CAMPATH ® (alemtuzumab): Status of Phase IV Post-marketing Commitments

1. CAMPATH® (alemtuzumab): Status of Phase IV Post-marketing Commitments Oncology Drugs Advisory Committee 8 Nov 2005 Cynthia Sirard, MD

2. Genzyme Participants • Susan Beardslee Principal Medical Writer, Scientific Reporting • Stephen Eckert, Ph.D. Senior Director, Biostatistics • Mark Goldberg, M.D. Senior Vice President, Clinical Research • Mark Hayes, Ph.D. Vice President, Regulatory Affairs • Jeanne Jones, RN, MSN Director, Clinical Research • Tracie Reed Senior Associate, Regulatory Affairs • Cynthia Sirard, M.D. Medical Director, Clinical Research ODAC CAMPATH Update

3. Agenda • Overview of treatment options for CLL • CAMPATH®: Review of data supporting approval • Review and status of post-approval commitments: CAM307 • Resolving challenges in meeting post-approval commitments ODAC CAMPATH Update

4. Chronic Lymphocytic Leukemia (CLL) • Most common form of adult leukemia in U.S. • Incidence: ~ 9,730 patients/year • Prevalence: ~ 60,000 patients • Progressive and often fatal disease • Deaths: ~4,600/year • No current therapy is curative • No therapy has demonstrated prolonged survival ODAC CAMPATH Update

5. What is CLL and How is it Treated? Disease Characteristics 1st line therapy 9,730 Incidence Evolving standards of care: • Alkylator-based • Fludarabine • Rituximab • Combination • Chronic disease • Variable clinical course • Often asymptomatic at dx (no treatment required) • Requires multiple sequential treatments • Treatment goal • Palliative • Curative? • MRD No response Relapsed/ refractory therapy 60,000 Prevalence • Re-tx with 1st line agents • Fludarabine • Rituximab • CAMPATH • 2nd line cytotoxic • PBSCT/ BMT • Clinical trials Response Remission Relapse/ progression ODAC CAMPATH Update

6. CAMPATH-1H (alemtuzumab) • Humanized monoclonal antibody directed against CD52 antigen • Expressed on B & T lymphocytes, NK cells, DCs, Mono/Mac, plasma cells, Thymocytes • Not expressed on bone marrow progenitor cells Carbohydrate Human IgG1 construct Murine CDR’s ODAC CAMPATH Update

7. Complement CAMPATH Leukemia Cell CD52 FC Receptor Effector cell Mechanism of action • Lyses lymphocytes via • Complement fixation • Antibody dependent cell mediated cytotoxicity • Induction of apoptosis • Different mechanism of action from available cytotoxic chemotherapeutic agents ODAC CAMPATH Update

8. Pivotal and Supportive Studies for ApprovalPatient Population ODAC CAMPATH Update

9. Pivotal and Supportive Studies for ApprovalEfficacy Results ODAC CAMPATH Update

10. Pivotal and Supportive Studies for ApprovalSafety • Most common adverse events are acute infusion-related events that decline with subsequent infusions • Variety of opportunistic infections reported; anti-infective prophylaxis is recommended on initiation of therapy • Hematologic toxicity which can be severe emerges on treatment in some patients, but is usually transient • Reasonable and manageable safety profile in this immunocompromised, refractory disease population ODAC CAMPATH Update

11. Accelerated Approval Granted 7 May 2001 • Indication • CAMPATHis indicated for the treatment of B-cell chronic lymphocytic leukemia (CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy • Nine post-approval commitments • Five completed • Four are ongoing • Three will be completed in Q1 2006 at the conclusion of randomized phase III study (CAM307) initiated in 2001 • Final commitment to be completed in a study being initiated in 2005 (CAM203) ODAC CAMPATH Update

12. CAMPATH Post-marketing CommitmentsCompleted ODAC CAMPATH Update

13. CAMPATH Post-marketing CommitmentsOngoing ODAC CAMPATH Update

14. CAM307Overview • Title • A Phase III Study to Evaluate the Efficacy and Safety of Front-Line Therapy with CAMPATH (alemtuzumab) versus Chlorambucil in Patients with Progressive B-Cell Chronic Lymphocytic Leukemia • Purpose • Verify the clinical benefit of CAMPATH therapy • General design • Open label, multi-center, randomized, active controlled trial ODAC CAMPATH Update

15. CAM307Objectives • Primary objective • To demonstrate that CAMPATH is superior to chlorambucil as front-line therapy in patients with progressive B-CLL as measured by progression free survival (PFS) • Secondary objectives are to compare treatment arms with respect to • Overall survival • CR and overall response rates • Duration of response (not statistically compared) • Time to treatment failure • Time to alternative therapy • Safety ODAC CAMPATH Update

16. CAM307Inclusion Criteria • Histopathologically confirmed diagnosis of B-CLL with CD5, CD19 and CD23 positive clone • Rai stage I through IV disease with evidence of progression • No previous chemotherapy for B-CLL • WHO performance status of 0, 1, or 2 • Serum creatinine ≤ 2.0 X the institutional upper limit of normal • Adequate liver function ODAC CAMPATH Update

17. CAM307Exclusion Criteria • ANC < 0.5 x 109/L or platelet count < 10 x 109/L • Autoimmune thrombocytopenia • Active infection • Serious cardiac or pulmonary disease • Central nervous system involvement with CLL • Positive quantitative CMV by PCR assay ODAC CAMPATH Update

18. CAM307Treatment Arms • Patients randomized 1:1 to receive either • CAMPATH • 30 mg/day IV • Dosing is 3 times per week, up to 12 total weeks, inclusive of any dose escalation period or • Chlorambucil • 40 mg/m2 PO • Dosing once every 28 days for a maximum of 12 months ODAC CAMPATH Update

19. CAM307Accrual Status • Total Enrollment = 297 patients • 149 patients enrolled on CAMPATH • 148 patients enrolled on Chlorambucil • Last patient enrolled 15 Jul 2004 • Accruing / active sites • 45 / 68 Total • 9 / 20 US sites ODAC CAMPATH Update

20. Poland Croatia Czech Republic Serbia United States Slovakia Netherlands Lithuania France Italy United Kingdom Estonia Ireland CAM307Patient Accrual Distribution 117 47 39 28 24 12 9 8 4 3 3 2 1 ODAC CAMPATH Update

21. CAM307Statistical Design • Randomization 1:1 by Interactive Voice Response System (IVRS) • Primary endpoint assumption • 50% improvement in PFS (21 months vs. 14 months) • Sample size • 284 patients (142 per treatment arm) ODAC CAMPATH Update

22. CAM307Interim and Final Analyses • April 2004 • First interim analysis (safety only) was conducted after 50 patients per arm reached 4 months following randomization • August 2005 • Second interim analysis (safety and efficacy) was completed after 95 patients progressed (or died) • Q2 2006 (projected) • Final analysis planned after a total of 190 failures (progressed/died) ODAC CAMPATH Update

23. CAM307Status and Timelines ODAC CAMPATH Update

24. CAM307Difficulties Encountered • Initial enrollment at U.S. sites slow, likely due to alternative first-line therapeutic options for CLL patients in U.S. • Enrollment increased substantially following opening of sites outside United States (particularly in eastern Europe) ODAC CAMPATH Update

25. CAM307Difficulties Encountered • Logistical difficulties encountered in immunological function assessment cohort. Data captured for only 4 patients in CAM307. • In a recent discussion with the Division of Oncology Drug Products (29 July 2005), Genzyme will fulfill this commitment in a new trial CAM203 ODAC CAMPATH Update

26. CAM203 A Phase II, open-label, prospective, multi-center study to evaluate the efficacy and safety of subcutaneously administered CAMPATH as therapy for patients with relapsed or refractory B-CLL who have previously received treatment with an alkylating agent and failed fludarabine ODAC CAMPATH Update

27. Summary • CAMPATH has emerged as an important treatment option for CLL • Post-marketing commitments will be fully met following completion of CAM307 and CAM203 trials • These trials will further provide support for CAMPATH use in first line CLL (CAM307) and for the subcutaneous route of administration (CAM203) ODAC CAMPATH Update