Presented at the March 13, 2003 Oncologic Drugs Advisory Committee meeting By Stephen Howell, M.D. Skyepharma, Inc.

1. Presented at the March 13, 2003 Oncologic Drugs Advisory Committee meeting By Stephen Howell, M.D. Skyepharma, Inc.

2. DepoCyte® (cytarabine liposome injection): NDA 21-041 • Sustained release formulation of cytarabine (ara-C) developed in 1987 • Ara-C is encapsulated in the chambers of 20 mm particles made up of phospholipids and cholesterol • After intrathecal injection the particles spread throughout the neuraxis and slowly release ara-C over 2 – 3 weeks • Indication: lymphomatous meningitis • Accelerated approval date: April 1, 1999 • Total drug development time: 11 years

3. DepoCyt ara-C 17 7 41% No. randomized and receiving drug No. responders Response rate 16 1 6% p=0.04 Basis of approval: High response rate in patients with lymphomatous meningitis

4. Clinical trials in NDA Solid Tumor Neoplastic Meningitis 61 Patients Phase IV 89 Patients Phase I 19 Patients Lymphomatous Meningitis 33 Patients Leukemia Meningitis 5 Patients Confirmatory PK Study 11 Patients European PK Study 13 Patients

5. Interim analysis4Q2001 Enrollment complete 9/02 Start 9/99 Report complete 2/04 Approval 4/99 1999 2000 2001 2002 2003 2004 Post-marketing commitment • A controlled, randomized trial to determine the patient benefit and safety of DepoCyt for the treatment of solid tumor neoplastic and lymphomatous meningitis • Trial to include a pharmacokinetic substudy • Trial to be initiated within 6 months • Total elapsed time:  4.5 years 4.5 yrs

6. SKY0101-010 controlled trial – Objective • Purpose: • Confirm the “clinical benefit” of DepoCyt treatment for patients with lymphomatous and solid tumor neoplastic meningitis • Provide additional evidence to support approval for solid tumor neoplastic meningitis • Design: prospective, randomized controlled • Primary endpoint: time to neurological progression • Secondary endpoints: • Survival • Improvement in neurological symptoms • Quality of life • Cytologic response rate • Safety • Interim assessment dropped

7. SKY0101-010 controlled trial – Eligibility criteria • Biopsy proven lymphoma or malignant solid tumor • Neoplastic meningitis diagnosed on basis of: • A positive CSF cytology within 21 days prior to randomization, OR • Characteristic signs and symptoms and an MRI or CT scan showing meningeal tumor • Age 18 years

8. Treatment Follow up Visits Solid tumor or lymphoma Induction 6 cycles Maintenance 4 cycles RANDOMIZATION Positive CSFcytology or CNS imaging Every 4 wks X 16 Weeks Every other month x 12 months Every 2 wks X 12 Weeks Every Month X 6 Months IT DepoCyt (50 mg) 0 3 7 12 24 Month IT standard therapy Every other month x 12 months Twice a wk X 12 wks Every Month X 6 Months Once a wk X 16 wks Stratifcation: lymphoma vs solid tumor, USA vs EC Patients on both arms are to receive dexamethasone 4 mg BID Days 1 – 5, 2 mg BID day 6, 1 mg BID day 7 of each cycle. SKY0101-010 controlled trial – Schematic

9. Treatment Follow up Visits Induction 6 cycles Maintenance 4 cycles RANDOMIZATION Every 4 wks X 16 Weeks Every other month x 12 months Every 2 wks X 12 Weeks Every Month X 6 Months IT DepoCyt (50 mg) Positive CSFcytology or CNS imaging 0 3 7 12 24 Month IT MTX (10 mg) Every other month x 12 months Twice a wk X 12 wks Every Month X 6 Months Once a wk X 16 wks Leucovorin 10 mg po q6h x 8 doses starting 24 hr after each dose of MTX Patients on both arms are to receive dexamethasone 4 mg BID Days 1 – 5, 2 mg BID day 6, 1 mg BID day 7 of each cycle. SKY0101-010 controlled trial – Schematic for patients with solid tumor neoplastic meningitis

10. Treatment Follow up Visits Induction 6 cycles Maintenance 4 cycles RANDOMIZATION Every 4 wks X 16 Weeks Every other month x 12 months Every 2 wks X 12 Weeks Every Month X 6 Months IT DepoCyt (50 mg) Positive CSFcytology or CNS imaging 0 3 7 12 24 Month IT ara-C (50 mg) Every other month x 12 months Twice a wk X 12 wks Every Month X 6 Months Once a wk X 16 wks Patients on both arms are to receive dexamethasone 4 mg BID Days 1 – 5, 2 mg BID day 6, 1 mg BID day 7 of each cycle SKY0101-010 controlled trial – Schematic for patients with lymphomatous meningitis

11. SKY0101-010 controlled trial – Evaluation • Neurological evaluation prior to treatment and at the beginning of each treatment cycle plus at each follow up visit • Detailed documentation of the basis for concluding that neurological progression has occurred • CSF cytology and chemistries at start of and end of each cycle • Adverse events occurring from 21 days prior to start of treatment through 28 days after last dose

12. Primary statistical analyses planned All patients randomized to DepoCyt (solid tumor & lymphoma) Analysis #1 All patients randomized to compator drug (either MTX or ara-C) (solid tumor & lymphoma) Solid tumor patients randomized to DepoCyt Analysis #2 Solid tumor patients randomized to MTX • Powered to detect a 50% reduction in the hazard function for time to neurologic progression in patients with solid tumor neoplastic meningitis. Estimated number of events necessary = 75 •  = 0.8,  = 0.038 (adjusted for multiple comparisons)

13. Post-marketing trial execution • Trial set up began immediately after approval • Investigator selection, IRB approvals, and contracts completed and trial opened 10/99 • All DepoCyt recalled from market 10/99: • No product available for clinical trials for 17 mo • FDA approved re-introduction 3/01 • Trial re-initiation began immediately in 3/01 • Investigator selection/site qualification • IRB approval • Contract negotiation • First patient entered 7/3/01

14. Interim analysis4Q2001 Enrollment complete 9/02 Report complete 2/04 Start 9/99 Approval 4/99 1999 2000 2001 2002 2003 2004 Original and revised timelines are the same 4.5 yr Drug availabale 3/01 Enrollment complete 8/04 Report complete 8/05 Start 7/01 17 mo 2001 2002 2003 2004 2005 2006 4.1 yr

15. Product recall • Oct 1999: some lots of DepoCyt found to release excess cytarabine on stability testing • Raw material supplier made unannounced change in manufacturing process of one lipid that eliminated small amount of EDTA • EDTA replaced, product again available March 2001 • New assays to assure quality of raw materials established

16. SKY0101-010 – Current patient accrual • Total study sites: 37 • USA - 16 • EU - 19 • Canada - 2 • Total patients entered: 57 • Solid tumor - 43 • Lymphoma - 14 • Accrual rate to date  2.4 patients/mo • Accrual rate last 6 months  4.7 patients/mo • Accrual rate of prior pivotal trial 2.9 patients/mo

17. SKY0101-010 – Current patient accrual • Total patients entered: 57 • USA/Canada - 38 • Solid tumor - 26 • Lymphoma –12 • Europe - 19 • Solid tumor - 17 • Lymphoma - 2

18. Challenges to study completion • Very limited number of cases/yr • Only a small fraction available for trial participation • Trial participation vs off-study treatment • Randomization reluctance: • Patient concern about possibility of having to receive 4 intrathecal injections (standard therapy) vs just 1 injection every 2 weeks (DepoCyt) • Competition for patients • Other drugs under development for this indication

19. THANK YOU