CML- Imatinib Mesylate (Gleevec™) Philadelphia Chromosome Short chromosome 22 Bcr region of chromosome 22 with Abl proto-oncogene of chromosome 9

CML- Imatinib Mesylate (Gleevec™) Normal Abl gene product is a tightly regulated tyrosine kinase involved in cell division and apoptosis Bcr-Abl gene product is a constitutively active tyrosine kinase induces a CML-like illness in mice induces CML in man

CML- Imatinib Mesylate (Gleevec™) Blocks proliferation and induces apoptosis of Bcr-Abl expressing cell lines and fresh leukemic cells.

CML- Imatinib Mesylate (Gleevec™) Potent inhibitor of the receptor tyrosine kinases for PDGF, stem cell factor and c-Kit (CD 117) Active in c-kit expressing GIST

CML- Imatinib Mesylate (Gleevec™) Toxicology 13-week dog 6-month rat 9-month monkey Toxicity: Hematopoietic, renal, hepatic, gastrointestinal, testis and ovary

CML- Imatinib Mesylate (Gleevec™) Clinical Pharmacology Bioavailability 98% 95% protein bound CGP74588 is major active metabolite. Its plasma AUC is 16% of Imatinib AUC Metabolized by CYP3A4

CML - Submitted Studies Phase I Phase II -Blast crisis (BC) CML -Accelerated Phase (AP) CML -Chronic phase (CP) CML - IFN Refractory, Resistant, Intolerant

Study Patient Characteristics BCAPCP Characteristic N=260)N=235N=532 Age Median Sex - Male/Female % 52/4850/5058/42 Race - Caucasian % PS % Ph + & other % Extramedullary disease STI % 400mg/d

BC CML - Definition > 30% blasts in PB or BM or Extramedullary involvement other than spleen or liver PB=peripheral blood; BM=bone marrow

BC CML - Hematologic Remission Characteristic N=260 Hematologic Response 68 (26%) -Complete11 (4%) -No evidence of leukemia 7 (3%) -Return to chronic phase 50 (19%) Time to HR- median (d)29 (26-64) Censored for response duration57 (84%)

BC CML - Cytogenetic Remission Characteristic n=260 Major response35 (13.5%) Complete 9 (3%) Confirmed 3 (1%)

Accelerated phase (AP) definition > 15% <30% blasts in PB or BM > 30% blasts+promyelocytes in PB or BM but <30% blasts in PB or BM > 20% basophils in PB <100 x 109/L platelets at least one of the 4 criteria must be fulfilled

AP CML - Hematologic Response Characteristic N=235 Hematologic Response 148 (63%) -Complete 60 (26%) -No evidence of leukemia 27 (11%) -Return to chronic phase 61 (26%) Time to HR- median (d) 29 (26-334) Censored for response duration 133 (90%)

AP CML - Cytogenetic Response Characteristic n=235 Major response50 (21%) Complete17 (7%) Confirmed10 (4%)

Chronic Phase (CP) CML Definition < 15% blasts in PB & BM < 30% blasts+promyelocytes in PB & BM < 20% basophils in PB > 100 x 109/L platelets No extramedullary involvement other than spleen or liver All 5 criteria must be fulfilled

CP CML - Patient Characteristics Characteristic n=532 IFN Hematologic resistant/refractory 152 (29) IFN Cytogenetic resistant/refractory 186 (35) IFN intolerant 194 (36) Median Duration of prior IFN (mo) IFN hematologic failure12.1 (1-83) IFN cytogenetic failure 22.0 (4-135) IFN intolerant 7.1 (3-15)

CP CML - Cytogenetic Response Characteristic n=532 Major response265 (49.8%) Complete107 (20%) Confirmed 84 (16%) Time to MCyR (d) 91 (77-315)

CP CML - Hematologic Remission Characteristic N=532 Complete Hematologic Response 468 (88%) Days to CHR- median (range) 22 (5-267) Censored for response duration 438 (93.6%)

Common SAE’s BC CML AP CML CP CML n= 260 (%) n=235 (%) n=532 (%) All grades 3/4 All grades 3/4 All grades 3/4 Nausea Fluid retent Vomiting Muscle cramps Diarrhea Dermatitis Hemorrhage

Grade 4 Hematology Abnormalities (%) BC APCP Hgb10 5<1 WBC ANC Platelets3112<1

Grade 3/4 Biochemistry Abnormalities (%) BC AP CP Hepatic Renal

Imatinib mesylate-FDA Action 5/10/01 Accelerated Approval, Subpart H, CFR§ , for CML BC, AP, and CP after interferon-  failure

Phase IV Commitments Interval F/U of Phase II BC, AP, CP trials Interval F/U of Phase III CP trial Pediatric trials Hepatotoxic drug interaction study Concomitant medication-Gleevec interaction Pathogenesis and Rx of fluid retention