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

2 Sustained release formulation of cytarabine (ara-C) developed in 1987 Ara-C is encapsulated in the chambers of 20  m 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 DepoCyte ® (cytarabine liposome injection): NDA

3 Basis of approval: High response rate in patients with lymphomatous meningitis No. randomized and receiving drug No. responders Response rate % % ara-CDepoCyt p=0.04

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

5 Post-marketing commitment l A controlled, randomized trial to determine the patient benefit and safety of DepoCyt for the treatment of solid tumor neoplastic and lymphomatous meningitis l Trial to include a pharmacokinetic substudy l Trial to be initiated within 6 months l Total elapsed time:  4.5 years Start 9/99 Interim analysis 4Q2001 Enrollment complete 9/02 Report complete 2/ Approval 4/ yrs

6 SKY controlled trial – Objective l 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 l Design: prospective, randomized controlled l Primary endpoint: time to neurological progression l Secondary endpoints:  Survival  Improvement in neurological symptoms  Quality of life  Cytologic response rate  Safety l Interim assessment dropped

7 SKY controlled trial – Eligibility criteria l Biopsy proven lymphoma or malignant solid tumor l 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 l Age  18 years

8 SKY controlled trial – Schematic 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. Follow up Visits IT DepoCyt (50 mg) RANDOMIZATIONRANDOMIZATION IT standard therapy Induction 6 cycles Every 2 wks X 12 Weeks Twice a wk X 12 wks Month Every 4 wks X 16 Weeks Once a wk X 16 wks Treatment Maintenance 4 cycles Every Month X 6 Months Every other month x 12 months Every Month X 6 Months Every other month x 12 months Positive CSF cytology or CNS imaging Solid tumor or lymphoma Stratifcation: lymphoma vs solid tumor, USA vs EC

9 SKY controlled trial – Schematic for patients with solid tumor neoplastic meningitis Positive CSF cytology or CNS imaging Follow up Visits IT DepoCyt (50 mg) RANDOMIZATIONRANDOMIZATION IT MTX (10 mg) Induction 6 cycles Every 2 wks X 12 Weeks Twice a wk X 12 wks Month Every 4 wks X 16 Weeks 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. Treatment Maintenance 4 cycles Every Month X 6 Months Every other month x 12 months Every Month X 6 Months Every other month x 12 months Leucovorin 10 mg po q6h x 8 doses starting 24 hr after each dose of MTX

10 SKY controlled trial – Schematic for patients with lymphomatous meningitis Follow up Visits IT DepoCyt (50 mg) RANDOMIZATIONRANDOMIZATION IT ara-C (50 mg) Induction 6 cycles Every 2 wks X 12 Weeks Twice a wk X 12 wks Month Every 4 wks X 16 Weeks 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 Treatment Maintenance 4 cycles Every Month X 6 Months Every other month x 12 months Every Month X 6 Months Every other month x 12 months Positive CSF cytology or CNS imaging

11 SKY controlled trial – Evaluation l 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 l CSF cytology and chemistries at start of and end of each cycle l Adverse events occurring from 21 days prior to start of treatment through 28 days after last dose

12 Primary statistical analyses planned Analysis #1 All patients randomized to DepoCyt (solid tumor & lymphoma) All patients randomized to compator drug (either MTX or ara-C) (solid tumor & lymphoma) Analysis #2 Solid tumor patients randomized to DepoCyt 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,  = (adjusted for multiple comparisons)

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

14 Original and revised timelines are the same Start 9/99 Interim analysis 4Q2001 Enrollment complete 9/02 Report complete 2/ Approval 4/99 Start 7/01 Enrollment complete 8/04 Report complete 8/ Drug availabale 3/ yr 17 mo 4.1 yr

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

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

17 SKY – Current patient accrual l Total patients entered: 57  USA/Canada - 38 »Solid tumor - 26 »Lymphoma –12  Europe - 19 »Solid tumor - 17 »Lymphoma - 2

18 Challenges to study completion l Very limited number of cases/yr  Only a small fraction available for trial participation l 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) l Competition for patients  Other drugs under development for this indication

19 THANK YOU