Transcript Slide 1

Proellex®
For the Treatment of Uterine Fibroids and Endometriosis
1
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
Efficacy Findings
ZPE-002
Endometriosis safety study
ZPU-003
Phase II Uterine Fibroid Study
T8A
3
Phase 1/2 Endometriosis Trial
Proof of Concept Safety Study
• Patient Population and Treatment
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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 Trial
Reduction in Pain
% Pain Free Days – 6 Months of Treatment
*
100
90
% Pain Free Days
80
70
60
• 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
50
40
30
20
= Range of pain free days
10
0
Lupron
12.5 mg Proellex
25 mg Proellex
50 mg Proellex
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:
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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*
Mean PBAC Score mL
160
12.5 and 25 mg
p < 0.0001 vs Pl
140
120
100
Menorrhagia
80
60
40
Placebo
Proellex 12.5 mg
Proellex 25 mg
20
0
BL
Mo 1
Mo 2
Mo 3
MITT* - All subjects who received study medication and have one post-dose primary efficacy measurement
ZPU-003
Phase II Uterine Fibroid Study
UFSQOL – Symptom Severity Questions 1-8
High score > severity
Month 3 significance values v.s. placebo; 12,5and 25 mg p <0.0001
UFSQOL Symptom Score
60
50
40
Placebo
12.5 mg Proellex
25 mg Proellex
Normal
30
20
10
0
BL
Mo 1
Mo 2
Mo 3
Spies et al, Obstetrics & Gynecology, vol. 99, No. 2, February 2002
ZPU-003
Phase II Uterine Fibroid Study
UFSQOL – Total Score
High HRQL scores indicate better HRQL
UFSQOL SCORE
Month 3 significance values v.s. placebo; 12,5 mg p = 0.024; 25 mg p = 0.0016
100
90
80
70
60
50
40
30
20
10
0
Placebo
12.5 mg Proellex
25 mg Proellex
Normal
BL
Mo 1
Mo 2
Mo 3
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*
Mean Hemoglobin g/dL
13
p values vs placebo
12
11
Mo 1
Mo 2
Mo 3
12.5mg
0.51
0.0002
0.016
25mg
1.0
0.0009
0.0008
10
9
8
Placebo
Proellex 12.5 mg
Proellex 25 mg
7
6
BL
Mo 1
Mo 2
Mo 3
MITT* - All subjects who received study medication and have one post-dose primary efficacy measurement
ZPU-003
Phase II Uterine Fibroid Study
Shift of Pain to No Pain – BL to 3 Months
Comparison: pain present at baseline to no pain at 3 months
Placebo p NS,
Proellex 12.5 mg p 0.034,
Proellex25 mg p 0.008
% women pain free after 3
months
45
40
35
30
25
Placebo
12.5 mg Proellex
25 mg Proellex
20
15
10
5
0
Month 3
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)
Safety Findings
ZPE-002
Endometriosis safety study
ZPU-003
Phase II Uterine Fibroid Study
T8A
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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
12.5mg
25mg
Placebo
140
6
120
5
100
80
P NS vs Pl
60
40
12.5mg
25mg
4
3
P NS vs Pl
2
1
20
0
Progesterone ng/mL
Mean Estrogen pg/mL
Placebo
BL
Mo 3
0
BL
Mo 3
Phase 1/2 Endometriosis Trial
ACTH
Median Serum ACTH (pg/mL)
30
25
20
15
10
5
0
Baseline
Lupron
12.5 mg Proellex
Month 3
25 mg Proellex
Month 6
50 mg Proellex
Phase 1/2 Endometriosis Trial
Bone Resorption Marker (β-Cross Laps)
Lupron 3 mo v.s. BL p = 0.023
Proellex all doses mo 3 & 6 v.s. BL p NS
Β-cross laps (ng/mL)
0.6
0.5
n=7
n=8
0.4
0.3
n=10
0.2
0.1
0
Baseline
Lupron
Month 3
12.5 mg Proellex
25 mg Proellex
Month 6
50 mg Proellex
Combined Safety Summary
ZPU-003 and ZPE-002
1.
Liver function
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Endometriosis study – no abnormals
Fibroid study – No abnormals except
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1 - gall stones – treated with cholecystectomy
2 with elevated enzymes and viral hepatitis
1 - asymptomatic autoimmune hepatitis +ve ANA
Bone metabolism – no significant effects in either study
Hormones
2.
3.
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LH and FSH unchanged
Estrogen maintained within physiological levels
Chemistry and ECGs – no change
Most common drug related side effects (>%% incidence)
4.
5.
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Amenorrhea: 78.6% - expected drug effect
Hot Flashes: 16.7%
Endometrial Safety Overview
Commonly Asked Questions
1. Uterine Bleeding
2. Endometrial thickening
and histology
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Proellex Safety – Uterine Bleeding
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
Phase 1/2 Endometriosis Trial
ZPE-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 premenopausal women treated with Proellex® results
in histological changes which may result in
unscheduled bleeding.
Phase 1/2 Endometriosis Trial
ZPE-002 Endometrial Thickness
Mean Thickness mm
25
20
Lupron
12.5mg
25mg
50mg
15
10
5
0
BL
Mo 3
Mo 6
Mo 9 F/U
Phase 2 Uterine Fibroid Trial
ZPU-003 Endometrial Thickness
Median Thickness mm
Placebo
12.5 mg
25 mg
10
9
8
7
6
5
4
3
2
1
0
BL
Mo 1
Mo 2
Mo 3
Management of Endometrial Thickening
and Uterine Bleeding
Endometrial thickening occurs with
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Prolonged treatment exposure
Lower dose after 3 months treatment exposure
Uterine bleeding
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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.
2.
3.
Treatment cycles of 4 months duration
Allow an “off-drug interval” until menstruation resumes (4-6 weeks after
drug stopped)
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