1 DepoCyt®: Enrollment Completed Oncology Drugs Advisory Committee November 8, 2005 Gordon L. Schooley, Ph.D. Chief Scientific Officer SkyePharma Inc.

2 Sustained release formulation of cytarabine (ara-C) Ara-C is encapsulated in the chambers of 20  m particles made up of phospholipids and cholesterol After intrathecal injection, the particles spread throughout neuraxis & slowly release ara-C over 2 – 3 weeks Indication: lymphomatous meningitis Accelerated approval date: April 1, 1999 DepoCyte™ (cytarabine liposome injection): NDA

3 DepoCyte ventricular CSF pharmacokinetics Free ara-C concentration (Ph I trial) Time (Days) Free ara-C Concentration (  g/mL) mg, DepoCyt 30 mg, Free Ara-C T 1/2  3.4 h T 1/2  141 h Assumed Minimum Cytotoxic Level Ventricular injection/ventricular sampling

4 Basis of approval: High Cytological response rate in lymphomatous meningitis patients No. randomized and receiving drug No. responders Response rate % % ara-CDepoCyt (P ≤ 0.04)

5 Phase IV Commitments A controlled randomized trial to determine patient benefit (clinical endpoint) and safety of DepoCyt® for the treatment of lymphomatous meningitis A pharmacokinetic study Trial to be initiated in 6 months (by 9/99)

6 DepoCyt SKY Phase IV Study Objective: Confirm clinical benefits of DepoCyt® vs. standard therapy in adult patients with lymphomatous or solid tumor neoplastic meningitis Design: Prospective, open-label, randomized, controlled Primary endpoint: Progression-free survival Neurological evaluation prior to treatment & start of each Tx cycle investigators decision that progression has occurred Documented with specific signs and symptoms Secondary endpoints: Survival, cytological response rate & chemistries (start & end of cycles) Improvements in neurological symptoms, quality of life, safety

7 DepoCyt SKY Phase IV Study Key Eligibility Criteria: Biopsy proven lymphoma or malignant solid tumor Neoplastic meningitis diagnosed on basis of: Positive CSF cytology, or Characteristic signs and symptoms plus an MRI or CT scan indicating presence of meningeal tumor

8 SKY controlled trial – Schematic All patients received 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 50mg ara-C or 10mg MTX 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 Stratification: lymphoma vs. solid tumor, USA vs. EC

9 SKY PK Study Objective: To evaluate CSF PK of free and total ara-C following intraventricular administration of DepoCyt® Study Sites: 2 sites in Europe Accrual: 12 subjects were treated & provided PK samples

10 DepoCyt NDA Status: Phase IV Commitment Study SKY Initiated: 9/99 Enrollment completed: 11/04 Study SKY Initiated: 9/04 Enrollment completed: 4/05 Submit final study reports Dec. 2005

11 DepoCyt Phase IV Status: Timelines Study Initiated: 9/99 Sponsor-initiated product recall: 10/99 Product re-introduced: 3/01 Study Re-initiated: 7/01 Enrollment completed: 11/04 Study Report: 12/ mo 4.5 yr

12 DepoCyt Phase IV Status: Patient Accrual Total study sites:45 (25 sites recruited patients) North America26 (12 sites recruited patients) EU19 (13 sites recruited patients) Total patients recruited 124USA/CanEurope Solid tumor Lymphoma Accrual rates U.S. / Canada / EU:~3.0 patients/mo U.S. / Canada~1.5 patients/mo (~2.9/mo in phase III) Ave. enrollment of ~1 patient per site per year Ave. enrollment of ~1 LM patient per site per 4 yrs.

13 Schematic of DepoCyte trials Solid Tumor Neoplastic Meningitis (STNM) 61 Patients DepoCyte vs. MTX Lymphomatous Meningitis (LM) 33 pts. Lymphoma 5 pts. DepoCyte vs. ara-C Phase I 19 Patients Phase IV 110 Patients Phase I Pediatric 19 Patients European PK Study 13 Patients USA PK Study 11 Patients SKYE & -011 LM: 24 Patients STNM: 100 Patients PK: 12 Patients DepoCyt N=296

14 Study Design Challenges It was anticipated – Enrollment of ≥ 75 LM pts. within 5 years was not possible NOTE: Only 24 LM patients were enrolled in 4 years In response – Solid tumor neoplastic meningitis patients were included in the study population Consequence Study population different than DepoCyt NDA population Increase in study variability due to multiple populations Sample size for LM sub-group analysis too small

15 Study Design Challenges One Example Availability of higher-resolution imaging equipment- Imaging widely used for diagnosis of neoplastic meningitis In Response – Investigator demands - phase IV inclusion criteria expanded - Beyond positive cytology used in phase III to include patients with positive MRI/CT scan Consequence – <50% of patients have cytology available for assessment Progression free survival (PFS) ~½ compared to phase III Did reliance upon CNS imaging (or other factors) have an impact upon type of LM patients enrolled? Ability to detect meaningful PFS differences compromised

16 Challenges to study completion Few number of lymphomatous meningitis cases –Only a small fraction available for trial participation Trial participation vs. off-study treatment –DepoCyt commercially available – no interest in participation –Fear of randomization to cytarabine group  4 intrathecal injections (IT) per cycle vs. one per cycle of DepoCyt  Quality of life issue with only months of survival remaining Competition for patients –Competiting clinical studies for lymphomatous meningitis patients

17 Challenges to study completion North America recruitment rate too slow to meet Phase IV commitment in a timely manner In response European study sites were recruited Standards of care & patient management Differences: Europe vs. US & Canada – increase in variability Study site-to-site variability – increase from 26 to 45 study sites Consequence - - Data from European sites complicated data interpretation

18 Summary Questions Has the Post marketing study commitment been fulfilled? Draft report sent to FDA although analysis continues Next step: SkyePharma - FDA discussion

19 Summary Questions Does this study provide useful information? Safety – yes. Efficacy – To be determined as confounding factors on a small sample of lymphomatous meningitis treated patients is problematic and subject to additional analysis

20 Summary Questions Is it feasible to conduct a confirmatory trial of a clinical endpoint in lymphomatous meningitis (LM) To conduct of a study in lymphomatous meningitis within a reasonable time frame (~5 yrs) some compromises must be (were) made that may confound the interpretation of the data To enroll sufficient number of patients based on most clinical endpoints in a controlled study may take years.