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 MRU-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 studyZPU-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
Free
Day
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*
0204060
80100120140160
BL Mo 1 Mo 2 Mo 3
PlaceboProellex 12.5 mgProellex 25 mg
Mea
n PB
AC
Sco
re m
L
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
UFS
QO
L Sy
mpt
om S
core
BL Mo 1 Mo 2 Mo 3
Placebo12.5 mg Proellex25 mg ProellexNormal
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
0102030405060708090
100
UFS
QO
L SC
OR
E
BL Mo 1 Mo 2 Mo 3
Placebo12.5 mg Proellex25 mg ProellexNormal
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
PlaceboProellex 12.5 mgProellex 25 mg
Mea
n H
emog
lobi
n g/
dL
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
05
1015202530354045
% w
omen
pai
n fr
ee a
fter 3
m
onth
s
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 studyZPU-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=44n (%)
Proellex 25 mg
N=40n (%)
PlaceboN=43n (%)
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
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60
80
100
120
140
BL Mo 3
Placebo 12.5mg 25mg
0
1
2
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6
BL Mo 3
Placebo 12.5mg 25mg
Mea
n Es
trog
en p
g/m
L
Prog
este
rone
ng/
mL
P NS vs Pl
Phase 1/2 Endometriosis TrialACTH
0
5
10
15
20
25
30
Med
ian
Seru
m A
CTH
(pg/
mL)
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)
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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
laps
(ng/
mL)
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 OverviewCommonly Asked Questions1. Uterine Bleeding2. Endometrial thickening
and histology
Study/Pt Treatment/ Duration
Age Findings Event and Outcome
ZPE-00202-201
Proellex 12.5 mg5 months
37/C Mo. 3 ET 19 mmMo. 5 ET 25 mm
Spotting 21 days after treatment stopped and severe uterine bleeding at 42 days. D&C. Full recovery
ZPE-00202-202
Proellex 25 mg5 months
29/C Mo. 4 ET 37 mmMo. 5 ET 62 mm
Severe uterine bleeding 19 days after treatment stopped. D&C. Full recovery
ZPE-00203-216
Proellex 50 mg5 1/2 months
35/C Mo. 0 ET 11 mmMo. 3 ET 11 mmMo. 6 ET 21 mm
Moderate bleeding at 5.5 mo on Rx – severe bleeding at 1 mo later. D&C. Full recovery.
ZPE-00203-209
Proellex 50 mg6 months
32/C Mo. 0 ET 8 mmMo. 3 ET 11 mmMo. 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
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20
25
BL Mo 3 Mo 6 Mo 9 F/U
Mea
n Th
ickn
ess
mm
Lupron12.5mg25mg50mg
Phase 2 Uterine Fibroid TrialZPU-003 Endometrial Thickness
0123456789
10
Med
ian
Thic
knes
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