Examining the Properties of Biologic Agents Robert J Moots, MD, PhD Professor of Rheumatology...

Examining the Properties of Biologic Agents

Examining the Properties of Biologic Agents

Robert J Moots, MD, PhDRobert J Moots, MD, PhD

Professor of RheumatologyProfessor of Rheumatology

University of Liverpool, UKUniversity of Liverpool, UK

Robert J Moots, MD, PhDRobert J Moots, MD, PhD

Professor of RheumatologyProfessor of Rheumatology

University of Liverpool, UKUniversity of Liverpool, UK

Academic Academic Rheumatology Rheumatology UnitUnit

Clinical Sciences CentreClinical Sciences CentreUniversity Hospital AintreeUniversity Hospital AintreeLiverpool, UKLiverpool, UK

Academic Academic Rheumatology Rheumatology UnitUnit

Clinical Sciences CentreClinical Sciences CentreUniversity Hospital AintreeUniversity Hospital AintreeLiverpool, UKLiverpool, UK

Inflammatory Arthritis: Inflammatory Arthritis: Traditional TherapyTraditional Therapy

Inflammatory Arthritis: Inflammatory Arthritis: Traditional TherapyTraditional Therapy

The Crime SceneThe Crime SceneThe Crime SceneThe Crime Scene

Protein

InflammationInflammationInflammationInflammation

Cytokines in InflammationCytokines in InflammationCytokines in InflammationCytokines in Inflammation

Pro-inflammatory Anti-inflammatory

TNFIL-1

sTNFRIL-10

IL-1Ra

Production of TNFProduction of TNFProduction of TNFProduction of TNF

ActivatedActivatedMacrophageMacrophage

TNF

TACE

TM-TNF

sTNFR

TNFTNF Mode of Action Mode of ActionTNFTNF Mode of Action Mode of Action

TargetTargetCellCell

SignalSignal

ActivatedActivatedMM

TNF

Anti-TNFAnti-TNF therapies therapies

Are they all Are they all the samethe same

Anti-TNFAnti-TNF Drugs DrugsAnti-TNFAnti-TNF Drugs Drugs

Conventional (eg, thalidomide) Conventional (eg, thalidomide) – Suppress production TNFSuppress production TNF

– Limited efficacy, side-effectsLimited efficacy, side-effects

Biologics Biologics – Protein-based, made by biological technologyProtein-based, made by biological technology

– Specific effects, neutralise TNFSpecific effects, neutralise TNF

– High efficacyHigh efficacy

– Etanercept, infliximab, adalimumabEtanercept, infliximab, adalimumab

Conventional (eg, thalidomide) Conventional (eg, thalidomide) – Suppress production TNFSuppress production TNF

– Limited efficacy, side-effectsLimited efficacy, side-effects

Biologics Biologics – Protein-based, made by biological technologyProtein-based, made by biological technology

– Specific effects, neutralise TNFSpecific effects, neutralise TNF

– High efficacyHigh efficacy

– Etanercept, infliximab, adalimumabEtanercept, infliximab, adalimumab

Drug Structures and KineticsDrug Structures and KineticsDrug Structures and KineticsDrug Structures and Kinetics

Constant (Fc)

Variable

Murine

InfliximabInfliximabInfliximabInfliximab

Constant (Fc)

Variable

Human

AdalimumabAdalimumabAdalimumabAdalimumab

EtanerceptEtanercept

Human p75 Human p75 TNFTNFreceptorreceptor

Human antibodyHuman antibodyfragmentfragment

Infliximab/AdalimumabInfliximab/AdalimumabMode of ActionMode of ActionInfliximab/AdalimumabInfliximab/AdalimumabMode of ActionMode of Action

ActivatedActivatedMM

TargetTargetCellCell

SignalSignal

TNFTNF

TNFRTNFR

Etanercept Mode of ActionEtanercept Mode of ActionEtanercept Mode of ActionEtanercept Mode of Action

sTNFR:FcsTNFR:FcActivatedActivatedMM

TargetTargetCellCell

SignalSignalsTNFR

sTNFR

TNFTNF

TNFRTNFR

sTNFR:FcsTNFR:Fc

Other PropertiesOther PropertiesOther PropertiesOther Properties

TNF

Lymphotoxin

PharmacokineticsPharmacokineticsPharmacokineticsPharmacokinetics

EtanercepEtanerceptt

InfliximabInfliximab AdalimumAdalimumabab

Half-life (days) Half-life (days) 55 9±19±1 16±216±2

Bind lymphotoxin Bind lymphotoxin

Bolus effectBolus effect

Fix complementFix complement

Lyse cellsLyse cells

T cell anergy T cell anergy

in vivoin vivo

??

Reversible bindingReversible binding

Clinical Efficacy……..All the Clinical Efficacy……..All the same?same?Clinical Efficacy……..All the Clinical Efficacy……..All the same?same?

DiseaseDisease EtanerceptEtanercept InfliximabInfliximab

InflammatorInflammatoryyArthritisArthritis

Heart FailureHeart Failure neutralneutral worsensworsens

Crohn’sCrohn’s

Clinical Efficacy…Inflammatory Clinical Efficacy…Inflammatory ArthritisArthritisClinical Efficacy…Inflammatory Clinical Efficacy…Inflammatory ArthritisArthritis

No head-to-head studiesNo head-to-head studies

Clinical trials: different study designs Clinical trials: different study designs

– MethodologyMethodology

– Inclusion/exclusion criteriaInclusion/exclusion criteria

– DemographyDemography

– GeographyGeography

– Disease severity/comorbidityDisease severity/comorbidity

– Placebo/active comparatorPlacebo/active comparator

No head-to-head studiesNo head-to-head studies

Clinical trials: different study designs Clinical trials: different study designs

– MethodologyMethodology

– Inclusion/exclusion criteriaInclusion/exclusion criteria

– DemographyDemography

– GeographyGeography

– Disease severity/comorbidityDisease severity/comorbidity

– Placebo/active comparatorPlacebo/active comparator

Clinical Efficacy……..Can we Clinical Efficacy……..Can we compare?compare?Clinical Efficacy……..Can we Clinical Efficacy……..Can we compare?compare?

Meta-analyses of published trialsMeta-analyses of published trials

Experience in normal clinical practiceExperience in normal clinical practice

No “perfect” way of comparing directlyNo “perfect” way of comparing directly

Meta-analyses of published trialsMeta-analyses of published trials

Experience in normal clinical practiceExperience in normal clinical practice

No “perfect” way of comparing directlyNo “perfect” way of comparing directly

Meta-analysis: Published Trial Meta-analysis: Published Trial Data Data Meta-analysis: Published Trial Meta-analysis: Published Trial Data Data

0.1 1 10 100

Relative Risk(± 95% CI)

Etanercept vsinfliximab

Infliximab vsadalimumab

Etanercept vsadalimumab

ACR20

ACR50

Meta-analysisMeta-analysisMeta-analysisMeta-analysis

Hochberg et al ARD 2003 62(s2): 13-16

0.1 1 10 100

Relative Risk(± 95% CI)

Etanercept vsinfliximab

Infliximab vsadalimumab

Etanercept vsadalimumab

ACR20

ACR50

Meta-analysisMeta-analysisMeta-analysisMeta-analysis

Hochberg et al ARD 2003 62(s2): 13-16

0.1 1 10 100

Relative Risk(± 95% CI)

Etanercept vsinfliximab

Infliximab vsadalimumab

Etanercept vsadalimumab

ACR20

ACR50

Meta-analysisMeta-analysisMeta-analysisMeta-analysis

Hochberg et al ARD 2003 62(s2): 13-16

Open Label ReportsOpen Label ReportsOpen Label ReportsOpen Label Reports

Geborek et alGeborek et alGeborek et alGeborek et al

ARD 2002ARD 2002ARD 2002ARD 2002

57% of 57% of patients on patients on infliximab infliximab had dose had dose adjustedadjusted

DiscontinuationsDiscontinuationsDiscontinuationsDiscontinuations

Differential Responses?Differential Responses?Differential Responses?Differential Responses?

NICE (UK) “no switching of biologics” 2002NICE (UK) “no switching of biologics” 2002

Clinical practice - switching may workClinical practice - switching may work

– Inefficacy or side effectsInefficacy or side effects

– Etanercept/infliximab/adalimumabEtanercept/infliximab/adalimumab

?mechanism?mechanism

– Efficacy etanercept after failure infliximabEfficacy etanercept after failure infliximab

lymphotoxin on biopsy lymphotoxin on biopsy ((Buch et al ARD 2004;63(10):1344-Buch et al ARD 2004;63(10):1344-6)6)

NICE (UK) “no switching of biologics” 2002NICE (UK) “no switching of biologics” 2002

Clinical practice - switching may workClinical practice - switching may work

– Inefficacy or side effectsInefficacy or side effects

– Etanercept/infliximab/adalimumabEtanercept/infliximab/adalimumab

?mechanism?mechanism

– Efficacy etanercept after failure infliximabEfficacy etanercept after failure infliximab

lymphotoxin on biopsy lymphotoxin on biopsy ((Buch et al ARD 2004;63(10):1344-Buch et al ARD 2004;63(10):1344-6)6)

Toxicity?Toxicity?Toxicity?Toxicity?

Etanercept Infliximab

Toxicity: in Clinical TrialsToxicity: in Clinical TrialsToxicity: in Clinical TrialsToxicity: in Clinical Trials

IJS reaction in 35% IJS reaction in 35%

Rate of infections < MTXRate of infections < MTX

No extra serious infectionsNo extra serious infections

Malignancy as per normalMalignancy as per normal

Haematological sfx < Haematological sfx < MTXMTX

No SLE/demyelinationNo SLE/demyelination

No neutralising antibodiesNo neutralising antibodies

IJS reaction in 35% IJS reaction in 35%

Rate of infections < MTXRate of infections < MTX

No extra serious infectionsNo extra serious infections

Malignancy as per normalMalignancy as per normal

Haematological sfx < Haematological sfx < MTXMTX

No SLE/demyelinationNo SLE/demyelination

No neutralising antibodiesNo neutralising antibodies

Anaphylaxis/infusion Anaphylaxis/infusion reactionreaction

Rate of infections ~MTXRate of infections ~MTX

No extra serious infectionsNo extra serious infections

Malignancy as per normalMalignancy as per normal

Haematological sfx ~MTXHaematological sfx ~MTX

No SLE/demyelinationNo SLE/demyelination

AutoantibodiesAutoantibodies

Anaphylaxis/infusion Anaphylaxis/infusion reactionreaction

Rate of infections ~MTXRate of infections ~MTX

No extra serious infectionsNo extra serious infections

Malignancy as per normalMalignancy as per normal

Haematological sfx ~MTXHaematological sfx ~MTX

No SLE/demyelinationNo SLE/demyelination

AutoantibodiesAutoantibodies

Toxicity: Real LifeToxicity: Real LifeToxicity: Real LifeToxicity: Real Life

Etanercept Infliximab IJS reaction in 35% IJS reaction in 35%

Rate of infections > MTXRate of infections > MTX

Conventional bacterialConventional bacterial

No dose adjustment No dose adjustment

Malignancy?Malignancy?

Haematological sfx ~ Haematological sfx ~ MTXMTX

No neutralising antibodiesNo neutralising antibodies

IJS reaction in 35% IJS reaction in 35%

Rate of infections > MTXRate of infections > MTX

Conventional bacterialConventional bacterial

No dose adjustment No dose adjustment

Malignancy?Malignancy?

Haematological sfx ~ Haematological sfx ~ MTXMTX

No neutralising antibodiesNo neutralising antibodies

Anaphylaxis/infusion Anaphylaxis/infusion reactionreaction

Rate of infections > MTXRate of infections > MTX

Frequency of TB etcFrequency of TB etc

Dose adjustment Dose adjustment

Malignancy?Malignancy?

Haematological sfx ~MTXHaematological sfx ~MTX

AutoantibodiesAutoantibodies

Anaphylaxis/infusion Anaphylaxis/infusion reactionreaction

Rate of infections > MTXRate of infections > MTX

Frequency of TB etcFrequency of TB etc

Dose adjustment Dose adjustment

Malignancy?Malignancy?

Haematological sfx ~MTXHaematological sfx ~MTX

AutoantibodiesAutoantibodies

Toxicity: Real LifeToxicity: Real LifeToxicity: Real LifeToxicity: Real Life

Etanercept Infliximab IJS reaction in 35% IJS reaction in 35%

Rate of infections > MTXRate of infections > MTX

Conventional bacterialConventional bacterial

No dose adjustment No dose adjustment

Malignancy?Malignancy?

Haematological sfx ~ Haematological sfx ~ MTXMTX

No neutralising antibodiesNo neutralising antibodies

IJS reaction in 35% IJS reaction in 35%

Rate of infections > MTXRate of infections > MTX

Conventional bacterialConventional bacterial

No dose adjustment No dose adjustment

Malignancy?Malignancy?

Haematological sfx ~ Haematological sfx ~ MTXMTX

No neutralising antibodiesNo neutralising antibodies

Anaphylaxis/infusion Anaphylaxis/infusion reactionreaction

Rate of infections > MTXRate of infections > MTX

Frequency of TB etcFrequency of TB etc

Often Dose adjustment Often Dose adjustment

Malignancy?Malignancy?

Haematological sfx ~MTXHaematological sfx ~MTX

AutoantibodiesAutoantibodies

Anaphylaxis/infusion Anaphylaxis/infusion reactionreaction

Rate of infections > MTXRate of infections > MTX

Frequency of TB etcFrequency of TB etc

Often Dose adjustment Often Dose adjustment

Malignancy?Malignancy?

Haematological sfx ~MTXHaematological sfx ~MTX

AutoantibodiesAutoantibodies

Keane et al: NEJM 2001Keane et al: NEJM 2001Keane et al: NEJM 2001Keane et al: NEJM 2001

Infliximab Infliximab – 121,000 treated121,000 treated

– 70 TB cases reported by 70 TB cases reported by PASSIVEPASSIVE surveillance surveillance

40 extrapulmonary40 extrapulmonary

17 disseminated17 disseminated

64 from low-incidence countries64 from low-incidence countries

EtanerceptEtanercept– 95,493 treated patients95,493 treated patients

– 9 TB cases reported by 9 TB cases reported by PASSIVEPASSIVE surveillance surveillance

Infliximab Infliximab – 121,000 treated121,000 treated

– 70 TB cases reported by 70 TB cases reported by PASSIVEPASSIVE surveillance surveillance

40 extrapulmonary40 extrapulmonary

17 disseminated17 disseminated

64 from low-incidence countries64 from low-incidence countries

EtanerceptEtanercept– 95,493 treated patients95,493 treated patients

– 9 TB cases reported by 9 TB cases reported by PASSIVEPASSIVE surveillance surveillance

Keane J, et al. N Eng J Med. 2001;345:1098-104Keane J, et al. N Eng J Med. 2001;345:1098-104

FDA update on TBFDA update on TBFDA update on TBFDA update on TB

Biologics as in vivo tools?Biologics as in vivo tools?Biologics as in vivo tools?Biologics as in vivo tools?

Infliximab Infliximab

Effective in Crohn’sEffective in Crohn’s

Recurrence TBRecurrence TB

Infliximab Infliximab

Effective in Crohn’sEffective in Crohn’s

Recurrence TBRecurrence TB

EtanerceptEtanercept

Not effective in Crohn’sNot effective in Crohn’s

No No reports of TBreports of TB

EtanerceptEtanercept

Not effective in Crohn’sNot effective in Crohn’s

No No reports of TBreports of TB

Bolus effect Bolus effect infliximab?infliximab?

C’ fixation C’ fixation cell lysis cell lysis infliximab/adalimumabinfliximab/adalimumab??

Bolus effect Bolus effect infliximab?infliximab?

C’ fixation C’ fixation cell lysis cell lysis infliximab/adalimumabinfliximab/adalimumab??

SummarySummarySummarySummary

Structural/kinetic/biological differences between Structural/kinetic/biological differences between biologicsbiologics

Differential efficacy in various diseasesDifferential efficacy in various diseases

Subtle differences in adverse event profiles (TB)Subtle differences in adverse event profiles (TB)

Monoclonal antibodies vs p75 TNFMonoclonal antibodies vs p75 TNF receptor fusion receptor fusion proteinprotein

Dosage creep mAbDosage creep mAb

Differences between biologics: important research Differences between biologics: important research tools for inflammatory diseasestools for inflammatory diseases

Structural/kinetic/biological differences between Structural/kinetic/biological differences between biologicsbiologics

Differential efficacy in various diseasesDifferential efficacy in various diseases

Subtle differences in adverse event profiles (TB)Subtle differences in adverse event profiles (TB)

Monoclonal antibodies vs p75 TNFMonoclonal antibodies vs p75 TNF receptor fusion receptor fusion proteinprotein

Dosage creep mAbDosage creep mAb

Differences between biologics: important research Differences between biologics: important research tools for inflammatory diseasestools for inflammatory diseases

Don’t blame TNFDon’t blame TNF……!……!Don’t blame TNFDon’t blame TNF……!……!

Men die younger….