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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….