1. Pilot and Pharmacokinetic Studies of Solubilized Estradiol Administered Vaginally in a Softgel Capsule
James H. Pickar, M.D., F.A.C.O.G.

2. Disclosures Consulted for: Wyeth / Pfizer Ausio Pharmaceuticals
Besins Healthcare
Shionogi
Metagenics
TherapeuticsMD

3. Introduction
TX-004HR is a new softgel vaginal capsule under development
Two bioavailability studies (10µg and 25µg) were conducted comparing TX-004HR vaginal estradiol softgel capsules (VagiCap™) versus approved estradiol vaginal tablets (Vagifem®)
A single center, randomized, placebo-controlled, clinical pilot study was conducted to test the safety and efficacy of the 10mcg dose of TX-004HR (VagiCap) versus placebo when give daily for 14 days

4. TX-004HR VagiCap™

5. Study Design-Pharmacokinetic Studies
Two single dose, randomized, open label, two-way crossover, bioavailability studies were conducted. Each had a 14 day wash-out between doses. There were 36 healthy postmenopausal women in each study.
Subjects were included if they were generally healthy, years old with BMI between They were required to have a normal ECG, chest X- ray, lab values, breast and gynecologic exam. E2< 50 pg/ml, FSH >40 IU/l, no vaginal bleeding for 12 months or 6 months post bi-lateral oophorectomy (w or w/o hysterectomy).

6. Study Design-Pharmacokinetic Studies
Subjects stayed in the research facility, fasted the night before, were fed a standard diet and estrogen blood levels were measured at 13 time points ( -1.0, -0.5, 0.0, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, 14.0, 18.0, 24.0 hours postdose) via in-dwelling catheter.
Thirty-five women completed the 10mcg study and 36 completed the 25mcg study.

7. PK Study Results - Estradiol Baseline Adjusted
10mcg Study mcg Study
PK Parameter
Geometric Mean ±SD
Test (T)
Reference (R)
Cmax (pg/ml)
14.38
20.38
AUC 0-24 (pg.hr/ml)
49.62
132.92
T max (hr)
1.75
9.28
PK Parameter
Geometric Mean ±SD
Test (T)
Reference (R)
Cmax (pg/ml)
23.08
42.70
AUC 0-24 (pg.hr/ml)
89.21
292.06
T max (hr)
1.85
11.18
Comparison detected as statistically significant (p < 0.05)

8. PK Study Results – Estrone Baseline Adjusted
10mcg Study mcg Study
PK Parameter
Geometric Mean ±SD
Test (T)
Reference (R)
Cmax (pg/ml)
5.15
6.98
AUC 0-24 (pg.hr/ml)
24.24
48.24
T max (hr)
5.87
9.07
PK Parameter
Geometric Mean ±SD
Test (T)
Reference (R)
Cmax (pg/ml)
10.69
23.58
AUC 0-24 (pg.hr/ml)
50.22
165.47
T max (hr)
5.14
11.48
Comparison detected as statistically significant (p < 0.05)

9. Study Design-Phase 2 Clinical Study
A randomized, double blind, placebo controlled pilot trial evaluated the safety and efficacy of 10mcg of TX-004HR in reducing moderate to severe symptoms of vulvovaginal atrophy in healthy postmenopausal women following once daily administration for 14 days.
n=50; aged 40-75yrs;
BMI≤34 kg/m²;
with ≤ 5% superficial cells and a vaginal pH>5.0;
at least one moderate to severe symptom of vulvovaginal atrophy

10. Clinical Study Results
In this clinical trial, significantly higher mean percent increases from baseline were observed with Test vs placebo for superficial cells (35% vs 4%, p=0.0002) and intermediate cells (13% vs 4%, p=0.0002) at 2 weeks.
The mean percent decrease from baseline in parabasal cells was significantly greater with Test vs placebo (54% vs 5%, p=0.0001), as was the mean decrease in vaginal pH (0.97 vs 0.34, p=0.0002).
The Test group also had significantly greater improvements in vaginal epithelial integrity and secretions than the placebo arm. Vaginal symptom improvement was similar between groups, likely due to the small size and short duration of the study.

11. Clinical Study Results
Out of the 50 subjects enrolled into the study, one subject discontinued due to an eye contusion (AE, not related) and one for family emergency.
Fourteen subjects (11-TX-004HR, 3-placebo) had experienced a total of 17 AEs(13-TX004HR, 4-placebo) over the course of the trial. Most were reported as not related or possibly related.
No serious AEs were reported.

12. Conclusions
Studies showed that both the 10µg and the 25µg doses of TX-004HR, a novel estradiol vaginal softgel capsule, were safe and well tolerated.
Systemic exposure with both doses was significantly less than with the equivalent doses of an approved vaginal estradiol tablet.
The clinical study of the 10µg dose of TX-004HR given daily for 2 weeks demonstrated significant improvement in vaginal cytology and pH compared with placebo.
Based on the results of these studies an additional lower dose of 4µg is being studied in the phase 3 trial.

13. Coauthors
Julia M. Amadio, M.B.A. John M. Hill, M.D. Brian A. Bernick, M.D. Sebastian Mirkin, M.D.

14. Thank You