Proellex

1
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 Antagonist _at_ 10-10 M
• Low affinity for corticosteroid receptors
• GR Antagonist _at_ 10-6 M
• RU-486gtCDB-2914gtCDB-4059gtProellex
• Anti-progestin effect oral (in vitro)
  ProellexgtCDB4059gtCDB-2914gtRU-486
• Androgenic No activity
• Antiandrogenic Weak activity
• Glucocorticoid No activity

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ZPE-002Endometriosis safety studyZPU-003Phase
II Uterine Fibroid Study

• Efficacy Findings

4
Phase 1/2 Endometriosis TrialProof of Concept
Safety Study

• Patient Population and Treatment
• N39
• 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

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Phase 1/2 Endometriosis TrialReduction 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) plt 0.05
• Lupron not statistically different from 12.5mg
  and 25mg Proellex dose

Range of pain free days
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ZPU-003Phase 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

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ZPU-003Phase II Uterine Fibroid Study Pictoral
Blood Loss - MITT Population
12.5 and 25 mg p lt 0.0001 vs Pl
Mean PBAC Score mL
MITT - All subjects who received study
medication and have one post-dose primary
efficacy measurement
8
ZPU-003Phase II Uterine Fibroid Study UFSQOL
Symptom Severity Questions 1-8
High score gt severity Month 3 significance
values v.s. placebo 12,5and 25 mg p lt0.0001
Spies et al, Obstetrics Gynecology, vol. 99,
No. 2, February 2002
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ZPU-003Phase 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 0.0016
Spies et al, Obstetrics Gynecology, vol. 99,
No. 2, February 2002
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ZPU-003Phase II Uterine Fibroid Study
Hemoglobin lt11.5 g/DL MITT Population
MITT - All subjects who received study
medication and have one post-dose primary
efficacy measurement
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ZPU-003Phase 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-003Phase II Uterine Fibroid Study Fibroid
Volume Reduction at Month 3- Ultrasound

Volume reduction
p 0.6
p 0.017
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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 lt 0.0001)
• Severity of symptoms UFSQOL (p lt 0.0001) and
  HRQOL improve over 3 months (p lt 0.025 12.5 mg
  p lt 0.002 25 mg)
• Associated reduction in pain (statistically
  significant)

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ZPE-002Endometriosis safety studyZPU-003Phase
II Uterine Fibroid Study

• Safety Findings

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ZPU-003Phase II Uterine Fibroid Study Number
() of Subjects with Treatment Emergent Adverse
Events for Reproductive System and Breast
Disorders (gt5 Prevalence Safety Subjects)
AE Profile Proellex 12.5 mg N44 n () Proellex 25 mg N40 n () Placebo N43 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 All other adverse events in other body systems similar to placebo All other adverse events in other body systems similar to placebo All other adverse events in other body systems similar to placebo
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ZPU-003Phase II Uterine Fibroid Study Proellex
Effects on Estradiol and Progesterone
P NS vs Pl
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Phase 1/2 Endometriosis TrialACTH
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Phase 1/2 Endometriosis TrialBone Resorption
Marker (ß-Cross Laps)
Lupron 3 mo v.s. BL p 0.023 Proellex all doses
mo 3 6 v.s. BL p NS
n7
n8
n10
?-cross laps (ng/mL)
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Combined Safety SummaryZPU-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 (gt
  incidence)
• Amenorrhea 78.6 - expected drug effect
• Hot Flashes 16.7

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Endometrial Safety Overview

• Commonly Asked Questions
• Uterine Bleeding
• 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. DC. 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. DC. 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. DC. 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. DC. Full recovery
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Phase 1/2 Endometriosis TrialZPE-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.

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Phase 1/2 Endometriosis TrialZPE-002 Endometrial
Thickness
25
Phase 2 Uterine Fibroid TrialZPU-003 Endometrial
Thickness
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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

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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