1 campath ® (alemtuzumab) millennium & ilex partners, lp oncologic drugs advisory committee...

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CampathCampath®®

(alemtuzumab)(alemtuzumab)

Millennium & ILEX Partners, Millennium & ILEX Partners, LPLP

Oncologic Drugs Advisory Oncologic Drugs Advisory CommitteeCommittee

December 14, 2000December 14, 2000

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Presentation AgendaPresentation Agenda

IntroductionIntroduction Lee R. Brettman, M.D., F.A.C.P.Lee R. Brettman, M.D., F.A.C.P.Senior VP, Medical AffairsSenior VP, Medical AffairsMillennium Pharmaceuticals, Inc.Millennium Pharmaceuticals, Inc.Millennium & ILEX Partners, LPMillennium & ILEX Partners, LP

Overview of CLL: NeedOverview of CLL: Need Michael J. Keating, M.B., B.S.Michael J. Keating, M.B., B.S. For New Therapeutic For New Therapeutic Professor of MedicineProfessor of MedicineOptions Options U.T.M.D. Anderson Cancer CenterU.T.M.D. Anderson Cancer Center

Presentation of Clinical Presentation of Clinical Lee R. Brettman, M.D., F.A.C.P.Lee R. Brettman, M.D., F.A.C.P.Data Data

Introduction

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Attending ExpertsAttending Experts

John M. Bennett, MDJohn M. Bennett, MD Professor of MedicineProfessor of MedicinePathology and Laboratory MedicinePathology and Laboratory MedicineUniversity of Rochester Cancer CenterUniversity of Rochester Cancer Center

John C. Byrd, MDJohn C. Byrd, MD Assistant Chief, Director of Clinical ResearchAssistant Chief, Director of Clinical ResearchHematology-Oncology ServicesHematology-Oncology ServicesWalter Reed Army Medical CenterWalter Reed Army Medical Center

Kanti R. Rai, MB, BSKanti R. Rai, MB, BS Chief, Division of Hematology/OncologyChief, Division of Hematology/OncologyLong Island Jewish Medical CenterLong Island Jewish Medical CenterProfessor of MedicineProfessor of MedicineAlbert Einstein College of MedicineAlbert Einstein College of Medicine

Introduction

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Proposed IndicationProposed Indication

CampathCampath is indicated for the treatment of patients is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have with chronic lymphocytic leukemia (CLL) who have been treated with alkylating agents and who have been treated with alkylating agents and who have failed fludarabine therapy.failed fludarabine therapy.

Introduction

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Introduction

Campath-1HCampath-1H

Humanized Humanized monoclonal antibody monoclonal antibody directed against directed against CD52 antigenCD52 antigen

– Expressed on B & T Expressed on B & T lymphocyteslymphocytes

– Not expressed on Not expressed on bone marrow bone marrow progenitor cellsprogenitor cells

Carbohydrate

Human IgG1 construct

Murine CDR’s

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Introduction

Mechanism of ActionMechanism of Action Lyses lymphocytes viaLyses lymphocytes via

– Complement fixationComplement fixation

– Antibody dependent cell Antibody dependent cell mediated cytotoxicitymediated cytotoxicity

– Induction of apoptosisInduction of apoptosis

Different mechanism of Different mechanism of action from available action from available cytotoxic cytotoxic chemotherapeutic agentschemotherapeutic agents

CD52CD52

Effector cellEffector cell

FCFCReceptorReceptor

CampathCampath

ComplementComplement

LeukemiaLeukemiaCellCell

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Historical TimelineHistorical Timeline

Campath murine mABs (Campath-1M & 1G) raised Campath murine mABs (Campath-1M & 1G) raised against Hu CD52 (Waldmann, Hale against Hu CD52 (Waldmann, Hale et.al.)et.al.)

Burroughs Wellcome licenses Campath-1H; Burroughs Wellcome licenses Campath-1H; humanized via CDR graftinghumanized via CDR grafting

BLA filed in DecemberBLA filed in December

Millennium & ILEX Partners, LP licensed CampathMillennium & ILEX Partners, LP licensed Campath

Introduction

Safety updates / Response to FDA questionsSafety updates / Response to FDA questions

19901990

19991999

19971997

19781978

20002000

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Overview of CLL:Overview of CLL:Need forNeed for

New Therapeutic OptionsNew Therapeutic Options

Michael J. Keating, M.B., B.S.Michael J. Keating, M.B., B.S.Professor of MedicineProfessor of Medicine

U.T.M.D. Anderson Cancer CenterU.T.M.D. Anderson Cancer Center

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CLL Overview

Chronic Lymphocytic Leukemia (CLL)Chronic Lymphocytic Leukemia (CLL)

Most common form of adult leukemia in U.S.Most common form of adult leukemia in U.S.– Incidence: ~ 10,000 patients/year Incidence: ~ 10,000 patients/year – Prevalence: ~ 60,000 patientsPrevalence: ~ 60,000 patients– Median age of 58 years (range = 20 - 90+)Median age of 58 years (range = 20 - 90+)

Progressive and usually fatal diseaseProgressive and usually fatal disease

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Rai StagingRai Staging

Rai Stage 0Rai Stage 0 Lymphocytosis onlyLymphocytosis only

Rai Stage IRai Stage I Lymphocytosis with lymphadenopathyLymphocytosis with lymphadenopathy

Rai Stage IIRai Stage II Lymphocytosis with hepatomegaly orLymphocytosis with hepatomegaly or

splenomegalysplenomegaly

Rai Stage IIIRai Stage III Lymphocytosis with anemiaLymphocytosis with anemia

Rai Stage IVRai Stage IV Lymphocytosis with thrombocytopeniaLymphocytosis with thrombocytopenia

CLL Overview

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CLL Overview

Complications of Progressive CLLComplications of Progressive CLL

Transformation (Richter’s, prolymphocytic)Transformation (Richter’s, prolymphocytic)

Bone marrow failureBone marrow failure

ImmunosuppressionImmunosuppression

Severe or life-threatening infectionsSevere or life-threatening infections

Eventual deathEventual death

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Standard Treatments in CLLStandard Treatments in CLL

First line treatmentFirst line treatment– Alkylating agentsAlkylating agents

Second line treatmentSecond line treatment– FludarabineFludarabine

Third line treatmentThird line treatment– NoneNone

CLL Overview

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CLL Overview

Benefits of Treatment to PatientsBenefits of Treatment to Patients

Reduce tumor burdenReduce tumor burden

ResponsesResponses

Clinical benefits Clinical benefits – Improvement in B-symptoms and fatigueImprovement in B-symptoms and fatigue

• Fever, night sweats and weight lossFever, night sweats and weight loss

– Improvement of disease related cytopeniasImprovement of disease related cytopenias– Resolution of symptomatic splenomegaly and Resolution of symptomatic splenomegaly and

lymphadenopathylymphadenopathy

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StudyStudy #Pts#Pts

Fludara labelFludara label 133133

Sorensen et al NCI Group CSorensen et al NCI Group C 724724

Anaissie et alAnaissie et al 248248

Keating et alKeating et al 113113

Fenchel et alFenchel et al 7777

Montserrat et alMontserrat et al 7575

Puccio et alPuccio et al 5151

TotalTotal 14211421

CLL Overview

Second Line Fludarabine: Second Line Fludarabine: Published ExperiencePublished Experience

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Parameter Parameter % of Patients% of Patients

Response Rate Response Rate 21-48%21-48%

Grade 4 thrombocytopeniaGrade 4 thrombocytopenia ~ 27%~ 27%

Grade 4 neutropeniaGrade 4 neutropenia 17-59%17-59%

Major InfectionsMajor Infections 16-58%16-58%

Died on StudyDied on Study 20-35%20-35%

Median SurvivalMedian Survival 9-12.6 months9-12.6 months

CLL Overview

Outcomes of Second Line Fludarabine Outcomes of Second Line Fludarabine TherapyTherapy

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Experience in Patients Who Have Experience in Patients Who Have Failed FludarabineFailed Fludarabine

Published experiencePublished experience– Cooperative group studies - noneCooperative group studies - none– Single center studies Single center studies

• CladribineCladribine• OtherOther

MDACC experienceMDACC experience– 147 patients 147 patients

CLL Overview

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MedianMedianResponseResponse SurvivalSurvival

Study Study Treatment Treatment # Pts# Pts RateRate (months) (months)

Keating et alKeating et alaa VariousVarious 147147 22%22% 10 10

Giles et al Giles et al Cis-plat/fludCis-plat/flud 4141 19%19% 66

O'Brien et al O'Brien et al CladClad 2828 7%7% 33

Saven et alSaven et al CladClad 1414 0% 0% ----

Published Experience: Investigational Published Experience: Investigational Salvage Therapy Following Fludarabine Salvage Therapy Following Fludarabine FailureFailure

CLL Overview

aa Manuscript in press - Leukemia and Lymphoma Manuscript in press - Leukemia and Lymphoma

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ConclusionsConclusions

Second-line fludarabine therapySecond-line fludarabine therapy– Median survival 9-12.6 monthsMedian survival 9-12.6 months– Substantial morbiditySubstantial morbidity

Third-line investigational therapyThird-line investigational therapy (fludarabine failures) (fludarabine failures)

– Median survival 3-10 monthsMedian survival 3-10 months– No approved or standard therapiesNo approved or standard therapies

New effective therapies are urgently neededNew effective therapies are urgently needed

CLL Overview

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Campath:Campath:Presentation of Clinical DataPresentation of Clinical Data

Lee R. Brettman, M.D., F.A.C.P.Lee R. Brettman, M.D., F.A.C.P.

Senior Vice President, Medical AffairsSenior Vice President, Medical Affairs

Millennium Pharmaceuticals, Inc.Millennium Pharmaceuticals, Inc.

Millennium & ILEX Partners, LPMillennium & ILEX Partners, LP

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Presentation OutlinePresentation Outline

Presentation of efficacy dataPresentation of efficacy data

Presentation of safety dataPresentation of safety data

Sponsor’s conclusionsSponsor’s conclusions

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Campath Development in CLLCampath Development in CLL

Phase I/II Dose Ranging Studies (001, 002, 003) Phase I/II Dose Ranging Studies (001, 002, 003) 30 mg 3x/week selected for Phase II studies30 mg 3x/week selected for Phase II studies

Phase II Studies (125-005, 125-009) Phase II Studies (125-005, 125-009) 30 mg 3x/week30 mg 3x/week

Pivotal study (CAM211) initiated AprilPivotal study (CAM211) initiated April30 mg 3x/week30 mg 3x/week

End of Phase II meetings with the FDAEnd of Phase II meetings with the FDA

Introduction

Burroughs Wellcome Burroughs Wellcome

Millennium and ILEX Partners, LP Millennium and ILEX Partners, LP

19921992

19931993

19981998

19971997

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Supportive Studies Supportive Studies

125-005 125-005 Relapsed / failedRelapsed / failed 3232prior therapyprior therapy

125-009125-009 Relapsed / failedRelapsed / failed 2424fludarabine fludarabine

Pivotal StudyPivotal Study

CAM211CAM211 Failed fludarabine Failed fludarabine 9393

Total PatientsTotal Patients 149149

Campath Pivotal and Supportive Campath Pivotal and Supportive Studies Studies (30 mg 3x/week)(30 mg 3x/week)

Study Number Study Number Previous Treatment Previous Treatment No. of Patients No. of Patients

Efficacy Results

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Efficacy ResultsEfficacy Results

125-005 and 125-009 Studies125-005 and 125-009 Studies

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125-005 and 125-009 Efficacy

Analysis of Supportive StudiesAnalysis of Supportive Studies

Burroughs WellcomeBurroughs Wellcome– Studies conducted 1993 - 1995Studies conducted 1993 - 1995

Millennium & ILEX Partners, LPMillennium & ILEX Partners, LP– Performed additional follow-up: survivalPerformed additional follow-up: survival– Verified databases Verified databases – Organized expert panel to assess responsesOrganized expert panel to assess responses

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Baseline CharacteristicsBaseline Characteristics

125-005125-005 125-009125-009N=32N=32 N=24N=24

Median Age (range)Median Age (range) 57 (46-75)57 (46-75) 62 (44-77)62 (44-77)

Rai Stage III-IV Rai Stage III-IV 71.9%71.9% 70.8%70.8%

Median number of priorMedian number of priorregimens (range)regimens (range) 3 (1-10)3 (1-10) 3 (1-8)3 (1-8)

Median years sinceMedian years sincediagnosis (range)diagnosis (range) 4.1 (0.3-11.3)4.1 (0.3-11.3) 5.1 (0.5-18.5)5.1 (0.5-18.5)

125-005 and 125-009 Efficacy

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125-005 and 125-009 Efficacy

Independent Expert Panel ReviewIndependent Expert Panel Review

MembersMembers– Michael J. Keating, M.B., B.S.Michael J. Keating, M.B., B.S.

Professor of MedicineProfessor of MedicineU.T.M.D. Anderson Cancer Center, TexasU.T.M.D. Anderson Cancer Center, Texas

– Emilio Montserrat, M.D.Emilio Montserrat, M.D.Head, Department of HematologyHead, Department of HematologyHospital Clinic, University of Barcelona, SpainHospital Clinic, University of Barcelona, Spain

– Steven Johnson, M.B., B.S., FRCPathSteven Johnson, M.B., B.S., FRCPathConsultant Haematologist Consultant Haematologist Taunton and Somerset Hospital, UKTaunton and Somerset Hospital, UK

NCIWG 1996 CriteriaNCIWG 1996 Criteria

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Formal Response AssessmentFormal Response AssessmentNCIWG Criteria (1996)NCIWG Criteria (1996)aa

Complete ResponseComplete Responsebb (CR)(CR) No detectable diseaseNo detectable disease

Partial ResponsePartial Responsebb (PR)(PR) At least a 50% reduction in disease At least a 50% reduction in disease burden. Improvement in burden. Improvement in

hematopoiesis of at least RBC, hematopoiesis of at least RBC, platelets or platelets or neutrophilsneutrophils

Progressive Disease Progressive Disease (PD)(PD) 50% or more increase in disease 50% or more increase in disease burdenburden

Stable Disease Stable Disease (SD)(SD) All othersAll others

aa Cheson et.al. Blood, 1996 Cheson et.al. Blood, 1996

b b CR and PR must persist for 2 monthsCR and PR must persist for 2 months

125-005 and 125-009 Efficacy

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Independent Panel Response AssessmentIndependent Panel Response Assessment (NCIWG 1996)(NCIWG 1996)

Study 125-005Study 125-005 Study 125-009Study 125-009Response Category Response Category N=32N=32 N=24N=24

Objective ResponseObjective Response 9 (28.1%)9 (28.1%) 8 (33.3%)8 (33.3%)95% CI 95% CI [14%, 47%][14%, 47%] [16%, 55%][16%, 55%]

125-005 and 125-009 Efficacy

CRCR 0 (0%)0 (0%) 0 (0%)0 (0%)

PRPR 9 (28.1%)9 (28.1%) 8 (33.3%)8 (33.3%)

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Time to Event Parameters - Time to Event Parameters - RespondersResponders

Time to ResponseTime to Response

Median MonthsMedian Months 3.83.8 3.93.995% CI95% CI [1.4, 4.4][1.4, 4.4] [1.6, 4.2][1.6, 4.2]

Duration of ResponseDuration of Response

Median MonthsMedian Months 7.17.1 15.4 15.495% CI95% CI [4.6, --][4.6, --] [10.4, --][10.4, --]

125-005125-005 125-009125-009Parameter Parameter N=9N=9 N=8N=8

125-005 and 125-009 Efficacy

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Based upon 125-005 and 125-009 dataBased upon 125-005 and 125-009 data

Single-arm, multicenter studySingle-arm, multicenter study Strictly defined fludarabine failure Strictly defined fludarabine failure Primary endpoint: response rate Primary endpoint: response rate 30 mg 3x/week30 mg 3x/week

CAM211 Study Design

Discussions with FDA: Design of Discussions with FDA: Design of CAM211 Pivotal StudyCAM211 Pivotal Study

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CAM211 Study Design

Rationale for Single-Arm Study DesignRationale for Single-Arm Study Design

Unmet medical needUnmet medical need

No approved third-line agentNo approved third-line agent

No consensus on alternate salvage therapy No consensus on alternate salvage therapy

Placebo control not acceptablePlacebo control not acceptable

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CAM211 Study Design

Prior TherapyPrior Therapy

Must have received alkylating agent and failed Must have received alkylating agent and failed fludarabine therapyfludarabine therapy

– Failure to achieve CR or PR to at least one Failure to achieve CR or PR to at least one fludarabine regimenfludarabine regimen

– Relapse within 6 months of last fludarabine doseRelapse within 6 months of last fludarabine dose

2-5 previous therapy regimens2-5 previous therapy regimens

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CAM211 Study Design

Criteria for Treatment: NCIWGCriteria for Treatment: NCIWG

Rai Stage III/IVRai Stage III/IV

Rai Stage 0-II (progressive)Rai Stage 0-II (progressive)– Rapid doubling of peripheral lymphocyte countRapid doubling of peripheral lymphocyte count– Progressive lymphadenopathy and/or splenomegalyProgressive lymphadenopathy and/or splenomegaly– B-symptomsB-symptoms– OthersOthers

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CAM211 Study Design

Primary EndpointPrimary Endpoint

Objective response rate (CR + PR) according Objective response rate (CR + PR) according to 1996 NCIWG criteria to 1996 NCIWG criteria

Target response rate of 20% and significantly Target response rate of 20% and significantly better than 10%better than 10%

– N=75 patientsN=75 patients

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CAM211 Study Design

Secondary EndpointsSecondary Endpoints

Time-to-event parameters Time-to-event parameters – Survival, duration of response, time to disease Survival, duration of response, time to disease

progressionprogression

Clinical BenefitClinical Benefit– Resolution of B-symptoms and fatigueResolution of B-symptoms and fatigue

– Resolution/reduction in massive splenomegalyResolution/reduction in massive splenomegaly

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CAM211 Study Design

Day 1 - 3 mg CampathDay 1 - 3 mg Campath

30 mg Campath30 mg Campath3x/week schedule3x/week schedule

e.g. Monday, Wednesday, Fridaye.g. Monday, Wednesday, Friday

I.V. AdministrationI.V. Administration



Duration of Treatment 4-12 Weeks Based on ResponseDuration of Treatment 4-12 Weeks Based on Response

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CAM211 Study Design

Concomitant TherapyConcomitant Therapy

Premedication to reduce incidence of Premedication to reduce incidence of infusion-related adverse eventsinfusion-related adverse events

– DiphenhydramineDiphenhydramine– AcetaminophenAcetaminophen

Infection prophylaxisInfection prophylaxis– Trimethoprim/sulfamethoxazole DSTrimethoprim/sulfamethoxazole DS– Famciclovir (or equivalent)Famciclovir (or equivalent)

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Baseline CharacteristicsBaseline Characteristics

Total Number of PatientsTotal Number of Patients N=93N=93

Median Age (range)Median Age (range) 66 (32-86)66 (32-86)

Rai Stage III-IVRai Stage III-IV 76.3%76.3%

Performance Status 2Performance Status 2 20.4%20.4%

Median number of priorMedian number of priorregimens (range)regimens (range) 3 (2-7)3 (2-7)

Median years sinceMedian years sincediagnosis (range)diagnosis (range) 6.1 (0.7 - 37.0)6.1 (0.7 - 37.0)

CAM211 Efficacy

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CAM211 Efficacy

Therapy After Failing FludarabineTherapy After Failing Fludarabine

Prior TherapyPrior Therapy n/N (%)n/N (%)

Any salvage therapy Any salvage therapy 61/93 (65.6) 61/93 (65.6)

Combination salvage Combination salvage therapy therapy 38/61(62.3) 38/61(62.3)

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CAM211 Efficacy

Response AssessmentResponse Assessment

Prospectively planned independent expert panelProspectively planned independent expert panel– John Bennett, M.D.John Bennett, M.D.

Professor of MedicineProfessor of Medicine

University of Rochester Cancer Center, New YorkUniversity of Rochester Cancer Center, New York

– Federico Caligaris-Cappio, M.D.Federico Caligaris-Cappio, M.D.Professor of Clinical ImmunologyProfessor of Clinical ImmunologyDivisione Universitaria di Immunologia Clinica e EmatologiaDivisione Universitaria di Immunologia Clinica e Ematologia

Torino, ItalyTorino, Italy

– Martin S. Tallman, M.D.Martin S. Tallman, M.D.Associate Professor of MedicineAssociate Professor of MedicineNorthwestern University Medical School, IllinoisNorthwestern University Medical School, Illinois

FDAFDA

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Response Assessment Response Assessment (ITT; N=93)(ITT; N=93)

Response CategoryResponse Category

CRCR 2 (2.2%) 2 (2.2%)

PRPR 29 (31.2%) 29 (31.2%)

Non-RespondersNon-Responders 62 (66.7%) 62 (66.7%)

Objective Response (CR + PR)Objective Response (CR + PR) 31 (33.3%)31 (33.3%)95% CI 95% CI [24%, 44%][24%, 44%]

CAM211 Efficacy

n (%)n (%)

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Time to Event Parameters Time to Event Parameters (Responders N=31)(Responders N=31)

Time to ResponseTime to Response

MedianMedian 1.51.595% CI95% CI [1.0, 1.7][1.0, 1.7]

Duration of ResponseDuration of Response

MedianMedian 8.78.795% CI95% CI [5.9, 11.5][5.9, 11.5]

Parameter Parameter MonthsMonths

CAM211 Efficacy

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Kaplan-Meier Survival CurveKaplan-Meier Survival CurveAll PatientsAll Patients

CAM211 Efficacy

Survival (months)Survival (months)

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

00 33 66 99 1212 1515 1818 2121 2424

Su

rviv

al p

rob

abili

tyS

urv

iva

l pro

bab

ility

Median = 16 monthsMedian = 16 months[11.8, --][11.8, --]

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Response Rate & 95% CI for the Response Rate & 95% CI for the Pivotal and Supportive Studies Pivotal and Supportive Studies

00 1010 2020 3030 4040 5050 6060 7070 8080 9090 100100

Percent Objective ResponsePercent Objective Response(CR + PR)(CR + PR)

CAM211 (N=93)CAM211 (N=93)

125-005 (N=32)125-005 (N=32)

125-009 (N=24)125-009 (N=24)

10%10%TargetTargetLower Lower BoundBound

Summary of Efficacy

33.3%33.3%

28.1%28.1%

33.3%33.3%

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Median Survival for Pivotal and Median Survival for Pivotal and Supportive StudiesSupportive Studies

MedianMedianStudyStudy # Pts# Pts (months)(months) 95% CI95% CI

CAM211CAM211 9393 16.0 16.0 [11.8, --][11.8, --]

125-005125-005 3232 25.925.9 [11.7, 44.3][11.7, 44.3]

125-009125-009 2424 27.527.5 [7.1, 32.6][7.1, 32.6]

Summary of Efficacy

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CAM211 Clinical Benefit

Clinical Benefit EvaluationClinical Benefit Evaluation

Prospectively planned protocol analysis of Prospectively planned protocol analysis of all patientsall patients

Agency requested analysis in respondersAgency requested analysis in responders

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Important Clinical Benefit ParametersImportant Clinical Benefit Parameters

Fever, night sweats and weight loss Fever, night sweats and weight loss FatigueFatigue Massive splenomegalyMassive splenomegaly Disease-related anemiaDisease-related anemia Performance statusPerformance status

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Clinical Benefits in Responders Clinical Benefits in Responders (N=31)(N=31)

B-symptoms and/or fatigueB-symptoms and/or fatigue– 100% (17/17) with baseline symptoms experienced 100% (17/17) with baseline symptoms experienced

resolutionresolution

Massive splenomegaly Massive splenomegaly (>6 cm below costal margin-NCIWG) (>6 cm below costal margin-NCIWG)

– 90% (9/10) experienced complete resolution90% (9/10) experienced complete resolution

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Disease-related anemia Disease-related anemia (baseline Hgb (baseline Hgb 11 g/dL) 11 g/dL)

– 73.3% (11/15) improved by >2 g/dL to >11 g/dL 73.3% (11/15) improved by >2 g/dL to >11 g/dL • Range 2.2 - 6.4 g/dLRange 2.2 - 6.4 g/dL• Not attributable to transfusions or erythropoietinNot attributable to transfusions or erythropoietin

Performance Status (PS)Performance Status (PS)– 40.0% (8/20) improved PS40.0% (8/20) improved PS

• 74.2% (23/31) maintained or improved PS74.2% (23/31) maintained or improved PS


Clinical Benefits in Responders Clinical Benefits in Responders (N=31)(N=31)

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Summary of Clinical BenefitSummary of Clinical Benefit

Responders Responders Non-Responders Non-Responders All Patients All Patients Clinical Benefit Clinical Benefit n/N (%)n/N (%) n/N (%)n/N (%) n/N (%) n/N (%)

Resolution ofResolution ofB-symptoms or fatigueB-symptoms or fatigue 17/17 17/17 (100)(100) 28/42 28/42 (66.7)(66.7) 45/59 45/59 (76.3)(76.3)

Resolution ofResolution ofmassive splenomegalymassive splenomegaly 9/10 9/10 (90.0)(90.0) 7/19 7/19 (36.8)(36.8) 16/29 16/29 (55.2)(55.2)

Improvement in Improvement in WHO PS WHO PS 8/20 8/20 (40.0)(40.0) 9/49 9/49 (18.4)(18.4) 17/69 17/69 (24.6)(24.6)

Improvement in Improvement in anemiaanemia 11/15 11/15 (73.3)(73.3) 14/36 14/36 (38.9)(38.9) 25/51 25/51 (49.0)(49.0)


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Efficacy Summary (CAM211)Efficacy Summary (CAM211)

Campath was effective in patients with CLL Campath was effective in patients with CLL who had failed fludarabinewho had failed fludarabine

– Objective response rate - 33.3% Objective response rate - 33.3% (95% CI [24, 44])(95% CI [24, 44])

– Survival - 16 months Survival - 16 months (95% CI [11.8, --])(95% CI [11.8, --])

Measurable clinical benefitsMeasurable clinical benefits

Supportive studies consistentSupportive studies consistent(125-005 and 125-009 Studies)(125-005 and 125-009 Studies)

Efficacy Results

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Presentation of efficacy data

Presentation of safety dataPresentation of safety data

Sponsor’s conclusions

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Integrated Safety Database (N=149) Integrated Safety Database (N=149)

Studies CAM211, 125-005, 125-009Studies CAM211, 125-005, 125-009– Patients with CLL who have been previously treated Patients with CLL who have been previously treated – Campath 30 mg 3x/weekCampath 30 mg 3x/week

Safety Results

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Demographics of Safety PopulationDemographics of Safety Population

N=149N=149

Rai Stage III/IVRai Stage III/IV 74.5%74.5%

Median prior treatmentsMedian prior treatments 33

Prior fludarabinePrior fludarabine 85.9%85.9%

Hgb Hgb 11g/dL 11g/dL 58.4%58.4%

ANC < 1500/ANC < 1500/LL 26.2%26.2%

Platelets Platelets 100,000/ 100,000/L L 61.7%61.7%

CD4 < 500/CD4 < 500/L L (CAM211)(CAM211) 46.2%46.2%

Integrated Safety Database (N=149)

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On-Study Adverse EventsOn-Study Adverse Events

EventEvent n (%)n (%)

DeathDeath 15 (10.1)15 (10.1)

Discontinuation due to Adverse EventsDiscontinuation due to Adverse Events 44 (29.5)44 (29.5)

Grade 3 or 4 Adverse EventGrade 3 or 4 Adverse Event 98 (65.8)98 (65.8)

Grade 3 or 4 InfectionGrade 3 or 4 Infection 42 (28.2)42 (28.2)


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n (%)n (%)

Total DeathsTotal Deaths 15 (10.1) 15 (10.1)

InfectionInfection 7 (4.7)7 (4.7)

Disease progression Disease progression 5 (3.4)5 (3.4)

OtherOtheraa 3 (2.0)3 (2.0)a a Suicide, pulmonary emboli, cerebral hemorrhageSuicide, pulmonary emboli, cerebral hemorrhage


On-Study DeathsOn-Study Deaths(within 30 days of last dose)(within 30 days of last dose)

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Post-Study Deaths Post-Study Deaths (>30 days but within 180 days of Campath last dose)(>30 days but within 180 days of Campath last dose)

n (%)n (%)

Total DeathsTotal Deaths 27 (18.1)27 (18.1)

Disease progression Disease progression 14 (9.4)14 (9.4)

Infection Infection 8 (5.4) 8 (5.4)

OtherOtheraa 5 (3.4)5 (3.4)a a Inanition, AIHA, ITP, respiratory distress, pulmonary embolusInanition, AIHA, ITP, respiratory distress, pulmonary embolus


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00 2020 4040 6060 8080 100100

RigorsRigors

FeverFever

NauseaNausea

VomitingVomiting

PneumoniaPneumonia

SepsisSepsis

AnemiaAnemia

GranulocytopeniaGranulocytopenia

ThrombocytopeniaThrombocytopenia

Most Common Adverse EventsMost Common Adverse Events

Grade 0-2

Grade 3

Grade 4

PercentPercent


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Rate of Acute Infusion-Related Adverse Rate of Acute Infusion-Related Adverse Events by Week on TreatmentEvents by Week on Treatment

>Wk 2>Wk 2

Wk 2Wk 2

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

Nu

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ents

per

Nu

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per

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sure

Grade 3/4 EventsGrade 3/4 EventsAll EventsAll EventsWk 1Wk 1

Wk 1Wk 1

Wk 1Wk 1Wk 2Wk 2

Wk 2Wk 2

>Wk 2>Wk 2

>Wk 2>Wk 2

RigorsRigors FeverFever HypotensionHypotension


61

Acute Infusion Related Adverse EventsAcute Infusion Related Adverse Events

High frequency, low gradeHigh frequency, low grade

Decrease over timeDecrease over time

Discontinuations due to these events Discontinuations due to these events infrequent (3.4%)infrequent (3.4%)


62

InfectionsInfections n (%) n (%)

Any grade 3 and 4Any grade 3 and 4 42 (28.2)42 (28.2)

PneumoniaPneumonia 23 (15.4)23 (15.4)

Line infectionsLine infections 8 (5.4)8 (5.4)

Sepsis/BacteremiaSepsis/Bacteremia 7 (4.7)7 (4.7)

CMV InfectionCMV Infection 4 (2.7) 4 (2.7)

Herpes infectionsHerpes infections 3 (2.0)3 (2.0)

On-Study Grade 3/4 InfectionsOn-Study Grade 3/4 InfectionsIntegrated Safety Database (N=149)

63

On-Study Grade 3 or 4 PneumoniasOn-Study Grade 3 or 4 Pneumonias

Pathogen - OriginPathogen - Origin n (%)n (%)

PneumoniaPneumonia 23 (15.4)23 (15.4)

BacterialBacterial 8 (5.4)8 (5.4)

PCPPCP 5 (3.4)5 (3.4)

FungalFungal 4 (2.7)4 (2.7)

InterstitialInterstitial 2 (1.3)2 (1.3)

Not identifiedNot identified 5 (3.4)5 (3.4)


64

Definition of Opportunistic InfectionsDefinition of Opportunistic Infections

Infections caused by uncommon pathogens, Infections caused by uncommon pathogens, e.g., Pneumocystis carinii, cryptococcosise.g., Pneumocystis carinii, cryptococcosis

Unusually severe infections caused by common Unusually severe infections caused by common pathogens, e.g, CMV, Herpes zoster, candidapathogens, e.g, CMV, Herpes zoster, candida


65

Opportunistic InfectionsOpportunistic Infections

On-StudyOn-Study Post-StudyPost-StudyOpportunistic Infections (O.I.) Opportunistic Infections (O.I.) n (%)n (%) n (%)n (%)

Any O.I.Any O.I. 20 (13.4)20 (13.4) 6 (4.0)6 (4.0)

PCPPCP 5 (3.3)5 (3.3) 2 (1.3)2 (1.3)

CMVCMV 4 (2.7)4 (2.7) 0 (0)0 (0)

Herpes zosterHerpes zoster 3 (2.0)3 (2.0) 2 (1.3)2 (1.3)

CandidaCandida 3 (2.0)3 (2.0) 0 (0) 0 (0)

Other fungalOther fungal 5 (3.3)5 (3.3) 1 (0.7) 1 (0.7)

Listeria meningitisListeria meningitis 0 (0) 0 (0) 1 (0.7)1 (0.7)


66

Incidence of PCP and Herpes Zoster: Incidence of PCP and Herpes Zoster: Impact of ProphylaxisImpact of Prophylaxis

00112233445566778899

1010

PCPPCP H. ZosterH. Zoster

005 & 009

CAM211

Per

cen

tP

erce

nt


67

Median CD4 Cell Counts Over Time Median CD4 Cell Counts Over Time On Study On Study (CAM211)(CAM211)

Safety Results (N=93)

Study PeriodStudy Period

00

100100

200200

300300

400400

500500

600600

700700

BaselineBaseline WeekWeek44

WeekWeek88

WeekWeek1212

2 Mos2 Mos 4 Mos4 Mos 6 Mos6 Mos

CD

4 C

ou

nt

(x10

CD

4 C

ou

nt

(x10

66 /L

)/L

)

2-Month Cohort2-Month Cohort



68

Pancytopenia: Adverse Event or Pancytopenia: Adverse Event or Study Discontinuation Study Discontinuation

Reported in 6.7% (10/149) of patients; Reported in 6.7% (10/149) of patients; – Not reported in patients with Rai Stage 0-IINot reported in patients with Rai Stage 0-II– All 10 were Rai Stage III or IV CLLAll 10 were Rai Stage III or IV CLL

All 8 patients with more than 3 weeks follow-up All 8 patients with more than 3 weeks follow-up recovered and experienced improvement over recovered and experienced improvement over baseline platelet countbaseline platelet count


69

Median Hematological Parameters Median Hematological Parameters (Last Value Carried Forward)(Last Value Carried Forward)

00

11

22

33

44

55

66

77

88

99

1010

1111

1212

00 22 44 88 1212 1616 2020 2424

Time on study (weeks)Time on study (weeks)

00

2020

4040

6060

8080

100100

120120

Hemoglobin

ANC

Platelet count

Me

dia

n H

gb

an

d A

NC

Me

dia

n H

gb

an

d A

NC

Me

dian

pla

telet c

ou

nt

Me

dian

pla

telet c

ou

nt


70

ParameterParameter Rai Stage 0-IIRai Stage 0-II Rai Stage III-IVRai Stage III-IV(Median)(Median) n=38n=38 n=111n=111

Hemoglobin Hemoglobin (g/dL)(g/dL) 12.9 12.9 9.99.9

Platelet Count Platelet Count (/(/L)L) 178,000 178,000 62,00062,000

ANC ANC (/(/L)L) 3,1003,100 2,3002,300

Baseline Hematologic Parameters by Baseline Hematologic Parameters by Rai StageRai Stage


71

Incidence of Grade 4 Cytopenias by Incidence of Grade 4 Cytopenias by Baseline Rai Stage Baseline Rai Stage (from Baseline Grade 0-2)(from Baseline Grade 0-2)

Rai 0-IIRai 0-II Rai III/IVRai III/IVCytopenia Cytopenia % (n/N)% (n/N) % (n/N)% (n/N)

AnemiaAnemia 2.6%2.6% (1/38) (1/38) 5.0%5.0% (5/101) (5/101)

ThrombocytopeniaThrombocytopenia 00 (0) (0) 8.0%8.0% (6/75) (6/75)

NeutropeniaNeutropenia 12.5%12.5% (4/32) (4/32) 46.1%46.1% (41/89) (41/89)


72

Grade 4 Neutropenia by Rai StageGrade 4 Neutropenia by Rai Stage

0

10

20

30

40

50

60

70

80

90

100

Rai 0-II

Rai III-IV

BaselineBaseline 1-21-2 3-43-4 5-65-6 7-87-8 9-109-10 11-1211-12 14 day14 day 1 mo1 mo

Follow upFollow up

2 mo2 mo

Week On TreatmentWeek On Treatment

Per

cen

t o

f P

atie

nts

Per

cen

t o

f P

atie

nts


73

Hematologic Toxicity: SummaryHematologic Toxicity: Summary

Hemoglobin, platelet count and ANC decline on Hemoglobin, platelet count and ANC decline on treatment and then improve treatment and then improve

– ANC recovery may be delayed ANC recovery may be delayed

Grade 3/4 hematologic toxicity occurs Grade 3/4 hematologic toxicity occurs predominately in patients with severely predominately in patients with severely compromised marrowcompromised marrow

– Temporary discontinuation in 16.1%Temporary discontinuation in 16.1%– Permanent discontinuation in 4.7%Permanent discontinuation in 4.7%


74

Campath: Extent of ExposureCampath: Extent of Exposure

Exposure ParameterExposure Parameter % of Patients% of Patients

Reached target dose of 30mg Reached target dose of 30mg 98% 98%

Received >4 weeks of therapy Received >4 weeks of therapy 89% 89%

Duration of therapyDuration of therapy(median)(median) 9 weeks9 weeks


75

FludaraFludara®® Label: Safety Label: Safety

SecondlineSecondline ThirdlineThirdlineParameterParameter FludaraFludara®® CampathCampath

No. PatientsNo. Patients 133133 149149

Died on study (%)Died on study (%) 2222 1010

Grade 4 ANC (%)Grade 4 ANC (%) 5959 3737

Pneumonia (%)Pneumonia (%) 16-2216-22 1515

Survival Survival (months)(months) 10,1210,12 16, 26, 27 16, 26, 27

Safety Results

76


Presentation of efficacy data

Presentation of safety data

Sponsor’s conclusionsSponsor’s conclusions

77

Conclusions

SafetySafety

Most common adverse events are acute infusion Most common adverse events are acute infusion related eventsrelated events

Severe infections are seen in 28% of patients Severe infections are seen in 28% of patients including those due to opportunistic pathogensincluding those due to opportunistic pathogens

Hematologic toxicity which can be severe Hematologic toxicity which can be severe emerges on treatment in some patientsemerges on treatment in some patients

Reasonable and manageable safety profile in Reasonable and manageable safety profile in this immunocompromised, refractory disease this immunocompromised, refractory disease populationpopulation

78

Conclusions

EfficacyEfficacy

Campath is effective in a population of patients Campath is effective in a population of patients for whom no approved therapies are available for whom no approved therapies are available (CAM211)(CAM211)

– Objective response 33.3% Objective response 33.3% (95% CI [24, 44])(95% CI [24, 44])

– Median survival 16 months Median survival 16 months (95% CI [11.8, --])(95% CI [11.8, --])

Supportive studies consistentSupportive studies consistent– Objective response (28.1%, 33.3%)Objective response (28.1%, 33.3%)

– Median survival (25.9 months, 27.5 months)Median survival (25.9 months, 27.5 months)

Meaningful clinical benefitMeaningful clinical benefit

79

Campath: Benefit /RiskCampath: Benefit /Risk

CAM211: advanced refractory populationCAM211: advanced refractory population– Majority had received salvage therapy after failing Majority had received salvage therapy after failing

fludarabinefludarabine– Immunocompromised at study entryImmunocompromised at study entry– Compromised marrow at study entryCompromised marrow at study entry– No approved or effective therapiesNo approved or effective therapies

Effective and manageably safeEffective and manageably safe

Addresses significant unmet needAddresses significant unmet need

Conclusions

80

Conclusions

Proposed IndicationProposed Indication

Campath is indicated for the treatment of patients Campath is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who with chronic lymphocytic leukemia (CLL) who have been treated with alkylating agents and who have been treated with alkylating agents and who have failed fludarabine therapy.have failed fludarabine therapy.

1 campath ® (alemtuzumab) millennium & ilex partners, lp oncologic drugs advisory committee...

Documents

lymphadenopathycll overviewwww

ptsfludara label133sorensen

lymphocytosis onlyrai

fatal diseasecll overviewwww

comrai stagingrai stage

comsecond line fludarabine

anderson cancer centerwww

lpoverview of cll