1

Tipifarnib (ZARNESTRA®)

Treatment of Elderly Patients with Newly

Diagnosed Poor-risk AML

Oncologic Drugs Advisory Committee

May 5, 2005

2

Introduction

Robert J. DeLap, MD, PhD

Vice President, Global Regulatory Affairs

Johnson & Johnson

Pharmaceutical Research & Development, L.L.C.

3

Proposed Indication

ZARNESTRA (tipifarnib) is indicated for the treatment of elderly patients with newly

diagnosed, poor-risk acute myeloid leukemia

4

Tipifarnib in AMLClinical and Regulatory History

IND filed 1996

CRADA (Cooperative R&D Agreement) with NCI 1999

CTEP-1 Phase 1 study 1999

CTEP-20

– Initiated 2001

– Final revised CTEP-20 protocol and analysis plans 2003

Orphan Indication and Fast Track Status 2004

SPA for AML Phase 3 study (AML-301) 2004

NDA accepted in CMA-1 program 2004

5

Tipifarnib AML Development Program

1999 2001 2003 2004 May 2005

CTEP-1

INT-17: Relapsed/Refractory AML

CTEP-20: Elderly poor-risk AML

AML-301: Phase 3 study – tipifarnib vs. BSC in

Elderly AML

CTEP-50: Phase 2 study – alternate doses and

schedules

6

CTEP-20: Summary of Study Population

136 elderly poor-risk AML

Median age: 75 years

82% prior MDS

49% unfavorable karyotypes

90% with 2 or more risk factors

7

Favorable Benefit-RiskCTEP-20 Elderly Patients with Poor-risk AML

Patients who do not receive standard AML therapy

Efficacy– 15% complete remission rate; median duration, 220 days

Safety– Extensive safety database (monotherapy studies N>1,000)– Predictable myelosuppression– Low rate of grade 4 non-hematologic toxicity– Low treatment-related mortality

Oral, outpatient therapy

8

Agenda

Introduction R. DeLap, MD, PhDJ&JPRD

AML in Elderly Patients R. Stone, MD Dana-Farber Cancer Institute

CTEP-20 Data A. Thibault, MDJ&JPRD

Summary A. Zukiwski, MD J&JPRD

9

Medical Experts

Acute Myeloid Leukemia

Dr. J. Karp – Johns Hopkins University

Dr. M. Sekeres – Cleveland Clinic

Dr. R. Stone – Dana-Farber Cancer Institute

Cancer Therapy Evaluation Program (CTEP), NCI

Dr. J. Wright – Investigational Drug Branch

Independent Hematopathology Review

Dr. M. Albitar – Nichols Institute

10

Dr. Richard Stone

Clinical Director, Adult Leukemia Program

Dana Farber Cancer Institute

Elderly AML - Unmet Need

11

AML in Older Adults

Incidence: Not uncommon and increasing

Biologically and therapeutically distinct from AML in younger adults

– Intrinsically resistant and inferior outcomes

Some subgroups have a worse than (the poor) average prognosis

Many are not offered and/or refuse standard induction and post-remission therapy

– An efficacious, relatively non-toxic approach would be welcomed by patients and leukemia specialists

12

Epidemiology of AML

Estimated new cases of acute myeloid leukemia (AML) in 2004 – 11,920

– Estimated deaths from AML 8,870

Median age – 68 years

Incidence: 3.8 per 100,000– < 65 years of age – 1.8/100,000– > 65 years of age – 17.7/100,000

Chance of having leukemia:– For a 50-year-old, 1 in 50,000– For a 70-year-old, 1 in 7,000

1. Jemal A et al. CA Cancer 2004 2. Hiddemann W. J Clin Oncol. 1999; 3. National Cancer Institute. SEER Cancer Statistics Review. 1975-2000.

13

AML is Primarily a Disease of Older Adults

Incidence (per 100,000)

Age at diagnosis (years)National Cancer Institute. SEER Cancer Statistics Review. 1975-2000. Available at: http://seer.cancer.gov/csr/1975_2000/results_merged/sect_13_leukemia.pdf.

0

5

10

15

20

25

<1 1-4 5-9 10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85+

14

The US Population is Aging

US Bureau of the Census. 1996.

0

50

100

150

200

250

300

350

1950 1990 2030

< 65 years> 65 years

Nu

mb

er

of

Pe

rso

ns

(in

Mill

ion

s)

8.1%12.7%

20.0%

8.1%12.7%

20.0%

15

Inferior Outcomes in Older Adults with AML Enrolled on Large Cooperative Group Trials

(excluding prior MDS)

Patients

Age (years) < 60 > 60

Complete response (%) 70 45

Disease-free survival (%) 45 20

Early death (%) 10 25

Overall survival (%) 30 10

Median survival (months) 24 10

Mayer, CALGB 8525, NEJM 1994; Rees , MRC 6, Lancet 1986

16

Reasons for Inferior Outcomes in Older Patients with AML

Decreased host tolerance– Comorbid diseases– Decreased chemotherapy clearance– Impaired stem cell reserve

Intrinsically increased disease resistance

Hiddemann W, J Clin Oncol 1999; Estey EH, Blood 2000.

17

AML in the Older Patient is Inherently Resistant

Unfavorable chromosomal abnormalities in older patients

-5

-7

-11q23

Complex

Incidence of antecedent hematologic abnormalities

Expression of genes encoding drug resistance (MDR-1, MRP, LRP, MSH-2)

Grimwade D, Blood 2001; Bloomfield CD, Cancer Res 1998.MDR-1 = Multidrug resistance; MRP = Multiple drug resistance protein; LRP = Leucine-responsive regulatory protein; MSH-2 = MutS homolog 2

Leith CP, Blood 1997; Leith CP, Bood 1999.

18

Chemotherapy-based trials in Older Adults with AML*

Remarkably similar induction rate, high toxic death rate, and poor overall survival across studies:

Med age CR Toxic death Survival– CALGB 8923 69 52% 25% 9.6 mo– SWOG 9031 68 45% 16% 8.5 mo– HOVON AML 9 68 42% 18% 9.5 mo– CALGB 9720 70 46% 20% 10 mo– ECOG 3351 68 42% 17% 7.5 mo– SWOG 9333 68 43% 18% 9 mo

Stone NEJM, 1995; Godwin Blood, 1998; Lowenberg J Clin Oncol, 1998; Baer Blood, 2002, Anderson, Blood, 202; Rowe Blood, 2004

* Deemed chemotherapy candidates, all age > 55

19

Risk Factors and Outcome to Chemotherapy

Usually the ‘best patients’ are included on chemotherapy trials– The community reality is likely much worse

Subgroups with a worse outcome (CR)

– Prior MDS1: 24% vs 52%

– Poor cytogenetics1: 21% vs 55%

– Age > 702: 29% vs 51%

Only 13% were above age 75

– Age > 803 14% vs 43%

Only 5% were above age 80

1 Leith, Blood 1997, SWOG 9031; 2 Rowe [ECOG]. Blood 2004; 3 Lowenberg, JCO, 1998

AML Survival by Age All Pts Chemo and Ineligible –

Worsens with Age

3.92.21.4

2.4

Median

Menzin: Arch Intern Med, Volume162(14).July 22, 2002.1597-1603

0%10%20%30%40%50%60%70%80%90%

100%

0 3 6 9 12 15 18 21 24

Number of Months Following Diagnosis

Per

cen

t S

urv

ivin

g Overall65-74 Years75-84 Years85+ Years

21

Is There a ‘Standard of Care’ for the Older Adult with AML?

Value of chemotherapy is debated, particularly in poor prognosis

patients

– Randomized studies suggest a small survival advantage for early aggressive chemo vs less intense approaches but high upfront mortality

Lowenberg J Clin Oncol, 1989; Tilly J Clin Oncol, 1990

NCCN guidelines: (age > 60, good KPS) – Clinical trial (preferred)

– Standard 3+7 induction

22

How do Older Adults with AML Decide on Treatment?

Studied prospectively via patient/doctor questionnaires by Sekeres et al1

– Patients consistently inflate the chance of cure – Patients state that multiple options not offered

1. Sekeres MA, Leukemia 2004.

23

Patient Choice and Consequences

Age (years) 65-74

n = 1507 75-84

n = 140785+

n = 525

IV Chemotherapy No Yes No Yes No Yes

51% 49% 72% 28% 93% 7%

Menzin J et al. J Clin Oncol. 2004;; Lang K et al. Drugs & Aging. 2004. submitted

Hospital days 11 58 9 44 7 24

(median)Percent time 18% 22% 17% 30% 18% 32%

In Hospital

24

Problems with Intensive Chemotherapy In Older Adults with AML

Risk-Benefit Issues– Efficacy reduced– Therapy poorly tolerated– High therapy-related mortality rate

No trials have really addressed QOL cost of chemo

Small improvement in survival could be offset by increase in hospitalization

66% of patients > age 65 do not receive chemo

Non-chemotherapeutic options beside supportive care with efficacy and low toxicity are needed

25

Conclusions

AML in elderly patients is a biologically and clinically distinct entity

Even in ‘best’ patients, the chance for treatment-related death with induction chemo is greater than the chance for cure– In poor prognosis pts (older, prior MDS, adverse cytogenetics) the

advisability of chemotherapy is very low

Patients and doctors often choose a ‘non-intensive’ approach, but currently there is no such therapy which offers an appreciable chance for remission

26

CTEP-20 Data

Alain Thibault, MD

Senior Director, Oncology Development

Johnson & Johnson

Pharmaceutical Research & Development, L.L.C.

27

NCI CTEP-20

Evaluation of Tipifarnib

Newly Diagnosed Poor-Risk AML in the Elderly

28

Tipifarnib Mechanism of ActionPotential Effector Pathways

Farnesyltransferase

H,N-RasH,N-Ras RhoBRhoB CNPE/CNPFCNPE/CNPF

Lamin BLamin B

MAPKMAPKAkt3Akt3

GrowthSurvival G2/M Transition

Transformation

TranscriptionalModulation

TranscriptionalModulation

Growth

TGF RIITGF RII VEGFVEGF

Angiogenesis

X tipifarnib

29

Tipifarnib Clinical Pharmacology

Oral administration

Hepatic metabolism– CYP 3A4; 2C19; 2A6; 2D6– Glucuronidation

Low potential for drug interactions– Weak P450 inhibition in vitro– No P450 induction

30

Tipifarnib Dose Rationale

Recommended Dose: 600 mg po BID x 21 d q 4 wks

Phase 1 (CTEP-1)

– N=34 patients with poor-risk leukemia

– Dose escalation:100, 300, 600, 900, 1200 mg po BID

– 600 mg dose associated with:

Sustained farnesyltransferase inhibition

Plasma concentrations > IC50 of AML cell lines

Acceptable patient tolerability

31

CTEP-20: Review

Design

Population

Efficacy

Safety

32

CTEP-20: Background

NCI CRADA

Multi-center Phase 2

Poor-risk Myeloid Neoplasms

33

CTEP-20: Inclusion Criteria - Original Design

Poor-risk MDS, CMML and AML– Newly diagnosed – WHO AML criteria ( 20% myeloblasts)

Age of AML Patients– 18-65 years

Unfavorable cytogenetics [del 5, del 5q, del 7, del 7q, trisomy 8, 11q23, complex (≥ 3 abnormalities)]

Or Prior MDS/Chemotherapy

– > 65 years regardless of risk factors

ECOG 0–2

Normal Bilirubin: ALT/AST grade 1

Creatinine grade 1

34

CTEP-20: Inclusion Criteria - Amended

AML only

Patient Age

– 65-74 years with prior MDS

– ≥ 75 years regardless of risk factors

ECOG 0-1

35

CTEP-20: Efficacy Endpoints

Primary– Complete Remission (CR), by investigator

Secondary– Duration of CR– Anti-leukemic activity

Partial remission Hematological improvement

– Overall survival

36

CTEP-20: Complete Remission Criteria

< 5% bone marrow blasts– No identifiable leukemic cell

Trilineage maturation– ANC ≥ 1,000/μL– Platelets ≥ 100,000/μL

No peripheral blasts

No extramedullary leukemia

37

Other Indicators of Activity

Partial Response (PR)– Bone marrow blasts 5-19% and 50% reduction from baseline– ANC > 1,000/L– Platelets > 100,000/L

Hematologic Improvement (HI)– Bone marrow blasts 5-19% and 50% reduction from baseline– ANC > 500/L– Platelets > 20,000/L

38

CTEP-20: Outpatient Treatment Plan

OFF STUDY

Tipifarnib 600 mg BID x 21 days

Bone Marrow Biopsy

PD

CONTINUE TREATMENTUNTIL PD/ RELAPSE

PR, HI or SDCR

STOP and RE-TREAT UPON RELAPSE

3 Cycles

39

CTEP-20: Dose Modifications

Stepwise dose reductions

– 400, 200, and 100 mg BID

Treatment interruptions– Maximum cycle duration: 63 days

Treatment delays– Minimum rest period: 7 days

40

CTEP-20: Review

Design

Population

Efficacy

Safety

41

CTEP-20: Study Population

171 Myeloid Neoplasms

13 Non-AML

158 Poor-risk AML

21 Other AML137 Elderly Poor-Risk AML

(136 treated)

61

75 Age 75

Age 65-74, Prior MDS

42

CTEP-20: Demographics (N=136)

Age, (yrs)

Median 75.0

Range 65-85

Gender, n (%)Male 86 (63)

Female 50 (37)

Race, n (%)White 129 (95)

Other 7 (5)

ECOG performance status, n (%)

0 32 (24)

1 86 (63)

2 15 (11)

NA 3 (2)

43

CooperativeGroups

Patient Age CTEP-20 vs. Other AML Populations

Inci

den

ce

(per

100

,000

)

Age (years)

SEER Cancer Statistics Review. 1975-2000.

CTEP-20

0

5

10

15

20

25

<1 1-4 5-9 10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85+

44

CTEP-20: Reasons for Not Giving Standard Induction Chemotherapy

Reason Patients *n (%)

Age 106 (78)

Risk factors 60 (44)

Physician preference 15 (11)

Patient preference 10 (7)

.

* More than 1 reason per patient

45

CTEP-20: High Prevalence of Risk Factors

Patient %

55%

82%

49%

61%

Age 75

Prior MDS

Unfavorable Karyotype

Organ Dysfunction

0 20 40 60 80 100

82%

49%

55%

61%

46

CTEP-20: Number of Risk Factors Per Patient

1

2

4

3

N=13690% with 2 or more risk factors

10%

35%

44%

11%

47

CTEP-20: Leukemic Burden at Baseline Site Assessment

N=136

Marrow Blasts

Median 46%

Range (9-100)

Circulating Blasts

Median 8%

Range (0-92)

48

CTEP-20: Hematologic Parameters at Baseline

N=136

ANC

Median 660/L

Grade 3, n (%) 29 (21)

Grade 4, n (%) 55 (40)

Platelets

Median 41,500/L

Grade 3, n (%) 68 (50)

Grade 4, n (%) 8 (6)

49

CTEP-20: Summary of Study Population

136 elderly poor-risk AML

Median age: 75 years

82% prior MDS

49% unfavorable karyotypes

90% with 2 or more risk factors

50

CTEP-20: Review

Design

Population

Efficacy

Safety

51

CTEP-20: Efficacy Site Assessment

N=136

n (%) 95% CI

Complete Remission 20 (15) (9, 22)

Partial Remission 3 (2)

Hematologic Improvement 7 (5)

Stable Disease 44 (32)

Progressive Disease 48 (35)

Not Evaluable 14 (10)

.

52

CTEP-20: CR Rates by Risk Factor

16%

14%

12%

16%

CR Rate (%)0 5 10 15 20

OrganDysfunction

Age 75+

UnfavorableKaryotype

Prior MDS 16%

14%

12%

16%

53

CTEP-20: Complete Remission Rate by Site

Treated N=136

CRN=20

Site n (%) n (%)

Stanford 35 (26) 5 (14)

Maryland 32 (24) 8 (25)

Johns Hopkins 28 (21) 3 (11)

Cornell 22 (16) 0

Rochester 16 (12) 4 (25)

Georgia 3 (2) 0

54

CTEP-20: Confirmation of Complete Remissions at 1 Month by Investigators

20 CompleteRemissions

17 Confirmed> 4 weeks

1 Early RelapseCRF ID 318

1 Early DeathCRF ID 336

1 Patient RefusalCRF ID 508

3 Without f/u Bone Marrow at > 4 weeks

55

CTEP-20: Patients with Complete Remissions and No Follow up Bone Marrow at 4 weeks

CRF ID

Reason(s) AgeNo. Risk

Factors

BL BM Blasts

CR Duration (days)

Notes Survival (days)

318 Early Relapse

81 3 90 58 – 151

336 Early Death 80 4 22 35 – Drug-related Death in CR 67

508 Patient Refusal

79 4 90 121 – CBC compatible with CR 279

56

CTEP-20 QC Independent Review

Verification of CR (N=20)– 18 of 20 patient slides available– 18/18 verified resulting in a 100% concordance

Verification of the CR Confirmation at 1 month– 16 of 17 patient slides available– 15/16 verified resulting in a 94% concordance

57

Response by Number of Risk Factors

Response

Number of Risk Factors

1N=14

2N=60

3N=47

4N=15 N=136

Complete response, n (%) 3 (21) 9 (15) 4 (9) 4 (27) 20 (15)

Partial response, n (%) 0 1 (7) 2 (4) 0 3 (2)

Hematologic improvement, n (%) 0 4 (7) 3 (6) 0 7 (5)

TOTAL 3 (21) 14 (29) 9 (19) 4 (27) 30 (22)

58

CTEP-20: Duration of CR

Number of patients 20 18 14 9 5 4 2 2 0 0 0

Days

Pat

ien

ts (

%)

0

50

40

30

10

20

60

70

80

90

100

0 50 100 150 200 300 350250 500400 450

Median: 220 daysCensored

CR Patients

59

CTEP-20: Survival of Complete Responders

0

50

40

30

10

20

60

70

80

90

100

0 100 200 300 400 600 700500 1000800 900

CR Patients

Censored

Number of patients 20 19 14 9 7 5 2 2 1 0 0

Median 433 days

Days

Pat

ien

ts (

%)

60

CTEP-20: Overall Survival

0

50

40

30

10

20

60

70

80

90

100

0 100 200 300 400 600 700500 1000800 900

Censored

All Patients

Number of patients 136 68 31 19 13 10 4 3 1 0 0

Median 164 days

Days

Pat

ien

ts (

%)

61

CTEP-20: Re-treatment of Complete Responders

Treated with tipifarnib (N=136)

Achieved CR(N=20)

Achieved 2nd CR (N=1)

Retreated with tipifarnib(N=7)

62

CTEP-20: Limited Use of Chemotherapy after Tipifarnib

N

Non-CR Patients 116

Supportive care alone 72

Hydroxyurea alone 21

Low-intensity chemotherapy 13

Combination chemotherapy 10

CR Patients 20

Supportive care alone 14

Hydroxyurea alone 0

Low-intensity chemotherapy 4

Combination chemotherapy 2

63

CTEP-20: Summary of Efficacy

CR rate: 15% (95% CI: 9, 22)

Median duration of CR: 220 days (7.2 months)

CR rate consistent across risk groups

Median survival of patients with CR: 433 days (14.2 months)

64

CTEP-20: Review

Design

Population

Efficacy

Safety

65

CTEP-20: Tipifarnib Exposure

N=136

Cycle Duration, days

Median 38

Number of Cycles, n (%)

1 cycle 72 (53)

2 cycles 37 (27)

3 cycles + 27 (20)

66

CTEP-20: Dose Modifications Due to Adverse Events

N=136n (%)

Dose Reductions 47 (35)

Dose Interruptions 56 (41)

Cycle Delay 99 (73)

67

CTEP-20: Overview of Adverse Events

N=136n (%)

AEs 134 (99)

Drug-related 118 (87)

Grade 3/4 AEs 113 (83)

Drug-related 83 (61)

Drug-related Grade 4 21 (15)

AEs leading to withdrawal 21 (15)

Drug-related 14 (10)

AEs leading to deaths 9 (7)

Drug-related 1 (1)

Within 28 days of first dose 5 (4)

68

CTEP-20: Myelosuppression

N=136 (%)

Grade 3/4 Neutropenia 82

Treatment-emergent Grade 4 67

Febrile neutropenia or sepsis 51

Grade 3/4 Thrombocytopenia 88

Treatment-emergent Grade 4 30

Grade 3/4 Bleeding events 9

69

CTEP-20: Most Common Adverse EventsNonhematologic, Drug-Related

AnyGrade

%Grade 3/4

%Grade 4

%

Diarrhea 30 4 1

Nausea 30 4 0

Anorexia 18 0 0

Vomiting 18 4 0

Rash 22 7 0

Fatigue 26 4 0

Dizziness 13 1 0

Confusion 11 4 1

Ataxia 10 2 0

Creatinine elevation 13 2 0

Mucositis 5 3 0

70

CTEP-20: Selected Adverse Events

Renal– Dose-related increase in serum creatinine– 2% grade 3 – 2% withdrawal– <1% death

CNS– Dose-related confusion, ataxia– 14% grade 3/4– 2% withdrawal– No death

71

CTEP-20: Adverse Events Leading to Treatment Termination

N=136

Alln (%)

Drug-Relatedn (%)

Total 21 (15) 14 (10)

Creatinine increased 4 (3) 3 (2)

Rash 4 (3) 3 (2)

Pancreas enzymes increased 2 (1) 2 (1)

Dehydration 1 (1) 1 (1)

Diarrhea 1 (1) 1 (1)

Dizziness 1 (1) 1 (1)

Fatigue 1 (1) 1 (1)

Insomnia 1 (1) 1 (1)

Nausea 1 (1) 1 (1)

Peripheral Neuropathy 1 (1) 1 (1)

Sweating increased 1 (2) 1 (2)

72

CTEP-20: Hospitalizations

N=136

Admissions, n (%)

0 55 (40)

1-2 71 (52)

3+ 10 (7)

Reason, n (%)

Tipifarnib 51 (38)

Complications of AML 33 (24)

Other 21 (15)

Duration

Median days (range) 15 (2-73)

% Study time (range) 14 (2-98)

73

CTEP-20: Adverse Events Leading to Death*

n (%)

Cardiac Failure 3 (2)

Sepsis 3 (2)

Fungal Infection 2 (1)

Pneumonia 2 (1)

Arrhythmia 2 (1)

Circulatory Failure 1 (1)

GI Hemorrhage 1 (1)

Hypoxia 1 (1)

Multiple Organ Failure 1 (1)

Febrile Neutropenia 1 (1)

Pulmonary Hemorrhage 1 (1)

Acute Renal Failure 1 (1)

*N=9; >1 cause per patient; 1 tipifarnib-related death due to neutropenic sepsis

74

CTEP-20: Clinical Summary

Unmet Medical Need– Median age: 75 years– 90% with multiple risk factors

Durable Efficacy– Complete Remission rate: 15% (95%CI: 9, 22%)– Durable remissions: median 7.3 months

Outpatient Therapy– 14% of study time spent in hospital– Low rate of life-threatening (grade 4) non-hematological AEs

3% grade 3/4 mucositis– 1 death attributed to tipifarnib by investigator

75

Summary

Alex Zukiwski, MD

Vice President, Oncology Development

Johnson & Johnson

Pharmaceutical Research & Development, L.L.C.

76

Tipifarnib Proposed Indication

Tipifarnib is indicated for the treatment of elderly patients with newly diagnosed poor-risk acute myeloid leukemia – NDA is based on complete remissions, an accepted efficacy

endpoint in AML which has been shown to correlate with overall survival

77

Elderly Patients with Poor-risk AMLUnmet Medical Need

Limited therapeutic options– 66% of patients 65 years do not receive IV chemotherapy– Poor benefit-risk due to secondary AML (e.g. MDS),

unfavorable cytogenetics, significant comorbidities or compromised performance status

– Current options Investigational studies Low-intensity chemotherapy Best supportive care

78

CTEP-20: Population

Patients felt not to be optimal candidates for intensive induction chemotherapy

Unique population, not well represented in the literature– Median age: 75 years– 90% had 2 risk factors

82% had prior MDS 49% with unfavorable karyotype

79

Antileukemic Activity

15% Complete Remission Rate– Patient population studied often excluded from prior studies– CR median duration 220 days – CRs consistent across risk groups– Exploratory analysis of survival is encouraging for the future

development of tipifarnib

80

Risk Factors and Outcomes to Induction Chemotherapy

Usually the ‘best patients’ are included in chemotherapy trials

Subgroups with a worse outcome

1 Leith, Blood 1997, SWOG 9031; 2 Rowe [ECOG]. Blood 2004; 3 Lowenberg, JCO, 1998

Risk Factor Yes

CR Rate

No

CR Rate

MDS1 24% 52%

Poor cytogenetics1 21% 55%

Age > 702 29% 51%

Age > 803 14% 43%

81

CTEP-20: Tipifarnib Safety

Manageable and predictable safety profile in an already compromised patient population – Adverse events handled with supportive care measures, dose

interruptions and dose reductions

Limited time in hospital

Low rate of early deaths ( 30 days)

Low incidence of treatment-related death

82

Tipifarnib in AML Conclusions

Patient population with unmet medical need

Outpatient treatment

Positive benefit-risk

Will provide a new treatment for elderly patients with poor-risk AML who are not optimal candidates for induction chemotherapy