1. CLOLAR™(clofarabine) Pediatric Subcommittee ODAC Meeting 20 October 2005

2. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 2 Rekha Abichandani, MD Medical Director, Clinical ResearchRekha Abichandani, MD Medical Director, Clinical Research Marie Bonneterre, MD Medical Director, Clinical ResearchMarie Bonneterre, MD Medical Director, Clinical Research Stephen Eckert, PhD Senior Director, BiostatisticsStephen Eckert, PhD Senior Director, Biostatistics Manny Fernandez Manager, Clinical ResearchManny Fernandez Manager, Clinical Research Mark Hayes, PhD Vice President, Regulatory AffairsMark Hayes, PhD Vice President, Regulatory Affairs Edda Tschirhart Associate, Regulatory AffairsEdda Tschirhart Associate, Regulatory Affairs Mike Vasconcelles, MD Vice President, Clinical ResearchMike Vasconcelles, MD Vice President, Clinical Research Genzyme participants

3. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 3 Agenda IntroductionIntroduction Pre-approval clinical development highlightsPre-approval clinical development highlights Post-approval clinical development plansPost-approval clinical development plans Clinical development risks and challengesClinical development risks and challenges SummarySummary

4. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 4 Treatments for newly diagnosed patients with ALL use aggressive multi-drug regimensTreatments for newly diagnosed patients with ALL use aggressive multi-drug regimens 21% ALL have relapsed/refractory disease21% ALL have relapsed/refractory disease Relapsed leukemia is the third most common childhood cancerRelapsed leukemia is the third most common childhood cancer Relapsed and refractory pediatric leukemia

5. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 5 Annual incidence of pediatric ALL (SEER) 2,470 Pediatric ALL 2,347 95% CR 124 5% Refractory 375 16% Relapse 499 Pediatric ALL Patients

6. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 6 Heterogeneous populationHeterogeneous population Multi-drug resistance is common in leukemia cells, particularly at relapseMulti-drug resistance is common in leukemia cells, particularly at relapse Dose intensification with combination therapies has resulted in significant co-morbidities and organ dysfunctionDose intensification with combination therapies has resulted in significant co-morbidities and organ dysfunction Transplant is the best curative option but requires disease control and time to identify donorTransplant is the best curative option but requires disease control and time to identify donor Challenges in relapsed and refractory Pediatric leukemia

7. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 7 Clofarabine is the first drug specifically approved for pediatric leukemia in 20 yearsClofarabine is the first drug specifically approved for pediatric leukemia in 20 years Most commonly used agents approved many years agoMost commonly used agents approved many years ago –methotrexate (1953) –6-mercaptopurine (1953) –vincristine (1963) –Ara-C (1969) –doxorubicin (1974) Development of new pediatric oncology agents has lagged behind adult oncology drug developmentDevelopment of new pediatric oncology agents has lagged behind adult oncology drug development Approved agents for relapsed or Refractory pediatric leukemia

8. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 8 deoxyadenosine cladribine fludarabine clofarabine Nucleoside analogs dAdo and its analogs Resistant to Deamination Resistant to Phosphorolysis

9. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 9 clofarabine dCK dNTP pool DNA incorporation Inhibition of DNA synthesis/ repair CELL DEATH clofarabine P P P Polymerase , ε Cytochrome C Release 5’NT Mitochondria ΔΨ m RNR Transporter Mechanism of action

10. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 10 Agenda IntroductionIntroduction Pre-approval clinical development highlightsPre-approval clinical development highlights Post-approval clinical development plansPost-approval clinical development plans Clinical development risks and challengesClinical development risks and challenges SummarySummary

11. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 11 19991999200020002001200120022002 2003200320042004 Pre-approval development timeline Adult studies  Phase I Solid/Hem Malignancies (DM93-036) (N=51)  Phase I CLL (DM99-225) (N=11)  Phase II AML, ALL, MDS, CML (ID00-038) (N=62)  Phase II AML (CLO 221) (N=40)  Phase I/II COMBO: CLO+ Ara-C, AML, MDS (CLO 141) (N=32) (CLO 141) (N=32) Pediatric studies  Phase I Hem Malignancies (ID99-383)(N=25)  Phase II AML (CLO 222) (N=35)  Phase II ALL (CLO 212) (N=49)  Phase II AML (BIVN-121) (N=65) (N=65)

12. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 12 Key regulatory milestones for Pediatric acute leukemia 200320032004200420042004FebJulMarAug Dec 01 Dec 28 Orphan drug designation Fast track designation Rolling NDA submission completed Efficacy update submitted ODAC recommends accelerated approval (in relapsed and refractory pediatric ALL) FDA grants approval

13. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 13 EfficacyEfficacy –Single Phase II study of 49 patients (CLO 212) –Pediatric ALL: Second or subsequent relapse and/or refractory –Clofarabine single agent –Endpoint: overall response (CR + CRp=20%) SafetySafety –113 pediatric leukemia patients (includes AML patients) Basis for approval

14. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 14 Approved indication On 28 Dec 2004, FDA granted marketing approval for clofarabine for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory ALL after at least two prior regimensOn 28 Dec 2004, FDA granted marketing approval for clofarabine for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory ALL after at least two prior regimens Approval wasApproval was –under provisions of accelerated approval regulations, and –based on the induction of complete responses Sponsor required to conduct a randomized, Phase III post-marketing study demonstrating clinical benefitSponsor required to conduct a randomized, Phase III post-marketing study demonstrating clinical benefit

15. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 15 Agenda IntroductionIntroduction Pre-approval clinical development highlightsPre-approval clinical development highlights Post-approval clinical development plansPost-approval clinical development plans Clinical development risks and challengesClinical development risks and challenges SummarySummary

16. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 16 Initial pediatric ALL post-approval Clinical development plan Step 1Step 1 –Phase I / II dose-escalation study of CLO plus Ara-C and L-asparaginase (L-asp) in refractory or relapsed ALL Step 2Step 2 –Randomized Phase III study of (Ara-C + L-asp) ± CLO in pediatric ALL in first relapse Concepts from COG protocol AALL01P2Concepts from COG protocol AALL01P2 Innovative, yet complicated, multi-agent designInnovative, yet complicated, multi-agent design

17. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 17 Original proposed Phase III design First relapse Block 1 vincristineprednisonePEG-asparaginasedoxorubicinIT cytarabine IT methotrexate MRD Block 3-A Ara-CL-asp Block 3-B clofarabineAra-CL-asp Block 2 etoposidecyclophosphamideIT methotrexate MRD

18. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 18 FDA comments on Proposed development plan Agreed to step 1 (Phase I / II combination)Agreed to step 1 (Phase I / II combination) Stated that step 2 (Phase III) “does not appear to have a realistic chance of showing a clinical benefit of clofarabine in children with ALL in first relapse”Stated that step 2 (Phase III) “does not appear to have a realistic chance of showing a clinical benefit of clofarabine in children with ALL in first relapse” COG AALL01P2 designed to identify optimal combination therapies for patients with ALLCOG AALL01P2 designed to identify optimal combination therapies for patients with ALL Genzyme’s understanding is that the complex multi-agent design would make it difficult to isolate the clinical benefit of clofarabineGenzyme’s understanding is that the complex multi-agent design would make it difficult to isolate the clinical benefit of clofarabine

19. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 19 Additional issue with Proposed development plan Combination CLO + Ara-C + L-asp did not have wide investigator supportCombination CLO + Ara-C + L-asp did not have wide investigator support –Potential toxicity concerns Ara-C + L-asp already “maximally toxic”Ara-C + L-asp already “maximally toxic” Thus, may not be able to effectively dose-escalate clofarabineThus, may not be able to effectively dose-escalate clofarabine

20. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 20 Revised pediatric ALL post-approval Clinical development plan Step 1Step 1 –Conduct at least two Phase I / II combination studies CLO + cyclophosphamide + etoposide (protocol CLO 21800205)CLO + cyclophosphamide + etoposide (protocol CLO 21800205) CLO + Ara-C (protocol COG AAML0523)CLO + Ara-C (protocol COG AAML0523) Step 2Step 2 –Build from Phase II results to design appropriate randomized Phase III study to demonstrate clinical benefit

21. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 21 Potential Phase III study design Randomized Phase III Study of combination selected based on the results of the Phase I/II studiesRandomized Phase III Study of combination selected based on the results of the Phase I/II studies Patient populationPatient population –1 st relapse –2 nd /Subsequent relapse Potential endpointsPotential endpoints –Event free survival –Remission rate/duration of remission –Overall survival FDA/Genzyme to discuss details of the Phase III study design once data available from the Phase I/II studiesFDA/Genzyme to discuss details of the Phase III study design once data available from the Phase I/II studies

22. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 22 Pediatric leukemia development timeline Post-approval 200520052006200620072007  Phase I / II CLO+etoposide+cyclophosphamide (CLO 21800205) (N=39)  Phase II CLO+Ara-C (COG AAML0523) (N=70)  Phase III comparator ± CLO (N=TBD) New pediatric studies New adult studies  Phase 3 Ara-C +/- CLO (CLO 34100405) (N=~360)  Phase 3 CLO vs low dose Ara-C (CLO-34200505) (N=~360)

23. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 23 Agenda IntroductionIntroduction Pre-approval clinical development highlightsPre-approval clinical development highlights Post-approval clinical development plansPost-approval clinical development plans Clinical development risks and challengesClinical development risks and challenges SummarySummary

24. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 24 Risks and challenges with Pediatric ALL development proposal No standard chemotherapeutic options in second or subsequent relapsed or refractory diseaseNo standard chemotherapeutic options in second or subsequent relapsed or refractory disease –Challenge: No standard comparator arm Defining an appropriate primary endpoint for a Phase III studyDefining an appropriate primary endpoint for a Phase III study –Allogeneic SCT only potentially curative option –Challenge: SCT may confound remission duration and potentially other endpoints Small patient population (~500 per year)Small patient population (~500 per year) –Competing clinical trials –Challenge: Difficult to enroll Phase III trial in reasonable timeframe

25. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 25 Agenda IntroductionIntroduction Pre-approval clinical development highlightsPre-approval clinical development highlights Post-approval clinical development plansPost-approval clinical development plans Clinical development risks and challengesClinical development risks and challenges SummarySummary

26. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 26 In the 10 months since receiving approval, Genzyme has made progress toward meeting post-marketing commitmentsIn the 10 months since receiving approval, Genzyme has made progress toward meeting post-marketing commitments –Initial plan proposed and required revision –One Phase I / II trial initiated: CLO 21800205 –Second Phase II protocol (collaboration with COG) finalized: AAML0523 Many challenges to designing an appropriate confirmatory trial, particularly in relapsed or refractory ALLMany challenges to designing an appropriate confirmatory trial, particularly in relapsed or refractory ALL Genzyme looks forward to collaborating with FDA and COG to face these challengesGenzyme looks forward to collaborating with FDA and COG to face these challenges Summary

27. 20 Oct 2005ODAC Pediatric Subcommittee: Clofarabine 27 CLOLAR™(clofarabine) Pediatric Subcommittee ODAC Meeting 20 October 2005