1 agenda overview –burt adelman md efficacy and pharmacodynamics –akshay vaishnaw md, phd ...

1

AgendaAgenda

OverviewOverview– Burt Adelman MDBurt Adelman MD

Efficacy and PharmacodynamicsEfficacy and Pharmacodynamics– Akshay Vaishnaw MD, PhDAkshay Vaishnaw MD, PhD

SafetySafety– Gloria Vigliani MDGloria Vigliani MD

Alefacept Risk Benefit ProfileAlefacept Risk Benefit Profile– Mark Lebwohl MDMark Lebwohl MD

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Safety OverviewSafety Overview

Size of databaseSize of database

Adverse EventsAdverse Events

Serious Adverse EventsSerious Adverse Events

DeathsDeaths

InfectionInfection

MalignancyMalignancy

ImmunogenicityImmunogenicity

3

Total clinical experienceTotal clinical experience(n=1357)(n=1357)

1 coursen= 1357

2 coursesn= 756

3 coursesn= 199

4 coursesn= 81

5 coursesn= 46

Safety DatabaseSafety Database

3 placebo-controlled studies3 placebo-controlled studies(1 course, n=876)(1 course, n=876)

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Comparison of Placebo vs. Alefacept ExperienceComparison of Placebo vs. Alefacept Experience

0

200

400

600

800

1000

1200

Placebo Alefacept TotalAlefacept

178 p-y

401 p-y

1056 p-y

n= 413 n= 876 n= 1357

Placebo-controlledexperience

Pe

rso

n-y

ear

s (

p-y

)e

xpo

su

re

5

SAESAE 55 55

DiscontinuationsDiscontinuations 11 22

DeathDeath 00 <1<1

PlaceboPlacebo(n=413)(n=413)

AlefaceptAlefacept(n= 876)(n= 876)

Any AEAny AE 7979 8383

Event CategoryEvent Category %% %%

Safety Overview Placebo-Controlled StudiesSafety Overview Placebo-Controlled Studies

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Safety Overview by CourseSafety Overview by Course

Course 1Course 1(n=1357)(n=1357)





SAESAE 55 44 55 00 22

DiscontinuationsDiscontinuations 22 <1<1 11 11 00

DeathDeath <1<1 <1<1 <1<1 00 00

Any AEAny AE 8383 7474 6464 7272 6161

Event category (%)Event category (%) %% %% %% %% %%

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Adverse Events Adverse Events 5% Incidence5% IncidencePlacebo-Controlled StudiesPlacebo-Controlled Studies


AlefaceptAlefacept(n=876)(n=876)

Event Event

HeadacheHeadache

Accidental InjuryAccidental Injury

PharyngitisPharyngitis

InfectionInfection

PruritisPruritis

RhinitisRhinitis

Flu SyndromeFlu Syndrome

Viral InfectionViral Infection

AstheniaAsthenia

ChillsChills

PainPain

DiarrheaDiarrhea

DizzinessDizziness

ArthralgiaArthralgia

NauseaNausea

1818

1313

1313

1111

88

1010

99

77

77

11

55

55

33

66

33

1717

1515

1515

1111

1111

1111

99

66

66

66

66

55

55

55

55

%%8383Percentage with an event

%%7979

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Serious Adverse EventsSerious Adverse Events

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Most Frequent Serious Adverse Events*Most Frequent Serious Adverse Events*

*Events occurring in >1 alefacept patient


2 (<1)2 (<1)4 (<1)4 (<1)3 (<1)3 (<1)3 (<1)3 (<1)2 (<1)2 (<1)2 (<1)2 (<1)2 (<1)2 (<1)2 (<1)2 (<1)2 (<1)2 (<1)2 (<1)2 (<1)

42 (5%)42 (5%)


6 (1)6 (1)00000000001 (<1)1 (<1)00001 (<1)1 (<1)

19 (5%)19 (5%)

PsoriasisPsoriasisCoronary Artery DisorderCoronary Artery DisorderCellulitisCellulitisMyocardial InfarctionMyocardial InfarctionAccidental InjuryAccidental InjuryCarcinomaCarcinomaChest PainChest PainDiabetes MellitusDiabetes MellitusGastroenteritisGastroenteritisPancreatitisPancreatitis

Any SAE N (%)Any SAE N (%)

Placebo-Controlled First Course ExperiencePlacebo-Controlled First Course Experience

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Most Frequent Serious Adverse Events*Most Frequent Serious Adverse Events*






Any SAE N (%)Any SAE N (%) 67 ( 5) 67 ( 5) 30 (4)30 (4) 9 (5)9 (5) 00 1 (2)1 (2)

Accidental InjuryAccidental Injury PsoriasisPsoriasis

CellulitisCellulitisCoronary Artery DisorderCoronary Artery DisorderSkin CarcinomaSkin CarcinomaChest PainChest PainCholelithiasisCholelithiasisDiabetes MellitusDiabetes MellitusMyocardial InfarctMyocardial InfarctAsthmaAsthmaCarcinomaCarcinomaGastroenteritisGastroenteritisHerniaHerniaInfectionInfectionInfection BacterialInfection BacterialPancreatitisPancreatitisSuicide AttemptSuicide Attempt

5 ( <1)5 ( <1)5 ( <1)5 ( <1)4 ( <1)4 ( <1)4 ( <1)4 ( <1)4 ( <1)4 ( <1)3 ( <1)3 ( <1)3 ( <1)3 ( <1)3 ( <1)3 ( <1)3 ( <1) 3 ( <1) 2 ( <1)2 ( <1)2 ( <1)2 ( <1)2 ( <1)2 ( <1)2 ( <1)2 ( <1)2 ( <1)2 ( <1)2 ( <1)2 ( <1)2 ( <1)2 ( <1)2 ( <1)2 ( <1)

5 ( <1)5 ( <1)0000001 ( <1)1 ( <1)004 ( <1)4 ( <1)000 0 001 ( <1)1 ( <1)1 ( <1)1 ( <1)002 ( <1)2 ( <1)000000

1 ( <1)1 ( <1)000000000000001 ( <1)1 ( <1)1 ( <1)1 ( <1)0000001 ( <1)1 ( <1)000000

0000000000000000000000000000000000

00000000000000001 (2)1 (2)0000000000000000

*Events occurring in more than 1 patient included.

Multiple Course ExperienceMultiple Course Experience

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DeathsDeaths

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DeathsDeaths

CauseCauseof Deathof Death

Age/Age/gendergender

UnderlyingUnderlyingfactorsfactors

AlefaceptAlefaceptReceivedReceived

SuicideSuicide 34M34M Psoriasis, family Psoriasis, family history of suicidehistory of suicide

YesYes

Myocardial Myocardial infarctioninfarction

47M47M CAD, HT,CAD, HT,obesity, smokerobesity, smoker

YesYes

EsophagealEsophagealcarcinomacarcinoma

53M53M Diaphragmatic hernia,Diaphragmatic hernia,Barrett’s esophagusBarrett’s esophagus

YesYes

Myocardial Myocardial infarctioninfarction

52M52M CAD, HTCAD, HT NoNo

Lung Lung carcinomacarcinoma

46M46M SmokerSmoker YesYes

SeizureSeizure 43M43MLife-longLife-long

history of seizureshistory of seizures YesYes

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InfectionsInfections

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Infections Infections 5% Incidence5% Incidence

EventEvent


NasopharyngitisNasopharyngitis

Flu syndromeFlu syndrome

Viral infectionViral infection

Percentage with an infectionPercentage with an infection

10%10%

7%7%

5%5%

7%7%

PlaceboPlacebon=413n=413

43%43%

AlefaceptAlefaceptn=876n=876

10%10%

8%8%

7%7%

6%6%

45%45%


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Infections by CD4+ T Cell Counts*Infections by CD4+ T Cell Counts*

AlefaceptAlefacept

Number with an infection n (%)Number with an infection n (%)

Event n (%)Event n (%)


NasopharyngitisNasopharyngitis

Flu syndromeFlu syndrome

Viral infectionViral infection

Infection fungalInfection fungal

SinusitisSinusitis

Urinary tract infectionUrinary tract infection

Accidental injuryAccidental injury

BronchitisBronchitis

ConjunctivitisConjunctivitis

Fungal dermatitisFungal dermatitis

Skin infectionSkin infection

Periodontal abscessPeriodontal abscess

174 (42)174 (42)

40 (10)40 (10)

28 (7)28 (7)

21 (5)21 (5)

27 (7)27 (7)

5 (1)5 (1)

15 (4)15 (4)

5 (1)5 (1)

1 (<1)1 (<1)

9 (2)9 (2)

5 (1)5 (1)

00

5 (1)5 (1)

4 (<1)4 (<1)

CD4CD4250250(n=411)(n=411)

22 (24)22 (24)

8 (9)8 (9)

5 (6)5 (6)

4 (4)4 (4)

3 (3)3 (3)

2 (2)2 (2)

2 (2)2 (2)

2 (2)2 (2)

1 (1)1 (1)

1 (1)1 (1)

1 (1)1 (1)

1 (1)1 (1)

1 (1)1 (1)

1 (1)1 (1)

CD4<250*CD4<250*(n=90)(n=90)

359 (46)359 (46)

80 (10)80 (10)

57 (7)57 (7)

58 (7)58 (7)

47 (6)47 (6)

10 (1)10 (1)

26 (3) 26 (3)

6 (<1)6 (<1)

1 (<1)1 (<1)

18 (2)18 (2)

10 (1)10 (1)

6 (<1)6 (<1)

6 (<1)6 (<1)

14 (2)14 (2)

CD4 CD4 250 250(n=786)(n=786)

PlaceboPlacebo


* Only infections which occurred after the onset of CD4+ T cell count < 250 cells/uL are included

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Serious InfectionsSerious Infections

Number with a serious infection N (%)Number with a serious infection N (%)

Event N (%)Event N (%)

CellulitisCellulitis

GastroenteritisGastroenteritis

AbscessAbscess

AsthmaAsthma

Wound infectionWound infection

BronchitisBronchitis

PancreatitisPancreatitis

2 (<1)2 (<1)

00

00

00

00

00

1 (<1)1 (<1)

1 (<1)1 (<1)



8 (<1)8 (<1)

3 (<1)3 (<1)

2 (<1)2 (<1)

1 (<1)1 (<1)

1 (<1)1 (<1)

1 (<1)1 (<1)

00

00


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Description Doses Age/Sex Details Prior CD4 Rechall

Skin Infections:

Facial cellultis 12 50 M Obesity, DM, recurrent 343 Cont. Rx

otitis externa

Pre-septal cellulitis 10 44 F Sty manipulation 600 (placebo)

Leg cellulitis 1 52 M DM, CAD, COPD, edema, 312 Withdrew

erythema around plaque

Finger abscess 8 43 M Olecranon bursitis 720 Cont. Rx

Peri-orbital infection 23 50 M Herpes simplex superinfection 868 N.A.

Burn infection 5 55 M Obesity, 18x24 cm burn, DM 1014 Cont. Rx

Toxic shock 6 56 F Cellulitis, renal and respiratory 673 Withdrew

failure - full recovery

Post-surgical Wound Infections:

Post-op infection 17 58 M DM, rotator cuff repair 616 Cont. Rx

Post-op infection 11 26 M Open tibial fracture repair 289 Cont. Rx

Post-op infection 12 32 M Post-appendiceal rupture 491 Cont. Rx

Serious Skin Infections - All StudiesSerious Skin Infections - All Studies

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Infection: ConclusionsInfection: Conclusions

Similar incidence alefacept vs. placeboSimilar incidence alefacept vs. placebo

Low CD4+ T cell counts not a risk factorLow CD4+ T cell counts not a risk factor

No increase by course No increase by course

Uncomplicated clinical course and outcomeUncomplicated clinical course and outcome

No opportunistic infectionsNo opportunistic infections

No TBNo TB

No deaths due to infectionsNo deaths due to infections

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Functional Integrity of Immune SystemFunctional Integrity of Immune System

Preservation of naïve T cellsPreservation of naïve T cells

Partial effect against memory T cells, Partial effect against memory T cells, preservation of antibody responsespreservation of antibody responses

Redundancy of immune systemRedundancy of immune system

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Malignancy Malignancy

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Number with a malignancy N (%)Number with a malignancy N (%)

Event N (%)Event N (%)

Non-melanoma skin cancerNon-melanoma skin cancer

Carcinoma*Carcinoma*

Prostatic carcinomaProstatic carcinoma

Skin melanomaSkin melanoma

2 (<1)2 (<1)

1 (<1)1 (<1)

00

1 (<1)1 (<1)

00



10 (1)10 (1)

6 (<1)6 (<1)

2 (<1)2 (<1)

1 (<1)1 (<1)

1 (<1)1 (<1)

Incidence of MalignanciesIncidence of Malignancies

*One case each of testicular and renal cell cancer


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Incidence of MalignanciesIncidence of Malignancies

Number With a Malignancy Number With a Malignancy n (%)n (%)

Event n (%)Event n (%)

Skin CarcinomaSkin Carcinoma

CarcinomaCarcinoma

Skin MelanomaSkin Melanoma

Prostatic CarcinomaProstatic Carcinoma

Carcinoma of LungCarcinoma of Lung

Gastrointestinal Gastrointestinal Carcinoma*Carcinoma*

GI Neoplasia**GI Neoplasia**

Course 1Course 1n=1357n=1357



16 ( 1)16 ( 1)

11 (<1)11 (<1)

2 (<1)2 (<1)

2 (<1)2 (<1)

1 (<1)1 (<1)

00

00

00



4 (<1)4 (<1)

2 (<1)2 (<1)

1 (<1)1 (<1)

00

00

00

1 (<1)1 (<1)

00

4 ( 2)4 ( 2)

2 ( 1)2 ( 1)

00

00

00

1 (<1)1 (<1)

1 (<1)1 (<1)

1 (<1)1 (<1)

1 ( 1)1 ( 1)

1 ( 1)1 ( 1)

00

00

00

00

00

00

1 ( 2)1 ( 2)

1 ( 2)1 ( 2)

00

00

00

00

00

00

* One case each of adenocarcinoma of colon and esophagus

** Benign colonic polyp

Multiple Course ExperienceMultiple Course Experience

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68 yr old female68 yr old female

Long-standing psoriasis, previous MTX and PUVALong-standing psoriasis, previous MTX and PUVA

During third course of alefacept (total 20 injections)During third course of alefacept (total 20 injections)

– Isolated 2 cm nodeIsolated 2 cm node

– Follicular B cell Non-Hodgkin’s lymphomaFollicular B cell Non-Hodgkin’s lymphoma

– No other lymphoid/bone marrow involvementNo other lymphoid/bone marrow involvement

Features consistent with sporadic B cell NHL and not Features consistent with sporadic B cell NHL and not with immunotherapy-related lesionwith immunotherapy-related lesion

Single case of B cell lymphomaSingle case of B cell lymphoma

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Overall Malignancy RatesOverall Malignancy Rates

Incidence Rate Per 1000 Person Years (p-y) Exposure

Alefacept(Overall)22/1056 p-y

Expected Rate(Psoriasis population)*

32.113

20.8

*Margolis (2001)

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3623

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Malignancy ConclusionsMalignancy Conclusions

No evidence of increase in malignancyNo evidence of increase in malignancy

Majority skin cancersMajority skin cancers

Observed rates for skin and total malignancies Observed rates for skin and total malignancies within expected rates within expected rates

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Percentage Testing PositivePercentage Testing Positivefor Anti-Alefacept Antibodiesfor Anti-Alefacept Antibodies

Course of Alefacept

First Second Third Fourth Fifth

Baseline

During course

<1

2

<1

2

2

<1

0

0

0

0

Number ofpatients dosed 1357 756 199 81 46

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Safety ConclusionsSafety Conclusions

Alefacept has a favorable safety profileAlefacept has a favorable safety profile

Similar incidence of adverse events alefacept vs. Similar incidence of adverse events alefacept vs. placeboplacebo

No convincing evidence of increased risk of infection or No convincing evidence of increased risk of infection or malignancy malignancy

No correlation between rates of malignancy, infections No correlation between rates of malignancy, infections and CD4+ T cell countsand CD4+ T cell counts

Low immunogenicityLow immunogenicity

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Plans for Extended Long-Term Safety EvaluationPlans for Extended Long-Term Safety Evaluation

Approximately 800 patients in ongoing Approximately 800 patients in ongoing safety-extension studiessafety-extension studies

Alefacept safety registryAlefacept safety registry– powered to specifically evaluate increase in powered to specifically evaluate increase in

risk of adverse events of interestrisk of adverse events of interest

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Alefacept ConclusionsAlefacept Conclusions

Selective and novel approach targeting memory T cellsSelective and novel approach targeting memory T cells

T-cell effects correlate with efficacy but not with adverse T-cell effects correlate with efficacy but not with adverse safety outcomes safety outcomes

Clinically meaningful benefit in the majority of patientsClinically meaningful benefit in the majority of patients

– Significant duration of remissionSignificant duration of remission

Improvements in disease activity associated with QOL Improvements in disease activity associated with QOL benefitbenefit

Well-toleratedWell-tolerated

First systemic disease-remittive agent First systemic disease-remittive agent

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AgendaAgenda

OverviewOverview– Burt Adelman MDBurt Adelman MD

Efficacy and PharmacodynamicsEfficacy and Pharmacodynamics– Akshay Vaishnaw MD, PhDAkshay Vaishnaw MD, PhD

SafetySafety– Gloria Vigliani MDGloria Vigliani MD

Alefacept Risk Benefit ProfileAlefacept Risk Benefit Profile– Mark Lebwohl MDMark Lebwohl MD

1 agenda overview –burt adelman md efficacy and pharmacodynamics –akshay vaishnaw md, phd ...

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