Ovulation Suppression and Cycle Control of Ethinyl Estradiol and Levonorgestrel Combination Patches

Daniel R Mishell Jr, MD ; David F Archer, MD ; Arkady Rubin, PhD ; Marie Foegh, MD, DrSc
1 2 3 4

Keck School of Medicine, University of Southern California, Los Angeles, CA; 2Jones Institute for Reproductive Medicine, Norfolk, VA; 3ARSTAT, Inc., Flemington, NJ; 4Agile Therapeutics, Inc., Princeton, NJ
1

Results
Table 2. Ovarian Suppression Table 4. Comparison of presumptive ovulation rate for Figure 3. Incidence of Breakthrough Bleeding/Spotting
AG200LE, AG200-12.5 and AG200-15 with published rates and Episodes–Cycle 3
Pearl Index for COCs
Serum Progesterone Levels in Cycles 1–3 — Women with BMI 17–52 kg/m2

Abstract Methods AG200LE AG200-12.5 AG200-15 Multiple progesterone measurements per cycle 35% Single progesterone measurement in
n=125 n=129 n=83 luteal phase per cycle
Objective or purpose of the study: To evaluate ovulation suppression (OS), A multicenter, open-label, randomized, parallel group study (Part I) Contraceptive Presumptive Pearl Index
Discussion
Serum Progesterone ng/mL 30%
cycle control, and safety of three transdermal contraceptive delivery followed by a multicenter, open-label, single-arm extension (Part II). Ovulation Rate Contraceptive Presumptive Pearl Index
systems (TCDS) containing differing amounts of LNG and EE; assess Ovulation Rate
Part I of the study evaluated 2 different contraceptive patch formulations, Mean 1.3 0.9 0.8
patch tolerability/wearability. AG200LE 36.5%a N/A 25% Progesterone blood level measurement is a sensitive method to determine whether
AG200-12.5 (identified as AG200 in Abstract) and AG200LE, while AG200LE 11.4% N/A ovulation occurs; for women on low-dose hormonal contraceptives, the sensitivity
Methods used for data collection: The multi-center, open-label, randomized Median 0.6 0.4 0.3 AG200-12.5 20.7%a N/A
Part II of the study evaluated AG200-15, a third contraceptive patch 20% increases with the frequency of progesterone measurements and the specificity
three cycles study evaluated 123 women with regular cycles using either with a similar formulation to AG200-12.5, but with a 20% larger drug AG200-12.5 3.2% N/A
SD 1.4 1.1 1.2 AG200-15 11.5% a
N/A increases with higher progesterone level cut-off. The specificity is low in women
Agile TCDS: AG200LE, AG200 and AG200-15 delivering LNG from 75 to 15%
delivery area. AG200-15 3.2% N/A taking low-dose hormonal contraceptives, as elevated progesterone levels may be
100 µg daily and EE from 15 to 30 µg daily. Serum-progesterone was Alesse ®
21.3% 1
0.84–1.68 present without ovulation in up to 60%–85% of cycles. We found that by changing
measured on days 1, 8, 11, 15, 19, 22 and 25. EE and LNG were In Part I of the study, subjects were randomly assigned to Ortho
10% Tri-Cyclen® 7.0%6 1.21
Triphasil ®
10.6% 1
1.25–2.18 4 the progesterone cut-off from 4.7 ng/mL to 9.0 ng/mL, the presumptive ovulation rate
determined on days 8, 15 and 22. Probable ovulation was defined as 1 of 2 treatment groups:
0.0%6 2.36
dropped 30%–50%. Limiting the frequency of progesterone measurements to one
two consecutive serum progesterone levels above 4.6 ng/mL. Daily diary Ortho Tri-Cyclen Lo®
Ortho Tri-Cyclen ®
13.3% 1
1.21 5% measurement in the luteal phase decreased the presumptive ovulation rate even
cards were used. Group 1: A
 G200-12.5 (24.5 cm2) for 3 cycles (21 days on treatment,
more (70%).
7 days no treatment) Ortho Evra® 0.7%1 1.0 0%
Result summarized: For the intent to treat population (ITT) wearing
AG200LE AG200-12.5 AG200-15 The literature is replete with wide variation in study designs for determining ovulation
AG200LE, AG200 or AG200-15, OS was 72.8%, 88.4% and 90.4% Group 2: A
 G200LE (24.5 cm ) for 3 cycles (21 days on treatment,
2 Mercilon ®
8.7% 2
0.3–0.6 5
inhibition. In 2 studies where both frequent progesterone sampling and trans-vaginal
respectively. For the ITT with verifiable compliance, OS was 75.0%, 7 days no treatment) Figure 2. Ovarian Suppression Triphasil® 9.1%3 1.25–2.184 ultrasound were done in low-dose oral contraceptive users, it was found that about
90.4% and 92.3% respectively. EE influenced LNG pharmacokinetics
30% of increased progesterone values reflected ovulation seen by ultrasound.2,7 The
and pharmacodynamics. No serious adverse events observed. The
In Part II of the study, all subjects were assigned to the third a Serum progesterone all ≥4.7ng/mL BMI ≤32kg/m2
presumptive ovulation rate for AG200-15 is within the range of COCs, whether the rate
a

INCIDENCE OF PRESUMPTIVE OVULATION BY SERUM PROGESTERONE Serum progesterone all ≥4.7 ng/mL BMI ≤32 kg/m2
AG200-15 showed good cycle control with 85% women reporting no
treatment group: Multiple Measurements per Cycle is determined by frequent serum progesterone measurements or by one luteal phase
breakthrough bleeding/spotting in cycle 3 compared to 71% in the
AG200-15 within established range for COCs measurement in each cycle. The Pearl Index is not proportional to the presumptive
AG200LE and AG200 groups. Skin irritation occurred for 2% of all Group 3: A
 G200-15 (26 cm2) for 3 cycles (21 days on treatment,
Rate ovulation rate in Phase 2 studies (Tables 4 and 5).
patches and was mild. Incidence of patch fall-off or detachment 7 days no treatment) Figure 4. Hormone-Related AEs
were <1% in cycle 3. 25% Table 5. Comparison of presumptive ovulation rate for
Enrollment included: AG200LE, AG200-12.5 and AG200-15 with published rates and
Conclusions reached: AG200-15 is the optimal formulation for OS and
Pearl Index for COCs Summary
20% 25%
cycle control and with hormone exposure equivalent to oral doses of • 45 subjects in the AG200LE treatment group
AG200LE
approximately 100 µg LNG daily and approximately 30 µg EE daily. 15%
20%
AG200-12.5
• 45 subjects in the AG200-12.5 treatment group Multiple progesterone measurements per cycle Single progesterone measurement in
Ovulation suppression for AG200-15 is similar to other low-dose COCs. AG200LE is an
AG200-15
luteal phase per cycle 15%
Ortho Evra®
ineffective dose.
• 33 subjects in the AG200-15 treatment group 10%
Contraceptive Presumptive Pearl Index
Ovulation Rate Contraceptive Presumptive Pearl Index 10% The bleeding profile with AG200-15 is within the range of low-dose (30 µg EE) COCs.
Enrolled subjects applied the assigned contraceptive patch to the lower 5%
Ovulation Rate
abdomen in the morning of Cycle Day 1 (Day 1 of their menstrual AG200LE 36.5%a N/A 5% Hormone-related AEs are substantially below those reported for the currently available
cycle). The patch was replaced on Cycle Days 8 and 15, and removed
0% contraceptive patch and within range of low-dose COCs.
AG200LE 11.4% N/A
15
® ® ® ®
sil
® ®
AG200-12.5 - se 20.7% l en a vra N/Asil l on 0%
without being replaced in the morning of Cycle Day 22. 00 es h a
yc E a ci
AG
2 Al Tr
i p C th
o
Tr
i ph er Headache Nausea Vomiting Mastalgia EE and LNG blood levels were consistent over 3 cycles and within range of low-dose
Tri- r
O a
M AG200-12.5 3.2% N/A
AG200-15 t h o 11.5% N/A COCs and substantially lower (60%) than those reported for the currently available
Technology Or
*Historical Ortho Evra® data.
AG200-15 3.2% N/A contraceptive patch. The mean EE levels for AG200-15 in this study ranged from
Alesse ®
AG200-15 primary 21.3% 0.84–1.68
endpoint vs published data. 1
24 to 32 pg/mL during the cycle.
The TCDS technology is composed of an inner, active Triphasil® data reported in separate studies. Ortho Tri-Cyclen® 7.0%6 1.21
Table 1. Demographics and Baseline Characteristics Triphasil® 10.6%1 1.25–2.184
matrix adhesive system that delivers both EE and LNG
Ortho Tri-Cyclen Lo® 0.0%6 2.36
at unique, targeted levels through the skin. Ortho Tri-Cyclen® 13.3%1 1.21
Characteristic AG200LE AG200-12.5 AG200-15
Ortho Evra® 0.7%1 1.0 Conclusion
The outer, peripheral (n=43) (n=44) (n=31)

adhesive system is Mercilon® 8.7%2 0.3–0.65 Figure 5. EE & LNG Blood Levels AG200-15 was selected as the lead contraceptive patch for Phase 3 based on the ovulation
Age (yrs)
responsible for patch INCIDENCE OF PRESUMPTIVE OVULATION BY SERUM PROGESTERONE suppression data, bleeding, and hormone-related AE profile. AG200-15 has substantially
Mean ± SD 31.7 ± 7.4 31.0 ± 6.9 32.1 ± 7.8
adherence, stability, Range 19–45 18–45 18–43 Triphasil One Measurement per Cycle in 9.1%
® 3
Luteal Phase 1.25–2.184 less EE exposure than reported for Ortho Evra® as reflected in both EE blood levels and
Race AG200-15 within established range for COCs Table 6. Bleeding Patterns During Reference Period (Days 1–84) Ethinyl Estradiol Levels (Median) Levonorgestrel Levels (Median) EE-related AEs. The wearability is excellent with minimal skin irritation and detachment.
and patient comfort.
Black 9 (21%) 10 (23%) 12 (39%) 30 1500
Hispanic 11 (26%) 6 (14%) 3 (10%) Rate

EE Concentrations (pg/mL)

LNG Concentrations (pg/mL)

White 18 (42%) 26 (59%) 14 (45%)
Other 5 (12%) 2 (5%) 2 (6%) 12% AG200-15
BMI (kg/m ) 20 1000
(n=27)
2

10%
Soft, flexible fabric Mean ± SD 28.7 ± 6.0 27.7 ± 6.6 27.5 ± 7.0
maximizes patient Range 19–46 18–45 17–52 Number of
comfort 8%
Weight (lbs) Scheduled/Unscheduled 10 500
Provides reliable Mean ± SD 170.4 ± 36.8 167.9 ± 42.6 164.5 ± 44.8 6% Bleeding/Spotting Days
Range 101–285 99–262 109–315
Levonorgestrel (LNG) adhesion for 7 days
Ethinyl Estradiol (EE) • Allows moisture to evaporate 4% Mean ± SD 14.4 ± 6.6 0 0
BMI = body mass index, SD = standard deviation
• Minimizes irritation Median 13.0 1/8 1/15 1/22 2/8 2/15 2/22 3/8 3/15 3/22 1/8 1/15 1/22 2/8 2/15 2/22 3/8 3/15 3/22
• Increases drug stability 2% Range 0–28
Cycle/Day Cycle/Day
0%
Study Evaluation: AG200-15 AG200-12.5 AG200 LE AG200-15 AG200-12.5 AG200 LE
15 /7 /5
®
n ET
® ®
n Number of Scheduled/
-
7/
7
1/
3 o N Lo cl
e
00 ic 0 en y
Ovulation suppression (efficacy assessment for this study) was based AG 2
um
®
um
®

M
od /1
0
yc
l
i-C Unscheduled Spotting Days
v v EE i- C Tr
No - No 30 Tr th
o
on serum progesterone concentrations determined at Days 1, 8, 11, ho
-
ho ho O r Mean ± SD 1.4 ± 2.9
rt rt rt
Background 15, 22, and 25 of the treatment cycle.
O O
AG200-15 data vs published data.
O Median
Range
0.0
0–13 REFERENCES:
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Objective to end of the study.

AG200LE AG200-12.5 AG200-15
Mean ± SD 1.2 ± 2.6
% of subjects 1.8% (n=2) Mercilon (desogestrel/ethinyl estradiol)
®
6. LaGuardia KD, et al. Efficacy, safety and cycle control of five oral contraceptive regimens containing norgestimate and ethinyl
estradiol. Contraception. 2003;67(6):431-437.
Serum Median 0.0
To determine which of the 3 TCDS, containing 3 different amounts of EE Progesterone % of patches 1.6% (n=17) Modicon® (norethindrone/ethinyl estradiol) 7. Coney P, DelConte A. The effects on ovarian activity of a monophasic oral contraceptive with 100 µg levonorgestrel and
BMI ≤32 kg/m2 BMI 17–52 kg/m2 BMI ≤32 kg/m2 BMI 17–52 kg/m2 BMI ≤32 kg/m2 BMI 17–52 kg/m2 Range 0–11 20 µg ethinyl estradiol. Am J Obstet Gynecol. 1999;181:S53-S58.
and 2 different amounts of LNG, to take into Phase 3 pregnancy prevention Cut-Off n=105 n=125 n=94 n=129 n=63 n=83
Mild n=3 Ortho Evra® (norelgestromin/ethinyl estradiol transdermal system)
studies by evaluating the adequacy of ovulation suppression, cycle control, Number of Unscheduled Irritation (% of subjects) 2.5% Moderate n=0 Ortho-Novum® (norethindrone/ethinyl estradiol)
Likely Ovulation 17.1% 17.6% 8.5% 7.8% 4.8% 4.8%
and safety. ≥9 ng/mL Bleeding Days Severe n=0
Ortho Tri-Cyclen® (norgestimate/ethinyl estradiol)
Mean ± SD 1.7 ± 2.9
Probable Pruritus (% of subjects) 0.8% (n=1) Ortho Tri-Cyclen Lo® (norgestimate/ethinyl estradiol)
26.7% 27.2% 12.8% 11.6% 9.5% 9.6% Median 0.0
Ovulation
≥4.7 ng/mL (x2) Range 0–10 Triphasil® (levonorgestrel/ethinyl estradiol)