1. 1 Presented by Martin Cohen, M.D. at the Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee

2. 2 NDA 21-673 Clofarabine Cl-F-Ara-A

3. 3 Indication Clofarabine is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens

4. 4 Clofarabine Dose and Schedule Recommended pediatric dose is 52 mg/m2 intravenously over 1 to 2 hours daily for 5 consecutive days. Treatment cycles are repeated every 2 to 6 weeks following recovery or return to baseline organ function.

5. 5 Clofarabine Pediatric ALL Studies ProtocolSponsorPhase# of Pts CLO-212Genzyme249 ID-99-383MDACC117

6. 6 Primary Objectives CR: - no circulating blasts or extramedullary disease; - an M1 bone marrow (< 5% blasts); and - platelets >100,000/mcL and ANC >1,000/mcL). CRp: Patients who have met all criteria for CR except for recovery of platelet counts to > 100,000/mcL.

7. 7 Phase 2 ALL Inclusion criteria Age < 21 > 25% marrow blasts Second or subsequent relapse and/or refractory Ambulatory performance status Adequate organ status

8. 8 Phase 2 Study 14 Sites – all in the United States - Independent response review panel - Independent pathology review

9. 9 ALL - Demographics and KPS VariableN=49 Age [median (range)12 (1 - 20) Sex Female Male 20 (41%) 29 (59%) Ethnicity Hispanic Caucasian Other 20 (41%) 9 (18%) KPS 100 90-80 70-50 15 (31%) 19 (39%) 14 (29%)

10. 10 ALL - Prior Therapies Prior therapyN=49 Median number of prior induction regimens (range) 3 (2 -6) Prior transplants 1 2 13 (27%) 2 (4%)

11. 11 ALL - Best Response Response CategoryN=49% CR 6 12 CRp48

12. 12 Response Duration – No Transplant CR (days)CRp (days) 43 50 82 93+ 160+ 32

13. 13 Safety Summary Toxicity was as expected for a heavily pretreated acute leukemia population receiving cytotoxic therapy. Principal toxicities were nausea, vomiting, diarrhea, hematologic toxicity, fever and febrile neutropenia, hepatobiliary toxicity, infections and renal toxicity. SIRS, tumor lysis syndrome, multi-organ failure, hypotension and left ventricular systolic dysfunction can also occur.

14. 14 Efficacy Summary Pediatric ALL Primary endpoint (CR + CRp) –6 CR’s (12%) and 4 CRp’s (8%) among 49 treated patients. –1 patient in CR and 3 in CRp went to transplant –Duration of response confounded by transplantation Granted Accelerated Approval (Subpart H) –Postmarketing study to verify and describe clinical benefit