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DepoCyt®: Enrollment Completed

Oncology Drugs Advisory Committee

November 8, 2005

Gordon L. Schooley, Ph.D.Chief Scientific Officer

SkyePharma Inc.

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• 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 21-041

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DepoCyte ventricular CSF pharmacokinetics Free ara-C concentration (Ph I trial)

Time (Days)0 7 14 21

Fre

e ar

a-C

Co

nce

ntr

atio

n (g

/mL

)

0.01

0.1

1

10

10050 mg, DepoCyt

30 mg, Free Ara-C

T1/23.4 h

T1/2141 h

AssumedMinimumCytotoxic

Level

Ventricular injection/ventricular sampling

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Basis of approval: High Cytological response rate in

lymphomatous meningitis patients

No. randomized and receiving drug

No. responders

Response rate

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7

41%

16

1

6%

ara-CDepoCyt

(P ≤ 0.04)

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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)

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DepoCyt SKY0101- 010Phase 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

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DepoCyt SKY0101- 010Phase 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

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SKY0101-010 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)

RANDOMIZATION

IT 50mg ara-Cor 10mg MTX

Induction 6 cycles

Every 2 wksX 12 Weeks

Twice a wkX 12 wks

Month

Every 4 wksX 16 Weeks

Once a wk X 16 wks

Treatment

Maintenance 4 cycles

Every MonthX 6 Months

Every other month x 12

months

0 3 7 12 24

Every MonthX 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

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SKY0101-011 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

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DepoCyt NDA 21-041 Status: Phase IV Commitment

Study SKY0101-010 • Initiated: 9/99

• Enrollment completed: 11/04

Study SKY0101-011• Initiated: 9/04• Enrollment completed: 4/05

Submit final study reports Dec. 2005

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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: 12/05

2001 2002 2003 2004 2005 2006

17 mo

4.5 yr

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DepoCyt Phase IVStatus: Patient Accrual

Total study sites: 45 (25 sites recruited patients)North America 26 (12 sites recruited patients)EU 19 (13 sites recruited patients)

Total patients recruited 124 USA/Can EuropeSolid tumor 100 51 49Lymphoma 24 14 10

Accrual ratesU.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.

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Schematic of DepoCyte trials

Solid Tumor Neoplastic Meningitis (STNM)

61 PatientsDepoCyte vs. MTX

Lymphomatous Meningitis (LM) 33 pts.

Lymphoma 5 pts.DepoCyte vs. ara-C

Phase I19 Patients

Phase IV 110 Patients

Phase I Pediatric19 Patients

European PK Study13 Patients

USA PK Study11 Patients

SKYE0101-010 & -011 LM: 24 PatientsSTNM: 100 Patients PK: 12 PatientsDepoCyt N=296

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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

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Study Design ChallengesOne 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 IIIDid reliance upon CNS imaging (or other factors) have an impact upon type of LM patients enrolled?

Ability to detect meaningful PFS differences compromised

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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

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Challenges to study completion

North America recruitment rate too slow to meet Phase IV commitment in a timely manner

In response - - 19 European study sites were recruited Standards of care & patient management

Differences: Europe vs. US & Canada – increase in variabilityStudy site-to-site variability – increase from 26 to 45 study sites

Consequence - - Data from European sites complicated data interpretation

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Summary Questions

Has the Post marketing study commitment been fulfilled?

Draft report sent to FDA although analysis continues

Next step: SkyePharma - FDA discussion

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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

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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 10-15 years.