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

BC AP CP

Characteristic N=260) N=235 N=532

Age Median 56 56 57

Sex - Male/Female % 52/48 50/50 58/42

Race - Caucasian % 85 89 87

PS - 0-1 % 58 77 91

Ph + & other % 64 54 16

Extramedullary disease 68 68 24

STI-571 - % 400mg/d 14 33 86

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%)

-Complete 11 (4%)

-No evidence of leukemia 7 (3%)

-Return to chronic phase 50 (19%)

Time to HR- median (d) 29 (26-64)

Censored for response duration 57 (84%)

BC CML - Cytogenetic Remission

Characteristic n=260

Major response 35 (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 response 50 (21%)

Complete 17 (7%)

Confirmed 10 (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=532IFN Hematologic resistant/refractory 152 (29)

IFN Cytogenetic resistant/refractory 186 (35)

IFN intolerant 194 (36)

Median Duration of prior IFN (mo)

IFN hematologic failure 12.1 (1-83)

IFN cytogenetic failure 22.0 (4-135) IFN intolerant 7.1 (3-15)

CP CML - Cytogenetic Response

Characteristic n=532

Major response 265 (49.8%)

Complete 107 (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 68 3 68 5 55 2

Fluid retent 67 10 68 6 52 2

Vomiting 49 3 54 3 28 1

Muscle cramps 25 .4 34 .4 46 .9

Diarrhea 39 3 49 4 33 .9

Dermatitis 32 4 39 4 36 3 Hemorrhage 48 16 35 8 13 .4

Grade 4 Hematology Abnormalities (%)

BC AP CP

Hgb 10 5 <1

WBC 46 34 8

ANC 61 34 8

Platelets 31 12 <1

Grade 3/4 Biochemistry Abnormalities (%)

BC AP CP

Hepatic 1.9-3.5 1.3-3.0 0.4-1.7

Renal 1.2 1.3 0

Imatinib mesylate-FDA Action

5/10/01

Accelerated Approval, Subpart H, CFR§314.510, 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