Slide 1: REJOICE Trial Data Presentation
REJOICE Trial Data Presentation March 7, 2016
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation by TherapeuticsMD, Inc. (referred to as “we” and “our”) may contain forward-looking statements. Forward-looking statements may include, but are not limited to, statements relating to our objectives, plans and strategies, as well as statements, other than
Slide 3: YUVVEXY (TX-004HR) Clinical Development Program
YUVVEXY (TX-004HR) TM Clinical Development Program YUVVEXY™ is an investigational drug and is not approved for use by the FDA. This is a non- promotional presentation of scientific and development information intended for investor audiences only. 3
Slide 4: Agenda
Agenda 1. Introduction to Vulvar and Vaginal Atrophy (VVA) 2. Rationale for Development 3. Presentation of REJOICE Trial Data 4. Labeling Implications 5. Questions/Answers 4
Slide 5: Panelists
Panelists • Robert Finizio – Co-founder and Chief Executive Officer, TherapeuticsMD • Brian Bernick, M.D. – Co-founder and Chief Clinical Officer, TherapeuticsMD • Sebastian Mirkin, M.D. – Chief Medical Officer, TherapeuticsMD • Sheryl Kingsberg, Ph.D.* – Chief, Division of OB/GYN Behavioral Medicin
Slide 6: Women’s Attitudes and Behaviors towards Vulvar and Vaginal Atrophy (VVA)
Women’s Attitudes and Behaviors towards Vulvar and Vaginal Atrophy (VVA) Sheryl Kingsberg, PhD University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH
Slide 7: The Scope of the Problem
The Scope of the Problem About 50% (~32 million) of all postmenopausal women in the US have VVA/GSM1 . . . but only ~7% are treated2,3 Many women are unaware that symptoms progress without treatment, and that safe and effective treatments are available 4 1. Simon JA, et al. Menopause. 2013;20:1043-1
Slide 8: The Survey Says….
The Survey Says…. • Several recent surveys on the impact of VVA on Quality of Life, 3 large surveys published within the past 2 years – REVIVE: Real Women’s Views of Treatment Options for Menopausal Vaginal Changes Kingsberg SA, et al. J Sex Med. 2013,10:1790-1799 – VIVA: Vaginal Health: Insights, V
Slide 9: VVA Market Dynamics - Ready for New Product
VVA Market Dynamics - Ready for New Product Only 2.3MM U.S. women 1 treated with Rx product Vaginal Creams Mean 2 • Messiness • Reusable Applicator treatment • Long-term safety 2 duration • Dose preparation Women by user required3 46 days 4 primed for conversion to new Vaginal product Tablets Mean •
Slide 10: VVA Market Opportunity
VVA Market Opportunity Brian Bernick, M.D. – Co-founder & Chief Clinical Officer TherapeuticsMD 10
Slide 11: YUVVEXY (TX-004HR): Rationale for Development
YUVVEXY (TX-004HR): TM Rationale for Development • TX-004HR is an investigational applicator-free vaginal softgel capsule that contains solubilized 17b-estradiol • TX-004HR is designed to provide improved efficacy, early onset of action and lower systemic estrogen levels vs. currently available prod
Slide 12: Established VVA Market
Established VVA Market U.S. sales approximately $1.5 billion in 20151 U.S. sales more than doubled since 20081 Global market expected to be $2.1 billion in 20224 Currently no generic competition 32 million U.S. women currently experiencing VVA symptoms5,6 Premarin® Vagifem® Estrace® Osphen
Slide 13: YUVVEXY (TX-004HR) Prototype Packs
YUVVEXY (TX-004HR) TM Prototype Starter Pack 0.69 x 0.3 inch Prototype Maintenance Pack • Small digitally inserted rapidly dissolving softgel capsule • No applicator • Proposed dose packaging to optimize compliance and convenience YUVVEXY™ is an investigational drug and is not approved for use by th
Slide 14: Presentation of REJOICE Trial Data
Presentation of REJOICE Trial Data Sebastian Mirkin, M.D. – Chief Medical Officer, TherapeuticsMD 14
Slide 15: YUVVEXY (TX-004HR) Product Target Profile
YUVVEXY™ (TX-004HR) TX-004HR Product Target Profile TARGET GOAL - No systemic absorption 0% 80% - Variable Dosing 4 mcg 10 mcg 25 mcg 30 mcg - Early onset of action 2 week 12 week - Highly Efficacious for full VVA symptoms 50% 100% - High Satisfaction 20% 100% 15
Slide 16: Clinical Program: YUVVEXY (TX-004HR)
Clinical Program: YUVVEXY™ (TX-004HR) (Completed) Phase 1 Studies (499 and 500) • Single dose, randomized, open label, two-way crossover vs. Vagifem®, bioavailability study Phase 2 Study (TXV-13-01) • A randomized, double blind, placebo controlled trial to evaluate the safety and efficacy of TX-
Slide 17: Phase 3 Clinical Study REJOICE TRIAL
Phase 3 Clinical Study REJOICE TRIAL ■ 12 Week Randomized, Double-blinded, Placebo-controlled1 ■ Subjects: 764; 89 Sites across the United States and Canada Main inclusion criteria Postmenopausal Sexually active ≤ 5% superficial cells on vaginal smear Vaginal pH > 5 Moderate to severe dy
Slide 18: REJOICE TRIAL Co-Primary and Key Secondary Endpoints
REJOICE TRIAL Co-Primary and Key Secondary Endpoints FDA Required Co-Primary Endpoints – mean change from baseline to week 12 in1,2: Vaginal superficial cells Vaginal parabasal cells Vaginal pH Moderate to severe dyspareunia (identified as the most bothersome symptom of VVA) Key componen
Slide 19: Baseline Characteristics
Baseline Characteristics 4 mcg 10 mcg 25 mcg Placebo N=191 N=191 N=190 N=192 Age (years) 59.8 ± 5.9 58.5 ± 6.3 58.9 ± 6.3 59.3 ± 6.1 Mean ± SD Race White 87.4% 88.0% 86.8% 84.4% Black 10.5% 11.0%% 12.6% 12.5% Other 2.1% 1.0% 0.5% 3.1% BMI (kg/m2) 26.5 ± 4.9 26.8 ± 4.7 26.7 ± 4.8 26.6 ± 4.5 Mean ± SD
Slide 20: Discontinuation Rates by Reason
Discontinuation Rates by Reason 4 mcg 10 mcg 25 mcg Placebo (N=191) (N=191) (N=190) (N=192) Number of Subjects 16 (8.4%) 17 (8.9%) 13 (6.8%) 14 (7.3%) Discontinued Adverse Event 2 (1.0%) 3 (1.6%) 4 (2.1%) 5 (2.6%) Investigator / Sponsor 1 (0.5%) 0 (0%) 1 (0.5%) 0 (0%) Decision Lack of Efficacy 2 (1.
Slide 21: Co-Primary Efficacy Endpoints
Co-Primary Efficacy Endpoints 21
Slide 22: Change in Percentage Superficial Cells
LS Mean Change from Baseline to Week 12: Vaginal Superficial Cells 4 mcg 10 mcg 25 mcg Placebo Change in Percentage Superficial Cells 26 23% 24 22 20 17% 17% 18 LS Mean ± SE 16 14 12 10 8 6% 6 4 p<0.0001 p<0.0001 p<0.0001 2 0 N=186 N=188 1 N=186 N=187 LS = Least Squares 22
Slide 23: Change in Percentage Parabasal Cells
LS Mean Change from Baseline to Week 12: Vaginal Parabasal Cells 4 mcg 10 mcg 25 mcg Placebo Change in Percentage Parabasal Cells 0 N=186 N=188 1 N=186 N=187 -10 - 7% p<0.0001 p<0.0001 p<0.0001 LS Mean ± SE -20 -30 -40 -50 -41% -44% -46% LS = Least Squares 23
Slide 24: Change in Vaginal pH
LS Mean Change from Baseline to Week 12: Vaginal pH 4 mcg 10 mcg 25 mcg Placebo 0 N=186 N=188 N=186 N=187 -0.2 -0.4 p<0.0001 p<0.0001 p<0.0001 Change in Vaginal pH -0.6 -0.3 LS Mean ± SE -0.8 -1 -1.2 -1.4 -1.6 -1.3 -1.3 -1.4 -1.8 LS = Least Squares 24
Slide 25: Change in Dyspareunia
LS Mean Change from Baseline to Week 12: Severity of Dyspareunia 4 mcg 10 mcg 25 mcg Placebo 0 N=151 N=154 N=159 N=163 -0.2 Change in Dyspareunia -0.4 p=0.0149 p<0.0001 p<0.0001 -0.6 LS Mean ± SE -0.8 -1 -1.2 -1.4 -1.6 -1.3 -1.8 -1.5 -1.7 -1.7 -2 25
Slide 26: Key Components of Secondary Efficacy Endpoints
Key Components of Secondary Efficacy Endpoints 26
Slide 27: Statistical Significance of Dyspareunia Change by Study Visit
Statistical Significance of LS Mean Change from Baseline Severity of Dyspareunia by Study Visit (Week) 4 mcg 10 mcg 25 mcg Week 2 0.026 0.0019 0.0105 Week 6 0.0069 0.0009 < 0.0001 Week 8 0.0003 < 0.0001 < 0.0001 Week 12 0.0149 < 0.0001 < 0.0001 MMRM P-value vs placebo 27
Slide 28: Change in Dryness
LS Mean Change from Baseline to Week 12: Severity of Vaginal Dryness 4 mcg 10 mcg 25 mcg Placebo 0 -0.2 N=171 N=173 N=176 N=174 Change in Dryness -0.4 LS Mean ± SE -0.6 p=0.0014 p<0.0001 p<0.0001 -0.8 -1 -1.2 -0.97 -1.4 -1.27 -1.6 -1.47 -1.47 -1.8 -2 LS = Least Squares 28
Slide 29: Co-Primary and Key Secondary Endpoints Compared to Placebo
Co-Primary and Key Secondary Endpoints LS Mean Change from Baseline to Week 12 Compared to Placebo 4 mcg 10 mcg 25 mcg Superficial Cells <0.0001 <0.0001 <0.0001 Parabasal Cells <0.0001 <0.0001 <0.0001 Vaginal pH <0.0001 <0.0001 <0.0001 Severity of Dyspareunia 0.0149 <0.0001 <0.0001 Severity of Vagin
Slide 30: Efficacy and Onset of Action Based on FDA-Approved Labeling
Efficacy and Onset of Action Based on FDA-Approved Labeling and Not Head-to-Head Comparative Studies Premarin® Vagifem® Estrace® Osphena® Estring® Onset of Action Week 4+ Week 12 Approval Approval Dyspareunia without without Week 8 dyspareunia dyspareunia Onset of (composite score) and dryness and d
Slide 31: Responder Analysis: Severity of Dyspareunia
Responder Analysis: Severity of Dyspareunia at Week 12 4 mcg 10 mcg 25 mcg Placebo 0 N=151 N=154 N=159 N=163 Percentage of subjects with a decrease in severity of dyspareunia of 2+ points -10 P 0.0317 P 0.0006 P 0.0001 -20 -30 -40 35.8% 41.0% -50 47.4% -60 55.4% Responder defined as reduction of 2+
Slide 32: Results from Pharmacokinetics Substudy
Results from Pharmacokinetics Substudy 32
Slide 33: Estradiol Serum Concentrations - TX-004HR 4 mcg
Arithmetic Mean Estradiol Serum Concentrations - Unadjusted TX-004HR 4 mcg (N=18) ( represents day 84) AUC0-24 Cavg(0-24) (pg.h/mL) (pg/mL) 4 mcg 87.22 (42.77) 3.634 (1.78) Placebo 104.16 (66.38) 4.34 (2.76) P-value vs Placebo 0.3829 0.3829 33
Slide 34: Estradiol Serum Concentrations - TX-004HR 10 mcg
Arithmetic Mean Estradiol Serum Concentrations - Unadjusted TX-004HR 10 mcg (N=19) AUC0-24 Cavg(0-24) (pg.h/mL) (pg/mL) 10 mcg 110.14 (54.57) 4.58 (2.27) Placebo 104.16 (66.38) 4.34 (2.76) P-value vs Placebo 0.7724 0.7724 34
Slide 35: Estradiol Serum Concentrations - TX-004HR 25 mcg
Arithmetic Mean Estradiol Serum Concentrations - Unadjusted TX-004HR 25 mcg (N=18) AUC0-24 Cavg(0-24) (pg.h/mL) (pg/mL) 25 mcg 171.56 (80.13) 7.14 (3.33) Placebo 104.16 (66.38) 4.34 (2.76) P-value vs Placebo 0.0108 0.0108 35
Slide 36: Acceptability of Product Administration
Acceptability of Product Administration 36
Slide 37: Was the product easy to use?
Was the product easy to use? 4 mcg 10 mcg 25 mcg Placebo (N=181) (N=181) (N=184) (N=185) YES 171 (94.5%) 172 (95.0%) 175 (95.1%) 164 (88.9%) Overall p-value = 0.035 37
Slide 38: Ease of insertion of the capsule
How would you rate the ease of insertion of the capsule? 4 mcg 10 mcg 25 mcg Placebo (N=181) (N=181) (N=184) (N=185) Excellent 79 (44.0%) 83 (46.0%) 83 (45.0%) 65 (35%) Good 77 (43.0%) 72 (40.0%) 74 (40.0%) 79 (43%) Fair 20 (11.0%) 23 (13.0%) 18 (10.0%) 25 (14%) Poor 5 (3.0%) 3 (1.7%) 9 (5.0%) 16 (9
Slide 39: Level of satisfaction with the product
Level of satisfaction with the product 4 mcg 10 mcg 25 mcg Placebo (N=181) (N=181) (N=184) (N=185) Very Satisfied 74 (40.1%) 84 (46.4%) 83 (45.1%) 41 (22.2%) Satisfied 57 (31.5%) 55 (30.4%) 62 (33.7%) 68 (36.8%) Unsure 23 (12.7%) 28 (15.5%) 21 (11.4%) 39 (21.1%) Dissatisfied 19 (10.5%) 9 (5.0%) 12 (
Slide 40: Safety Endpoints
TRIAL x | Safety Endpoints TherapeuticsMD’
Slide 41: Overview of Adverse Events (Safety Population)
Overview of Adverse Events (AEs) (Safety Population) 4 mcg 10 mcg 25 mcg Placebo (N=191) (N=191) (N=190) (N=192) Any Subject with 113 (59.2%) 105 (55.0%) 107 (56.3%) 124 (64.6%) Reported AE Any Subject with 96 (50.3%) 91 (47.6%) 90 (47.4%) 104 (54.2%) Reported TEAE Any Subject with 38 (19.9%) 28 (14
Slide 42: TEAEs by Preferred Term Occurring ≥ 3%
TEAEs by Preferred Term Occurring ≥ 3% (Safety Population) 4 mcg 10 mcg 25 mcg Placebo Preferred Term (N=191) (N=191) (N=190) (N=192) Nasopharyngitis 5 (2.6%) 6 (3.1%) 7 (3.7%) 10 (5.2%) Upper respiratory tract infection 5 (2.6%) 6 (3.1%) 3 (1.6%) 5 (2.6%) Urinary tract infection 5 (2.6%) 5 (2.6%) 8
Slide 43: Safety Protocol Procedures
Safety Protocol Procedures • No significant difference in safety labs or vital signs • No increase in estrogen sensitive tests (i.e., SHBG, Triglycerides) • No significance difference in EKG findings • No signal of estrogenic stimulation of the endometrium 43
Slide 44: Conclusions
Conclusions TX-004HR at 4, 10 and 25 mcg demonstrated a positive benefit/risk profile for the proposed indication of “treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy due to menopause” – Increased percentage of vaginal superficial cells – Decreased percentage of v
Slide 45: Regulatory Strategy
Regulatory Strategy • Proposed Indication: Treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy due to menopause • Clinical Program Completed • Positive Benefit/Risk profile demonstrated for 4, 10 and 25 mcg • Planned NDA under 505(b)(2) pathway for the 3 doses • Stra
Slide 46: Yuvvexy (TX-004HR) Proposed US Regulatory Approach/Labeling
Yuvvexy™ (TX-004HR) Proposed US Regulatory Approach/Labeling Lisa Rarick, M.D. Former FDA—Center for Drug Evaluation and Research (CDER) Medical Officer & Division Director (Division of Bone, Reproductive and Urologic Products) and FDA Office of the Commissioner, Office of Women’s Health (OWH)
Slide 47: FDA Scientific Workshop on Labeling Lower Dose Estrogen-Alone Products
FDA Scientific Workshop on Labeling “Lower” Dose Estrogen-Alone Products for Symptoms of VVA - November 10, 20151 • “On the topic of the labeling for lower-dose estrogen products delivered vaginally…” • “Lower-dose estrogen products [below 0.625 mg conjugated estrogens used in WHI, and below 0.0375
Slide 48: TherapeuticsMD Proposal for US Labeling
TherapeuticsMD proposal for US Labeling—Governed by Regulations and Guidance • Yuvvexy™ (TX-004HR)—Sections of label to be considered for modification • Highlights of Prescribing Information • Boxed Warnings • Contraindications • Warnings and Precautions • Adverse Reactions • Clinical Pharmacology •
Slide 49: Boxed Warning
Boxed Warning Proposed Elimination or Modifications to Boxed Warning • Estrogen-alone boxed warning information • Propose removal from Boxed Warning • Propose modified language in the “Warnings and Precautions” Section • Estrogen + Progestin boxed warning information • Propose removal from Boxed War
Slide 50: Contraindications
Contraindications • Possible opportunity to remove or modify current Contraindication “Known, suspected, or history of breast cancer”
Slide 51: Warnings and Precautions
Warnings and Precautions • Proposed modification re: “Risks from Systemic Absorption” • Propose modification of each of the current Warnings with draft language such as “When estrogens are used with resulting systemic absorption higher than demonstrated for Yuvvexy™, an increased risk of XX has been
Slide 52: Adverse Reactions, Clinical Pharmacology, Clinical Studies
Adverse Reactions Clinical Pharmacology Clinical Studies • Adverse Reactions tables/listings specific to Yuvvexy™ clinical trials • Clinical Pharmacology to reflect Yuvvexy™ pK data (negligble to very low systemic absorption) • Clinical Studies • Results for co-primary endpoints • May be able to inc
Slide 53: Dosage and Administration, Patient Information
Dosage and Administration Patient Information Vagifem®, Estrace® and Premarin® Vaginal Cream PI YUVVEXY™ PI Instructions for Use of Applicator 2 DOSAGE AND ADMINISTRATION “A single YUVVEXY capsule should be administered digitally intravaginally” All trademarks are the property of their respective ow
Slide 54: YUVVEXY (TX-004HR) TherapeuticsMD Label Proposal
YUVVEXY™ (TX-004HR) TherapeuticsMD Label Proposal • Potential Modification of Boxed Warnings Estrogen Warnings —Potential removal from Boxed Warning section —Potential modifications of estrogen warnings Estrogen + Progestin Warnings —Potential removal from Boxed Warning section —Potential removal of
Slide 55: Q&A
Q&A • Robert Finizio – Co-founder and Chief Executive Officer, TherapeuticsMD • Brian Bernick, M.D. – Co-founder and Chief Clinical Officer, TherapeuticsMD • Sebastian Mirkin, M.D. – Chief Medical Officer, TherapeuticsMD • Sheryl Kingsberg, Ph.D.* – Chief, Division of OB/GYN Behavioral Medicine, UH
Slide 56: Thank You
THANK YOU 56
Slide 57: Appendix
Appendix TherapeuticsMD”
Slide 58: YUVVEXY (TX-004HR) – Target Product Profile
YUVVEXY (TX-004HR) – Target Product Profile TM Target Goals Phase 3 Supportive Data Phase 3 data demonstrated statistical significance Efficacy for all 3 doses on the 4 co-primary endpoints Negligible to low systemic absorption with 4 mcg, Low systemic exposure 10 mcg and 25 mcg observed in phase 1
Slide 59: Phase 1 Single Dose PK Studies TX-004HR vs. Vagifem
Phase 1 Single Dose PK Studies TX-004HR vs. Vagifem® Systemic absorption AUC (0-24 hours) and Cavg (0-24 hours) for estradiol is 2- to 3-fold lower with TX-004HR relative to Vagifem® (p < 0.0001) Vagifem is a registered trademark of Novo Nordisk A/S Corp. Pickar, et al. Climacteric 2016 59
Slide 60: Less Sexual Dysfunction (FSFI Total Score)
LS Mean Change from Baseline to Week 12 The Female Sexual Function Index (FSFI) Total Score 4 mcg 10 mcg 25 mcg Placebo 12.00 Less Sexual Dysfunction 10.00 8.00 6.00 4.00 2.00 P=0.9075 P=0.0492 P=0.0019 * 0.00 4 mcg 10 mcg 25 mcg Placebo N=153 N=152 N=156 N=158 Total Score Range: 2.0 to 36.0 60
Slide 61: YUVVEXY (TX-004HR) Medical Differentiation Index
YUVVEXY™ (TX-004HR) TX-004HR Data results Medical Differentiation Index PROGRAM IMPLICATIONS - Negligible to Low Systemic Absorption 0% 80% - Variable Dosing 4 mcg 10 mcg 25 mcg 30 mcg - 2 week onset of action 2 week 12 week - Highly Efficacious for VVA/GSM 50% 100% - High Satisfaction 20% 95% 100%