safety Completed at 52 weeks Discontinued Adverse event Lost to follow‐up Subject withdrawal Other* VMS substudy 415 284 (68.4) 131 (31.6) 46 (11.1) 27 (6.5) 36 (8.7) 22 (5.3) 141 424 305 (71.9) 119 (28.1) 33 (7.8) 30 (7.1) 42 (9.9) 14 (3.3) 149 421 312 (74.1) 109 (25.9) 34 (8.1) 26 (6.2) 29 (6.9) 20 (4.8) 147 424 281 (66.3) 143 (33.7) 41 (9.7) 38 (9.0) 31 (7.3) 33 (7.8) 154 151 93 (61.6) 58 (38.4) 10 (6.6) 17 (11.3) 13 (8.6) 18 (11.9) 135 Lobo RA et al. Obstet Gynecol 2018;132:161‐170. ‐60 ‐50 ‐40 ‐30 ‐20 ‐10 1 2 3 4 5 6 7 8 9 10 11 12 Mean reduction from baseline Week 1 mg E2/100 mg P4* 0.5 mg E2/100 mg P4 0.5 mg E2/50 mg P4 0.25 mg E2/50 mg P4* Placebo

VMS Frequency and Severity Substudy

• Most TX‐001HR doses significantly reduced the frequency and severity of moderate to severe VMS
• ver 12 weeks; statistically significant reductions occurred as early as 4 weeks with the higher doses

‐1.2 ‐1.0 ‐0.8 ‐0.6 ‐0.4 ‐0.2 0.0 1 2 3 4 5 6 7 8 9 10 11 12

Mean reduction from baseline Week 1 mg E2/100 mg P4* 0.5 mg E2/100 mg P4* 0.5 mg E2/50 mg P4 0.25 mg E2/50 mg P4 Placebo

Weekly Reduction in VMS Frequency Weekly Improvement in VMS Severity

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. * * ‡ † † ‡ * *

Cholesterol Parameters

• No clinically significant changes in cholesterol levels observed with TX‐001HR or

placebo

50 100 150 200 250 1/ 100 0.5/ 100 0.5/ 50 0.25/ 50 Placebo Mean Concentration (SD), mg/dL E2/P4 (mg/mg)

Cholesterol

25 50 75 100 1/ 100 0.5/ 100 0.5/ 50 0.25/ 50 Placebo E2/P4 (mg/mg)

HDL‐Cholesterol

50 100 150 200 1/ 100 0.5/ 100 0.5/ 50 0.25/ 50 Placebo E2/P4 (mg/mg)

LDL‐Cholesterol

Baseline Month 12

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Cholesterol

• 36 of 1269 women (2.8%) had potentially clinically important cholesterol

increases (≥50 mg/dL or above normal levels) at 12 months

• Comparable between TX‐001HR (2.8%) and placebo (3.3%) groups

0.9 1.9 1.3 2.1 0.9 1.1 3.0 2.9 4.3 3.3 5 10 15 1/ 100 0.5/ 100 0.5/ 50 0.25/ 50 Placebo Change from Baseline (%) E2/P4 (mg/mg)

Cholesterol Increase

Week 12 Month 12

Triglyceride and Glucose Parameters

• No clinically significant changes in triglycerides and glucose levels observed with

TX‐001HR or placebo

50 100 150 200 1/ 100 0.5/ 100 0.5/ 50 0.25/ 50 Placebo Mean Concentration (SD), mg/dL E2/P4 (mg/mg)

Triglycerides

25 50 75 100 125 1/ 100 0.5/ 100 0.5/ 50 0.25/ 50 Placebo E2/P4 (mg/mg)

Glucose

Baseline Month 12

Triglycerides

• 111 of 1269 women (8.7%) had potentially clinically important triglycerides

increases (≥50 mg/dL or above normal levels) at 12 months

• Comparable between TX‐001HR (8.9%) and placebo (6.6%) groups

9 8 8 6 9 11 10 6 9 7 5 10 15 1/ 100 0.5/ 100 0.5/ 50 0.25/ 50 Placebo Change from Baseline (%) E2/P4 (mg/mg)

Triglycerides Increase

Week 12 Month 12 Lobo RA et al. Obstet Gynecol 2018;132:161‐170.

Coagulation Parameters

• No clinically significant changes in antithrombin activity, factor XIV and protein S

were observed with TX‐001HR compared with placebo

25 50 75 100 125 150 1/ 100 0.5/ 100 0.5/ 50 0.25/ 50 Placebo Percent (SD) E2/P4 (mg/mg)

Antithrombin Activity

25 50 75 100 125 1/ 100 0.5/ 100 0.5/ 50 0.25/ 50 Placebo E2/P4 (mg/mg)

Protein S

Baseline Month 12 25 50 75 100 125 150 175 1/ 100 0.5/ 100 0.5/ 50 0.25/ 50 Placebo E2/P4 (mg/mg)

Factor XIV

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Coagulation Parameters

• Fibrinogen levels, time for activated partial thromboplastin and prothrombin, and

prothrombin INR (ratio of 1) remained similar to baseline at 12 months

INR: international normalized ratio. 2 4 6 8 10 12 14 1/ 100 0.5/ 100 0.5/ 50 0.25/ 50 Placebo

Mean Concentration (Umol/L) E2/P4 (mg/mg) Fibrinogen 5 10 15

1/ 100 0.5/ 100 0.5/ 50 0.25/ 50 Placebo

Mean Time (s) E2/P4 (mg/mg) Prothrombin Baseline Month 12 10 20 30 40 50

1/ 100 0.5/ 100 0.5/ 50 0.25/ 50 Placebo

Mean Time (s) E2/P4 (mg/mg) Activated Partial Thromboplastin

Vascular Disease Outcomes

• Cardiovascular disease
• Two women experienced “coronary heart disease” adverse events considered

not related to treatment

• Unstable angina (0.5 mg E2/50 mg P4)
• Angina and coronary artery disease (1 mg E2/100 mg P4)
• Observed CHD event rate of 2/1684 was less than the expected annual rate of 2‐3/1000 in

women of this age1

• There were no stroke events
• Venous thromboembolism (VTE)
• One case of deep vein thrombosis (DVT) with 0.5 mg E2/50 mg P4, deemed possibly

related to treatment, occurred in a woman with a family history of DVT

• Observed VTE event rate of 1/1684 was less than the expected annual rate of 1.7/1000 in

women of this age2

• 1. Lobo RA et al. Arch Intern Med 2004;164:482‐484. 2. Cushman M, et al. JAMA 2004;292:1573‐1580.

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