Vaginal Rings with Progesterone Receptor Modulators for Regular
Contraception
Jeffrey T. Jensen, MD, MPH
Oregon Health & Science University
PRMs for regular contraception
• Mechanism: Suppression of ovulation – 90-95% with oral mifepristone (2-5mg daily)*
• Opportunity: Elimination of estrogen-related adverse effects
• Risk: New nontarget effects – Endometrial changes
– Antiglucocorticoid effect
* Brown et al JCEM, 2002;87(1):63-70.
PRMs for regular contraception RCT: oral daily Mifepristone 5 mg (n=74)
vs LNG 30 mcg (n=23) for 24 weeks
– Better bleeding pattern with mifepristone
• 49% vs. 0% amenorrhea
• 4% vs 39% with > 5 days bleeding/spotting
– Thicker endometrium • Mife 10.3mm;LNG 4.0 mm (p <.001)
• PAECs on biopsy
– 2 pregnancies with mifepristone
Lakha et al. Human Reproduction Vol.22, No.9 pp. 2428–2436, 2007
0
2
4
6
8
10
12
0 8 16 24 endo
met
rial
thck
ness
(mm
)
Weeks
Mifepristone
LNGPOP
0%
10%
20%
30%
40%
50%
60%
70%
0 1-5 6-10 11-20 21+
% o
f sub
ject
s
Days of bleeding and spotting
Mifepristone
LNGPOP
Ulipristal acetate
• Receptor binding affinity – Progesterone receptor UPA = Mife= P4
– Glucocorticoid receptor UPA < Mife
• Approved for use as an oral emergency contraceptive pill and in the EU for uterine fibroid treatment
• Results with short term oral dosing 5-10 mg – Ovulation suppression in 80%
– Amenorrhea in 81% -90% Chabbert-Buffet et al. JCEM 2007;92:3582-9
UPA Contraceptive Vaginal Ring • Developed by Population Council
– Support • NICHD NIH U54 HD 29990
• HRA Pharma, Paris, France.
• Goal: A highly effective continuous use estrogen-free and bleed-free contraceptive method
Ulipristal Acetate Vaginal Ring (~2.5 mg VA/CDB-2914/day)
Slicone elastomer fusion technology of a ring within a ring
International patent application number PCT/US2005/024474 to Sitruk-Ware and Tsong, for “Sustained Release Compositions Containing Progesterone Receptor Modulators” filed July 8, 2005
UPA CVR 600-800 µg/day; 12 weeks
Ovarian Activity % of cycles UPA (ng/mL)
Ovulation 32% (25/78) 4.7
Ovulatory dysfunction 1% (1/78) 5.7
LUF 13% (10/78) 5.5
Persistent follicle 31% (24/78) 5.6
No follicular resolution 14% (11/78) 4.7
No follicular development >10 mm
9% (7/78) 7.6
Brache et al, Contraception 85 (2012): 480-488
Bleeding days (mean) = 4.2 Spotting days (mean) = 7.5 Episodes (mean) = 1.4
Classification of Ovarian Activity
Each 28 day cycle of observation • Ovulation
• follicular rupture • P ≥ 10 nmol/L next 2 samples
• Ovulatory Dysfunction • Rupture with abnormal endocrine profile
• Luteinized unruptured follicle (LUF) • No rupture, P ≥ 5 nmol/L x 2
• Persistent Follicle • No Follicular Development • No Follicular Resolution
-14-10 -7 -3 0 3 7 10 140
200400600800
10001200
-14-10 -7 -3 0 3 7 10 1405
101520253035
Prot 422: Estradiol, progesterone and follicular diameter means of control cycles
Estradiol
Estra
diol (p
mol/L
)
Days from follicular rupture
010203040506070
Prog
Prog
ester
one (
nmol/
L)
n = 20
Follic
ular d
iamete
r (mm
)
Brache et al Contraception 85 (2012): 480-488
Ovulation Follicular rupture P ≥ 10 nmol/L next 2
-14-10 -7 -3 0 3 7 10 140
200400600800
10001200
-14-10 -7 -3 0 3 7 10 1405
101520253035
Prot 422: Estradiol, progesterone and follicular diameter means of control cycles
Estradiol
Estra
diol (p
mol/L
)
Days from follicular rupture
010203040506070
Prog
Prog
ester
one (
nmol/
L)
n = 20
Follic
ular d
iamete
r (mm)
Brache et al Contraception 85 (2012): 480-488
– Follicular rupture with abnormal endocrine profile:
• preceded by progesterone levels >10 nmol/L
• not followed by a luteal phase ( No P > 5 nmol/L)
• not followed by adequate luteal phase (P not > 10 nmol/L in at least two consecutive samples).
• Also associated with follicle > 30 mm
Ovulatory dysfunction
Brache et al Contraception 85 (2012): 480-488
Luteinized unruptured follicle (LUF) – no follicular rupture
– P ≥ 5 nmol/L in at least two consecutive samples.
Persistent follicle – a follicle developing beyond 15 mm and persisting
for ≥ 7 days without rupture and without P increase
No follicular development – No follicle > 10 mm with growth
No follicular resolution – Fate not determined in 30 d interval
Brache et al, Contraception 85 (2012): 480-488
0 28 56 840
200
400
600
800
1000
1200 0 28 56 840
10
20
30
40
E2
Estra
diol (p
mol/L)
Days of treatment
0
10
20
30
40 P
Proge
steron
e (nm
ol/L)
Ovulatory Dysfunction
LUF
0308No follicular resolution
Follic
ular d
iamete
r (mm)
0 28 56 840
400
800
1200
1600
2000
24000 28 56 84
0
10
20
30
40
E2
Estra
diol (p
mol/L)
Days of treatment
0
10
20
30
40 P
Prog
estero
ne (n
mol/L)
No follicularresolution
0306
Persistent follicleFo
llicula
r diam
eter (m
m)
0 28 56 840
200
400
600
800
1000
1200 0 28 56 840
10
20
30
40
E2
Estra
diol (p
mol/L)
Days of treatment
0
10
20
30
40
50 P
Proge
steron
e (nm
ol/L)
0305
No follicular event
Follic
ular d
iamete
r (mm)
Protocol 422: A Phase 2, randomized study to evaluate the safety and efficacy of two Contraceptive Vaginal Rings delivering a daily dose of 1500 or 2500 μg
of CDB-2914 on inhibition of ovulation, endometrial changes and bleeding patterns in normal cycling women
• Randomized, dose-finding, multicenter trial
• CDB-2914 CVR ( 3 month) 1500 µg or 2500 µg
• 3 ICCR sites
– Santo Domingo, Santiago, Portland (n = 20/site)
• Primary Objective: To develop a UPA CVR that will suppress ovulation in 90% of cycles
• Secondary Objectives: To assess bleeding patterns, endometrial effects, and clinical safety