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T8A 1
Proellex®For the Treatment of Uterine Fibroids and Endometriosis
Proellex – CBD 4124 Overview of Pharmacology
• Progesterone receptor modulator (PRM) with specific potential advantages– High affinity and selectivity; pure PR antagonist
• PR Antagonist @ 10-10 M
– Low affinity for corticosteroid receptors• GR Antagonist @ 10-6 M
RU-486>CDB-2914>CDB-4059>Proellex
• Anti-progestin effect oral (in vitro): Proellex>CDB4059>CDB-2914>RU-486
• Androgenic: No activity• Antiandrogenic: Weak activity• Glucocorticoid: No activity
T8A 3
ZPE-002
Endometriosis safety study
ZPU-003
Phase II Uterine Fibroid Study
Efficacy Findings
Phase 1/2 Endometriosis TrialProof of Concept Safety Study
• Patient Population and Treatment – N=39 – Laparoscopic diagnosis of endometriosis– Pain symptom severity mild to moderate– Age 20-41 yrs– Conducted in Europe– 6 mo treatment– Dosing; 12.5mg (n = 9), 25mg (n = 10) and 50mg (n = 10) Proellex, QD
Active control: open label GnRHa (n = 10) (Lucrin 3.75 mg IM monthly)
• Endpoints: – Pain – Daily Diary Questionnaire
– Bone loss – Biochemical markers and Dexascans
– Endometrial stripe measurement by TVUS
– Endometrial biopsies
Phase 1/2 Endometriosis TrialReduction in Pain
0
10
20
30
40
50
60
70
80
90
100
% P
ain
Fre
e D
ay
s
Lupron 12.5 mg Proellex 25 mg Proellex 50 mg Proellex
• Fewer mean days of pain with 50mg Proellex (higher percentage of pain free days than with Lupron) p< 0.05*
• Lupron not statistically different from 12.5mg and 25mg Proellex dose
% Pain Free Days – 6 Months of Treatment
= Range of pain free days
*
ZPU-003
Phase II Uterine Fibroid Study Study completed Q1 07
• Design:– Women with symptomatic bleeding uterine fibroids (menorrhagia)– Treatments: Placebo, 12.5mg, 25mg Proellex QD orally– Treated for 3 months with 15 month open label extension
• Status:– 127 patients enrolled, 96 completed, 114 intent-to treat
• Dropouts: Pbo-15, 12.5 mg-8, 25 mg-8
• Endpoints:– Efficacy:
• Primary: bleeding (Pictogram Bleeding Assessment Chart)• Secondary: pain, Uterine Fibroid QOL, fibroid size (ultrasound)
– Safety: • Endometrial stripe by ultrasound• Endometrial biopsies• Biochemical bone markers• Endocrine tests, serum chemistry, ECG
ZPU-003
Phase II Uterine Fibroid Study Pictoral Blood Loss - MITT Population*
0
20
40
60
80
100
120
140
160
BL Mo 1 Mo 2 Mo 3
PlaceboProellex 12.5 mgProellex 25 mg
Mea
n P
BA
C S
core
mL
12.5 and 25 mgp < 0.0001 vs Pl
MITT* - All subjects who received study medication and have one post-dose primary efficacy measurement
Menorrhagia
ZPU-003
Phase II Uterine Fibroid Study UFSQOL – Symptom Severity Questions 1-8
0
10
20
30
40
50
60
UF
SQ
OL
Sym
pto
m S
core
BL Mo 1 Mo 2 Mo 3
Placebo
12.5 mg Proellex
25 mg Proellex
Normal
High score > severity Month 3 significance values v.s. placebo; 12,5and 25 mg p <0.0001
Spies et al, Obstetrics & Gynecology, vol. 99, No. 2, February 2002
ZPU-003
Phase II Uterine Fibroid Study UFSQOL – Total Score
0
10
20
30
40
50
60
70
80
90
100
UF
SQ
OL
SC
OR
E
BL Mo 1 Mo 2 Mo 3
Placebo
12.5 mg Proellex
25 mg Proellex
Normal
High HRQL scores indicate better HRQL Month 3 significance values v.s. placebo; 12,5 mg p = 0.024; 25 mg p = 0.0016
Spies et al, Obstetrics & Gynecology, vol. 99, No. 2, February 2002
ZPU-003
Phase II Uterine Fibroid Study Hemoglobin <11.5 g/DL MITT Population*
MITT* - All subjects who received study medication and have one post-dose primary efficacy measurement
6
7
8
9
10
11
12
13
BL Mo 1 Mo 2 Mo 3
Placebo
Proellex 12.5 mg
Proellex 25 mg
Mea
n H
emo
glo
bin
g/d
L
0.00080.00091.025mg
0.0160.00020.5112.5mg
Mo 3Mo 2Mo 1
p values vs placebo
ZPU-003
Phase II Uterine Fibroid Study Shift of Pain to No Pain – BL to 3 Months
0
5
10
15
20
25
30
35
40
45
% w
om
en p
ain
fre
e af
ter
3 m
on
ths
Month 3
Placebo12.5 mg Proellex25 mg Proellex
Comparison: pain present at baseline to no pain at 3 monthsPlacebo p NS, Proellex 12.5 mg p 0.034, Proellex25 mg p 0.008
Proellex® Efficacy Conclusions
• Endometriosis – Pain is reduced significantly and the 50 mg dose overall
statistically is significantly better than other Proellex® doses and Lucrin® from week 2 – 26
– More pain-free days over 26 weeks with the Proellex® 50 mg dose than Lucrin® (p = 0.05)
• Uterine Fibroids – compared with placebo– Severe bleeding significantly reduced in the first month
of treatment (p < 0.0001)– Severity of symptoms UFSQOL (p < 0.0001) and
HRQOL improve over 3 months (p < 0.025 [12.5 mg] – p < 0.002 [25 mg])
– Associated reduction in pain (statistically significant)
T8A 14
ZPE-002
Endometriosis safety study
ZPU-003
Phase II Uterine Fibroid Study
Safety Findings
ZPU-003
Phase II Uterine Fibroid Study Number (%) of Subjects with Treatment Emergent Adverse Events for Reproductive System and Breast Disorders (>5% Prevalence – Safety Subjects)
AE Profile Proellex 12.5 mg
N=44
n (%)
Proellex 25 mg
N=40
n (%)
Placebo
N=43
n (%)
Subjects with at least one adverse event
37 (84.1) 34 (85.0) 13 (30.2)
Amenorrhea 31 (70.5) 30 (75.0) 4 (9.3)
Hot flush 9 (20.5) 6 (15.0) 1 (2.3)
All other adverse events in other body systems similar to placebo
ZPU-003
Phase II Uterine Fibroid Study Proellex Effects on Estradiol and Progesterone
P NS vs Pl
0
20
40
60
80
100
120
140
BL Mo 3
Placebo 12.5mg 25mg
0
1
2
3
4
5
6
BL Mo 3
Placebo 12.5mg 25mg
Me
an
Es
tro
ge
n p
g/m
L
Pro
ge
ste
ron
e n
g/m
L
P NS vs Pl
Phase 1/2 Endometriosis TrialACTH
0
5
10
15
20
25
30
Med
ian
Ser
um
AC
TH
(p
g/m
L)
Baseline Month 3 Month 6
Lupron 12.5 mg Proellex 25 mg Proellex 50 mg Proellex
Phase 1/2 Endometriosis TrialBone Resorption Marker (β-Cross Laps)
0
0.1
0.2
0.3
0.4
0.5
0.6
Baseline Month 3 Month 6
Lupron 12.5 mg Proellex 25 mg Proellex 50 mg Proellex
Lupron 3 mo v.s. BL p = 0.023Proellex all doses mo 3 & 6 v.s. BL p NS
n=10
n=8 n=7
Β-c
ross
lap
s (n
g/m
L)
Combined Safety SummaryZPU-003 and ZPE-002
1. Liver function– Endometriosis study – no abnormals– Fibroid study – No abnormals except
• 1 - gall stones – treated with cholecystectomy• 2 with elevated enzymes and viral hepatitis• 1 - asymptomatic autoimmune hepatitis +ve ANA
2. Bone metabolism – no significant effects in either study3. Hormones
• LH and FSH unchanged• Estrogen maintained within physiological levels
4. Chemistry and ECGs – no change5. Most common drug related side effects (>%% incidence)
– Amenorrhea: 78.6% - expected drug effect
– Hot Flashes: 16.7%
T8A 20
Endometrial Safety Overview
Commonly Asked Questions1. Uterine Bleeding2. Endometrial thickening
and histology
Study/Pt Treatment/
Duration
Age Findings Event and Outcome
ZPE-002
02-201
Proellex 12.5 mg
5 months
37/C Mo. 3 ET 19 mm
Mo. 5 ET 25 mm
Spotting 21 days after treatment stopped and severe uterine bleeding at 42 days. D&C. Full recovery
ZPE-002
02-202
Proellex 25 mg
5 months
29/C Mo. 4 ET 37 mm
Mo. 5 ET 62 mm
Severe uterine bleeding 19 days after treatment stopped. D&C. Full recovery
ZPE-002
03-216
Proellex 50 mg
5 1/2 months
35/C Mo. 0 ET 11 mm
Mo. 3 ET 11 mm
Mo. 6 ET 21 mm
Moderate bleeding at 5.5 mo on Rx – severe bleeding at 1 mo later. D&C. Full recovery.
ZPE-002
03-209
Proellex 50 mg
6 months
32/C Mo. 0 ET 8 mm
Mo. 3 ET 11 mm
Mo. 6 ET 20 mm
Bleeding at 6 mo on treatment. Increased in severity over 2 days. D&C. Full recovery
Proellex Safety – Uterine Bleeding
Phase 1/2 Endometriosis TrialZPE-002: Endometrial Thickness and Bleeding
Endometrial Thickening
• Post-menopausal women ET ≤ 5-7 mm (literature)• ET 9-20mm+ in placebo treated premenopausal
women• Normal cyclical shedding and regeneration of the
endometrium every 28 days• Prevention of normal endometrial shedding in pre-
menopausal women treated with Proellex® results in histological changes which may result in unscheduled bleeding.
Phase 1/2 Endometriosis TrialZPE-002 Endometrial Thickness
0
5
10
15
20
25
BL Mo 3 Mo 6 Mo 9 F/U
Mea
n T
hic
knes
s m
m
Lupron
12.5mg
25mg
50mg
Phase 2 Uterine Fibroid TrialZPU-003 Endometrial Thickness
0123456789
10
Me
dia
n T
hic
kn
es
s m
m
BL Mo 1 Mo 2 Mo 3
Placebo 12.5 mg 25 mg
Management of Endometrial Thickening and Uterine Bleeding
Endometrial thickening occurs with – Prolonged treatment exposure– Lower dose after 3 months treatment exposure
Uterine bleeding– Severe and unscheduled occurred only when the ET exceeded 20mm– When treatment duration exceeded 5 months
Therefore both endometrial thickening and the risk of severe bleeding can be managed by
1. Treatment cycles of 4 months duration2. Allow an “off-drug interval” until menstruation resumes (4-6 weeks after
drug stopped)3. Resume treatment on day 3-10 of the new menstrual cycle
29 women have gone through 3 treatment cycles successfully in the UF Extension study
Overall Conclusions
• Proellex is an effective medical treatment for– Endometriosis
• rapid cessation and reduction of pain – Uterine fibroids
• Rapid and maintained reduction in bleeding• Significant restoration of QOL• Rapid recovery of anemia
• Proellex safety profile very encouraging– No consistent involvement of any organ system – Issues of ET and unscheduled bleeding – prospective
management paradigm has been developed which makes medical management of endometriosis and uterine fibroids safe and effective
– Endometrial histology• Benign endometrium with class related secondary findings