Pilot and Pharmacokinetic Studies of
Solubilized Estradiol Administered
Vaginally in a Softgel Capsule
James H. Pickar, M.D., F.A.C.O.G.
Disclosures
• Consulted for:
• Wyeth / Pfizer
• Ausio Pharmaceuticals
• Besins Healthcare
• Shionogi
• Metagenics
• TherapeuticsMD
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
TX-004HR VagiCap™
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, 40-65 years old with BMI between 18.5-29.9.
They were required to have a normal ECG, chest Xray, 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).
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.
PK Study Results - Estradiol Baseline Adjusted
25 mcg Study
40
30
R e fe re n c e
T est
20
10
0
0
6
12
18
24
t im e a ft e r d o s in g ( h r s )
PK Parameter
Geometric Mean ±SD
m e a n p la s m a c o n c e n tr a tio n (p g /m L )
m e a n p la s m a c o n c e n tr a tio n (p g /m L )
10mcg Study
40
30
R e fe re n c e
T est
20
10
0
0
6
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
18
t im e a ft e r d o s in g ( h r s )
PK Parameter
Test (T)
12
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)
24
PK Study Results – Estrone Baseline Adjusted
25 mcg Study
15
R e fe re n c e
T est
10
5
0
0
6
12
18
24
t im e a ft e r d o s in g ( h r s )
PK Parameter
Cmax (pg/ml)
AUC 0-24 (pg.hr/ml)
T max (hr)
15
10
R e fe re n c e
T est
5
0
0
6
Reference (R)
5.15
6.98
24.24
48.24
5.87
9.07
12
18
t im e a ft e r d o s in g ( h r s )
PK Parameter
Geometric Mean ±SD
Test (T)
m e a n p la s m a c o n c e n tr a tio n (p g /m L )
m e a n p la s m a c o n c e n tr a tio n (p g /m L )
10mcg Study
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)
24
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
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.
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.
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.
Coauthors
Julia M. Amadio, M.B.A.
John M. Hill, M.D.
Brian A. Bernick, M.D.
Sebastian Mirkin, M.D.
Thank You