1. Doxil® (doxorubicin HCl liposome injection)
Doxil in the Treatment of Advanced, Metastatic Ovarian Cancer
Oncologic Drugs Advisory Committee Meeting June 8, 1999

2. Proposed New Indication
Doxil (doxorubicin HCl liposomal injection) is indicated for:
The treatment of patients with metastatic carcinoma of the ovary who are refractory to both paclitaxel- and platinum-based chemotherapy regimens and who may also be refractory to topotecan. Refractory is defined as a patient having progressive disease while on treatment, or within 6 months of treatment.

3. Agenda
Unmet Medical Need: Maurie Markman, MD, Director Cleveland Clinic Taussig
Cancer Center
STEALTH® Technology Frank Martin, PhD,
and Doxil Pharmacology: Principal Scientist
Efficacy of Doxil: Ed Schnipper, MD, VP, Clinical Research
Safety of Doxil: Ken Cunningham, MD, VP, European Clinical Research
Risk/Benefit: Ed Schnipper, MD, VP, Clinical Research

4. Experts Available for Questions
Consultants
Alan Gordon, MD, Sammons Cancer Center, Dallas
William McGuire, MD, University of Mississippi
Franco Muggia, MD, NYU Medical Center
Sponsor Representatives
Martin O’Connell, PhD, Sr Dir, Biostatistics
Randy Allred, Dr PH, Dir, Biostatistics
Peter Working, PhD, VP, Nonclinical Research
Tim Sharpington, Assoc Dir, Clinical Research
Tom Tarlow, Director, Regulatory Affairs

5. Agenda
Unmet Medical Need: Maurie Markman, MD, Cleveland Clinic Taussig
Cancer Center

6. Overview of Ovarian Cancer
25,200 patients diagnosed in US in 1999
14,500 deaths
70% present with advanced disease
Standard treatment is with platinum and paclitaxel
Despite improvements with combination therapy
>20% fail to respond to first-line chemotherapy
80% ultimately relapse

7. Patient Population Definitions for “second line therapy”
Sensitive patients (those who have a durable response >6 months) likely to respond to retreatment
Refractory patients (those who progressed while on or within 6 months of treatment) unlikely to respond to retreatment

8. Chemotherapy Agents Approved for Second Line Treatment in Ovarian Cancer
Paclitaxel (Taxol)
Altretamine (Hexalen)
Topotecan (Hycamtin)

9. Response Rates of Approved Agents in Second Line Treatment
Platinum/
Platinum/ Platinum/ Paclitaxel/
Paclitaxel Topotecan Topotecan
Agent Failure* Failure* Refractory
Topotecan 9.4% - -
Paclitaxel - 2.7% -
Altretamine - - -
* Does not necessarily meet strict definition of refractory

10. Factors Affecting Response
Patients are less likely to respond if they:
Progress while receiving platinum therapy
Progress after receiving multiple regimens

11. Patients with Ovarian Cancer
Relapse common
Long survival
Good Performance Status

12. Medical Need
Need for options and alternative treatments for patients who experienced toxicity on prior therapy:
Neurotoxicity
Bone marrow toxicity
Nausea/Vomiting

13. Quality of Life Patients treated for long periods
Need for agents which are well tolerated and convenient for patients

14. Agenda
Unmet Medical Need: Maurie Markman, MD, Cleveland Clinic Taussig
Cancer Center
STEALTH® Technology Frank Martin, PhD,
and Doxil Pharmacology: Principal Scientist

15. Lipid Membrane (Phospholipid +
Structure of Doxil
Doxorubicin
Lipid Membrane (Phospholipid +
Cholesterol) nm
Polyethylene Glycol 3

16. Plasma Levels of Total and Liposome-Encapsulated Doxorubicin after Doxil
25.00
10.00
Total Doxorubicin
5.00
Doxorubicin (g/mL)
2.50
Encapsulated Doxorubicin
1.00
0.50
0.25 1 2 3 4 5 6 7
Days After Infusion
Single 50 mg/m2 dose of Doxil
Mean values ± SD for 14 patients, mixed histologies
Gabizon et al, Cancer Res (1994)

17. Doxorubicin Levels in Prostate Carcinoma Xenograft
Doxil AUC = 919
Adriamycin AUC = 36.5 4 6 8 2
µg Drug/gm Tumor
Doxil
Adriamycin 50
100
150
200
Hours
Vaage J, et al. Cancer, 1994

18. Gamma Scan of Kaposi’s Sarcoma Patient
4 hr.
24 hr.
48 hr.
96 hr.

19. Doxorubicin in KS Lesions and Normal Skin (Biopsy at 48 Hrs
Doxorubicin in KS Lesions and Normal Skin (Biopsy at 48 Hrs. after Doxil) 25 20
K S Lesion
Normal Skin 15
Doxorubicin Concentration (mg/g) 10 5 1 2 3 4 5 6 7
Patient Number

20. Doxil Activity in Kaposi’s Sarcoma
Non-comparative Results in Refractory Patients N
42 23
Response
48% 52%
All Patients Prior Adria
Product Label
Randomized Trials N
62 64
Response
46% 25%
59% 23%
79% 80%
Doxil vs ABV
Doxil vs BV
Doxil vs Doxil + BV
Northfelt et al, JCO (1998)
Stewart et al, JCO (1998)
Mitsuyasu et al, Proc ASCO (1997)

21. Doxil Activity in Ovarian Carcinoma Xenograft (HEY)
140
Saline control
120
Adriamycin
(6 mg/Kg)
100 80
Mean Tumor Volume (mm)3 60 40
Doxil
(6 mg/Kg) 20 7 14 21 28 35 42 49
Days After Tumor Implantation
Vaage J, et al, Cancer (1993)

22. Rationale for Exploring Ovarian Indication
Preclinical activity superior to Adriamycin
Activity in heavily pretreated ovarian patients in Phase I trial (Muggia et al, JCO 1995)
1 PR
3 minor responses (CA125 , tumor shrinkage <50%)
1 disease stabilization

23. Agenda
Unmet Medical Need: Maurie Markman, MD, Cleveland Clinic Taussig
Cancer Center
STEALTH® Technology Frank Martin, PhD,
and Doxil Pharmacology: Principal Scientist
Efficacy of Doxil: Ed Schnipper, MD, VP, Clinical Research

24. Doxil Regulatory History in Ovarian Cancer
Clinical development program initiated 8/94
Orphan designation 11/98
sNDA (50-718, 006) in advanced ovarian cancer 12/98
Priority review 3/99

25. Doxil in Refractory Ovarian Cancer
Doxil is active
Doxil is generally well tolerated
Doxil is convenient

26. Program Overview Phase II non-comparative studies
3 studies in relapsed or refractory ovarian cancer
30-22, 30-47, and 30-47E
Phase III randomized comparative trial (study 30-49)
Doxil vs Topotecan
Second line following failure of platinum containing regimen

27. Design of Phase II Studies
Three multicenter non-comparative studies
All contained relapsed or refractory patients
Refractory defined as disease progression while receiving, or within 6 months of receiving prior therapy
Plat/Pac Refractory - patients refractory to both platinum and paclitaxel
Plat/Pac/Topo Refractory - patients refractory to platinum, paclitaxel, and topotecan

28. Endpoints of Phase II Studies
Primary endpoint was response rate
All responses based on measurable disease (SWOG criteria)
All responses confirmed
Independent radiological review
Secondary endpoints
Time to progression
Duration of response
Survival
Safety

29. Dosing in Phase II Studies
Study Initial Dosing Regimen
mg/m2 q 3 weeks
mg/m2 q 4 weeks
30-47E 50 mg/m2 q 4 weeks
Median dose received in all 3 studies
was 50 mg/m2 q 4 weeks

30. Demographics of Phase II Studies
Study Study Study 30-47E (n = 35) (n = 89) (n = 52)
Sites 2 (US) 18 (US) 14 (Europe)
Median age
Patients Plat/Pac
refractory
Patients Plat/Pac/Topo

31. Demographics of Phase II Studies
Study Study Study 30-47E (n = 35) (n = 89) (n = 52)
Months from
prior regimen
No. of prior regimens % 14.6% 19.2% % 52.8% 63.5% % 32.6% 17.3% % % - -

32. Study 30-22 - Response Data Responders 6 (21.4%)
Plat/Pac (n = 28)
Responders 6 (21.4%)
Complete 1 (3.6%) Partial 5 (17.9%)
95% CI (6.2%, 36.6%)
Stable disease 10 (35.7%)

33. Study 30-47 - Response Data Plat/Pac Plat/Pac/Topo (n = 49) (n = 33)
Responders 9 (18.4%) 6 (18.2%)
Complete (3.0%) Partial 9 (18.4%) 5 (15.2%)
95% CI (7.5%, 29.2%) (5.0%, 31.3%)
Stable disease 16 (32.6%) 15 (45.5%)

34. Study 30-47E - Response Data
Refractory patients - no responders

35. Comparative Demographics of Refractory Patients
Studies Study
30-47 and E
Median CA
Median bulky disease
Median duration of treatment (days)

36. Summary of Response Rates in ITT Refractory Patients
Combined Study Plat/Pac Plat/Pac/Topo Refractory
% %
% 18.2% 18.3%
30-47E 0% 0% 0%
Total 14.6% 14.0% 14.4%
95% CI (7.8% %) (3.6% %) (8.7% %)
(n = 103) (n = 43) (n= 146)

37. Response Rate by Time to Progression on Platinum Therapy
on Doxil
Patients who progressed:
on treatment (n = 70) 10%
<3 months after treatment (n = 20) 25%
3-6 months after treatment (n = 50) 18%

38. Duration of Response Median duration of response = 39.4 weeks
100
Median duration of
response = 39.4 weeks 80 60
Probability 40 20
Combined refractory, n=21 7 14 21 28 35 42 49 56 63
Weeks Since First Dose

39. Time to Progression Median TTP = 15.9 weeks Probability
100 80
Median TTP = 15.9 weeks 60
Probability 40
Combined refractory, n=146 20 15 30 45 60 75 90
105
120
Weeks Since First Dose

40. Time to Progression and Time to Decrease in Karnofsky Score Combined Refractory, (n=146)
100 90 80 70 60 50 40 30 20 10
Time to Progression
Time to Decrease in Karnofsky Score
Probability
Weeks Since First Dose
Slide 40

41. Phase III Randomized Comparative Trial (Study 30-49)
Study design
Second line study following failure of platinum-containing regimen
Patients randomized to receive
Doxil 50 mg/m2 q 4 weeks or
Topotecan 1.5 mg/m2 x 5 d q 3 weeks
Patients with measurable disease
Primary endpoint — time to progression
Secondary endpoints — response rate, duration of response, survival, and safety

42. Study 30-49 90 sites in US and Europe Target of 460 patients accrued
First planned interim analysis
200 evaluable patients (237 ITT) with at least 6 months follow-up
Patients stratified as platinum refractory or sensitive
Subset of 81 patients met the definition of Plat/Pac refractory

43. Interim Response Data - Study 30-49 Plat/Pac refractory patients
Doxil Topotecan
(n = 44) (n = 37)
Responders 6 (13.6%) 3 (8.1%)
Complete Partial 6 (13.6%) 3 (8.1%)
95% CI (3.5%, 23.8%) (0.0%, 16.9%)
Stable disease 15 (34.1%) 16 (43.2%)

44. Percentage Reduction in Lesion Area in Combined Refractory Patients (Studies 30-22, 30-47, 30-49, n=27)

45. Efficacy Summary from Phase II Studies
Response 14.4% in refractory patients
Duration of response 39.5 weeks
TTP 15.9 weeks

46. Agenda
Unmet Medical Need: Maurie Markman, MD, Cleveland Clinic Taussig
Cancer Center
STEALTH® Technology Frank Martin, PhD,
and Doxil Pharmacology: Principal Scientist
Efficacy of Doxil: Ed Schnipper, MD, VP, Clinical Research
Safety of Doxil: Ken Cunningham, MD, VP, European Clinical Research

47. 5 studies in ovarian cancer 16 studies in a variety of solid tumors
Safety Population
5 studies in ovarian cancer
Total patients 408
16 studies in a variety of solid tumors
Total patients 772
Kaposi’s sarcoma
Total patients 1721

48. Drug Exposure

49. Summary of Dosing Information for Ovarian Patients (n = 408)
Median cycle dose mg/m2
Median cycle length 29.5 days
Cumulative dose
Median mg/m2
Range ( )

50. Mean Dose Intensity per Week in Ovarian Patients (n=408)
12.5 10
7.5
mg/m2/week 5
Intended
Actual
2.5 1 2 3 4 5 6 7 8
Cycle

51. Adverse Events

52. Percent of Patients by Severity of Adverse Events (Ovarian Patients, n=396)

53. Drug Related Adverse Events Reported in >10% of Ovarian Patients (n=396)
Percent of Patients
PPE Nausea Rash Alopecia Mucositis Diarrhea
Stomatitis Asthenia Vomiting Constipation Anorexia

54. Hematologic Laboratory Data, Ovarian Patients (n=408)
Grade III Grade IV Comment
Neutropenia 19.6% 8.6% Growth Factor %
Anemia 23.5% 16.4% RBC Trans %
Epo %
Thrombocytopenia 0.5% 0.7% Platelet Trans 0.5%

55. Withdrawals Due to Drug-Related AEs, Ovarian Patients (n=396)
Total withdrawals 11.0%
Five most common AEs
PPE or other skin toxicity 3.5%
Cardiovascular disorder 1.0%
Stomatitis 0.8%
Asthenia %
Infusion reactions 0.5%

56. Palmar-Plantar Erythrodysesthesia (PPE) Management

57. PPE - Grading and Management
Symptoms Dose Adjustment
Grade I Mild erythema Redose, unless previous Grade III/IV
Grade II Erythema with Delay 1-2 weeks or until desquamation resolved to Grade 0-I
Grade III Blistering Delay 1-2 weeks or until resolved to Grade 0-I. Then redose at 75%
Grade IV Diffuse As for Grade III

58. Cardiotoxicity

59. Cardiotoxicity
0.8% (6/772) withdrew due to cardiotoxicity related to Doxil
5 asymptomatic LVEF declines
1 CHF (after 22 cycles — mg/m2)
5 additional drug related cardiac events, all Grade I

60. Cardiac Safety Doxil PK mimics continuous infusion of doxorubicin
Preclinical - Less cardiotoxic1
Biopsies in 10 KS patients (469 to 860 mg/m2) show minimal cardiotoxicity (Billingham scores ; median 0.3)2
Biopsies in 4 solid tumor patients (675 to 1680 mg/m2) show minimal cardiotoxicity (Billingham scores 0-1.5)
1 Working et al, JPET (1999)
2 Berry, et al, Ann Oncol (1998)

61. Phase III Randomized Comparative Trial (Study 30-49)
Doxil - 50 mg/m2 every 4 weeks
Topotecan mg/m2 x 5 days every 3 weeks

62. Terminations and Dose Modifications (Study 30-49)
Doxil Topotecan (n = 135) (n = 132)
Patient still on study 45.2% 40.2%
Termination due to adverse events 6.7% 9.1%
Delayed, interrupted or reduced doses % Patients 44.4% 65.9% % Cycles 32.1% 49.9%

63. Percent of Patients by Severity of Adverse Events (Study 30-49)

64. Doxil’s 5 Most Frequent Drug-Related Adverse Events (Study 30-49)80
Doxil
Topotecan
Grade III, IV 70
Grade I, II 60 50
Percent Patients 40 30 20 10
PPE
Stomatitis
Anemia
Asthenia
Nausea

65. Topotecan’s 5 Most Common Drug-Related Adverse Events (Study 30-49)
Doxil
Topotecan 80
Grade III, IV 70
Grade I, II 60 50
Percent Patients 40 30 20 10
Neutropenia
Alopecia
Leukopenia
Anemia
Thrombocytopenia

66. Safety Summary Generally well tolerated
PPE is the most common adverse event and is manageable
Adverse event profile is predictable

67. Agenda
Unmet Medical Need: Maurie Markman, MD, Cleveland Clinic Taussig
Cancer Center
STEALTH® Technology Frank Martin, PhD,
and Doxil Pharmacology: Principal Scientist
Efficacy of Doxil: Ed Schnipper, MD, VP, Clinical Research
Safety of Doxil: Ken Cunningham, MD, VP, European Clinical Research
Risk/Benefit: Ed Schnipper, MD, VP, Clinical Research

68. Summary
No approved therapy
Objective response rate of 14.4%
Duration of response of 39.4 weeks
Generally well tolerated
Convenient monthly dosing

69. Conclusions
Doxil is active in patients with ovarian cancer who are refractory to platinum and paclitaxel and who may also be refractory to Topotecan
Doxil represents a valuable addition to the treatment options for these patients