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

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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

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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

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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

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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

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5

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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

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5

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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