1. For the Treatment of Uterine Fibroids and Endometriosis
Proellex®
For the Treatment of Uterine Fibroids and Endometriosis

2. Proellex – CBD 4124 Overview of Pharmacology
Progesterone receptor modulator (PRM) with specific potential advantages
High affinity and selectivity; pure PR antagonist
PR M
Low affinity for corticosteroid receptors
GR 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

3. Efficacy Findings
ZPE-002 Endometriosis safety study ZPU-003 Phase II Uterine Fibroid Study
T8A

4. Phase 1/2 Endometriosis Trial Proof of Concept Safety Study
Patient Population and Treatment
N=39
Laparoscopic diagnosis of endometriosis
Pain symptom severity mild to moderate
Age 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

5. Phase 1/2 Endometriosis Trial Reduction in Pain
% Pain Free Days – 6 Months of Treatment *
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
= Range of pain free days

6. 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

7. ZPU-003 Phase II Uterine Fibroid Study Pictoral Blood Loss - MITT Population*
12.5 and 25 mg
p < vs Pl
Mean PBAC Score mL
Menorrhagia
MITT* - All subjects who received study medication and have one post-dose primary efficacy measurement

8. 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
Spies et al, Obstetrics & Gynecology, vol. 99, No. 2, February 2002

9. ZPU-003 Phase II Uterine Fibroid Study UFSQOL – Total Score
High HRQL scores indicate better HRQL Month 3 significance values v.s. placebo; 12,5 mg p = 0.024; 25 mg p =
Spies et al, Obstetrics & Gynecology, vol. 99, No. 2, February 2002

10. ZPU-003 Phase II Uterine Fibroid Study Hemoglobin <11
ZPU-003 Phase II Uterine Fibroid Study Hemoglobin <11.5 g/DL MITT Population*
Mean Hemoglobin g/dL
0.0008
0.0009
1.0
25mg
0.016
0.0002
0.51
12.5mg
Mo 3
Mo 2
Mo 1
p values vs placebo
MITT* - All subjects who received study medication and have one post-dose primary efficacy measurement

11. 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

12. ZPU-003 Phase II Uterine Fibroid Study Fibroid Volume Reduction at Month 3- Ultrasound*
% Volume reduction
p = 0.6*
p = 0.017*

13. 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 < )
Severity of symptoms UFSQOL (p < ) and HRQOL improve over 3 months (p < [12.5 mg] – p < [25 mg])
Associated reduction in pain (statistically significant)

14. Safety Findings
ZPE-002 Endometriosis safety study ZPU-003 Phase II Uterine Fibroid Study
T8A

15. 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
Placebo
N=43
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

16. ZPU-003 Phase II Uterine Fibroid Study Proellex Effects on Estradiol and Progesterone
Mean Estrogen pg/mL
Progesterone ng/mL
P NS vs Pl
P NS vs Pl

17. Phase 1/2 Endometriosis Trial ACTH

18. 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
n=8
n=7
n=10
Β-cross laps (ng/mL)

19. Combined Safety Summary ZPU-003 and ZPE-002
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
Bone metabolism – no significant effects in either study
Hormones
LH and FSH unchanged
Estrogen maintained within physiological levels
Chemistry and ECGs – no change
Most common drug related side effects (>%% incidence)
Amenorrhea: 78.6% - expected drug effect
Hot Flashes: 16.7%

20. Endometrial Safety Overview
Commonly Asked Questions
Uterine Bleeding
Endometrial thickening and histology

21. 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
02-202
Proellex 25 mg
29/C
Mo. 4 ET 37 mm
Mo. 5 ET 62 mm
Severe uterine bleeding 19 days after treatment stopped. D&C. Full recovery
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.
03-209
6 months
32/C
Mo. 0 ET 8 mm
Mo. 6 ET 20 mm
Bleeding at 6 mo on treatment. Increased in severity over 2 days. D&C. Full recovery

22. Phase 1/2 Endometriosis Trial ZPE-002: Endometrial Thickness and Bleeding

23. 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.

24. Phase 1/2 Endometriosis Trial ZPE-002 Endometrial Thickness

25. Phase 2 Uterine Fibroid Trial ZPU-003 Endometrial Thickness

26. 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
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

27. 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