Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Similar presentations


Presentation on theme: "Examining the Properties of Biologic Agents Robert J Moots, MD, PhD Professor of Rheumatology University of Liverpool, UK Robert J Moots, MD, PhD Professor."— Presentation transcript:

1 Examining the Properties of Biologic Agents Robert J Moots, MD, PhD Professor of Rheumatology University of Liverpool, UK Robert J Moots, MD, PhD Professor of Rheumatology University of Liverpool, UK

2 Academic Rheumatology Unit Clinical Sciences Centre University Hospital Aintree Liverpool, UK

3

4

5

6

7

8

9 Inflammatory Arthritis: Traditional Therapy

10 The Crime Scene

11 ProteinInflammationInflammation

12 Cytokines in Inflammation Pro-inflammatory Anti-inflammatory TNF  IL-1  sTNFR IL-10 IL-1Ra

13 Production of TNF  ActivatedMacrophage TNF  TACE TM-TNF

14 sTNFR TNF  Mode of Action Activated M  TNF

15 Anti-TNF  therapies Are they all the same

16 Anti-TNF  Drugs  Conventional (eg, thalidomide) –Suppress production TNF  –Limited efficacy, side-effects  Biologics –Protein-based, made by biological technology –Specific effects, neutralise TNF  –High efficacy –Etanercept, infliximab, adalimumab  Conventional (eg, thalidomide) –Suppress production TNF  –Limited efficacy, side-effects  Biologics –Protein-based, made by biological technology –Specific effects, neutralise TNF  –High efficacy –Etanercept, infliximab, adalimumab

17 Drug Structures and Kinetics

18 Constant (Fc) Variable Murine InfliximabInfliximab

19 Constant (Fc) Variable Human AdalimumabAdalimumab

20 EtanerceptEtanercept Human p75 TNF  receptor Human antibody fragment

21 Infliximab/Adalimumab Mode of Action Activated M M   Target Cell Signal TNF TNFR

22 Etanercept Mode of Action M   Target Cell Signal sTNFR TNF TNFR sTNFR:Fc

23 Other Properties TNF  Lymphotoxin

24 PharmacokineticsPharmacokinetics EtanerceptInfliximabAdalimumab Half-life (days) 59±116±2 Bind lymphotoxin   Bolus effect  Fix complement  Lyse cells   T cell anergy in vivo ? Reversible binding 

25 Clinical Efficacy……..All the same? DiseaseEtanerceptInfliximab InflammatoryArthritis Heart Failure neutralworsens Crohn’s

26 Clinical Efficacy…Inflammatory Arthritis  No head-to-head studies  Clinical trials: different study designs –Methodology –Inclusion/exclusion criteria –Demography –Geography –Disease severity/comorbidity –Placebo/active comparator  No head-to-head studies  Clinical trials: different study designs –Methodology –Inclusion/exclusion criteria –Demography –Geography –Disease severity/comorbidity –Placebo/active comparator

27 Clinical Efficacy……..Can we compare?  Meta-analyses of published trials  Experience in normal clinical practice  No “perfect” way of comparing directly  Meta-analyses of published trials  Experience in normal clinical practice  No “perfect” way of comparing directly

28 Meta-analysis: Published Trial Data

29 Meta-analysisMeta-analysis Hochberg et al ARD (s2): 13-16

30 Meta-analysisMeta-analysis

31 Meta-analysisMeta-analysis

32 Open Label Reports

33 Geborek et al ARD % of patients on infliximab had dose adjusted

34 DiscontinuationsDiscontinuations

35 Differential Responses?  NICE (UK) “no switching of biologics” 2002  Clinical practice - switching may work –Inefficacy or side effects –Etanercept/infliximab/adalimumab  ?mechanism –Efficacy etanercept after failure infliximab –   lymphotoxin on biopsy (Buch et al ARD 2004;63(10):1344-6)  NICE (UK) “no switching of biologics” 2002  Clinical practice - switching may work –Inefficacy or side effects –Etanercept/infliximab/adalimumab  ?mechanism –Efficacy etanercept after failure infliximab –   lymphotoxin on biopsy (Buch et al ARD 2004;63(10):1344-6)

36 Toxicity?Toxicity?

37 EtanerceptInfliximab Toxicity: in Clinical Trials  IJS reaction in 35%  Rate of infections < MTX  No extra serious infections  Malignancy as per normal  Haematological sfx < MTX  No SLE/demyelination  No neutralising antibodies  IJS reaction in 35%  Rate of infections < MTX  No extra serious infections  Malignancy as per normal  Haematological sfx < MTX  No SLE/demyelination  No neutralising antibodies  Anaphylaxis/infusion reaction  Rate of infections ~MTX  No extra serious infections  Malignancy as per normal  Haematological sfx ~MTX  No SLE/demyelination  Autoantibodies

38 Toxicity: Real Life EtanerceptInfliximab  IJS reaction in 35%  Rate of infections > MTX  Conventional bacterial  No dose adjustment  Malignancy?  Haematological sfx ~ MTX  No neutralising antibodies  IJS reaction in 35%  Rate of infections > MTX  Conventional bacterial  No dose adjustment  Malignancy?  Haematological sfx ~ MTX  No neutralising antibodies  Anaphylaxis/infusion reaction  Rate of infections > MTX   Frequency of TB etc  Dose adjustment  Malignancy?  Haematological sfx ~MTX  Autoantibodies  Anaphylaxis/infusion reaction  Rate of infections > MTX   Frequency of TB etc  Dose adjustment  Malignancy?  Haematological sfx ~MTX  Autoantibodies

39 Toxicity: Real Life EtanerceptInfliximab  IJS reaction in 35%  Rate of infections > MTX  Conventional bacterial  No dose adjustment  Malignancy?  Haematological sfx ~ MTX  No neutralising antibodies  IJS reaction in 35%  Rate of infections > MTX  Conventional bacterial  No dose adjustment  Malignancy?  Haematological sfx ~ MTX  No neutralising antibodies  Anaphylaxis/infusion reaction  Rate of infections > MTX   Frequency of TB etc  Often Dose adjustment  Malignancy?  Haematological sfx ~MTX  Autoantibodies  Anaphylaxis/infusion reaction  Rate of infections > MTX   Frequency of TB etc  Often Dose adjustment  Malignancy?  Haematological sfx ~MTX  Autoantibodies

40 Keane et al: NEJM 2001  Infliximab –121,000 treated –70 TB cases reported by PASSIVE surveillance  40 extrapulmonary  17 disseminated  64 from low-incidence countries  Etanercept –95,493 treated patients –9 TB cases reported by PASSIVE surveillance  Infliximab –121,000 treated –70 TB cases reported by PASSIVE surveillance  40 extrapulmonary  17 disseminated  64 from low-incidence countries  Etanercept –95,493 treated patients –9 TB cases reported by PASSIVE surveillance Keane J, et al. N Eng J Med. 2001;345:

41 FDA update on TB

42 Biologics as in vivo tools? Infliximab Infliximab  Effective in Crohn’s   Recurrence TB Infliximab Infliximab  Effective in Crohn’s   Recurrence TB Etanercept Etanercept  Not effective in Crohn’s  No  reports of TB  Bolus effect infliximab?  C’ fixation  cell lysis infliximab/adalimumab?  Bolus effect infliximab?  C’ fixation  cell lysis infliximab/adalimumab?

43 SummarySummary  Structural/kinetic/biological differences between biologics  Differential efficacy in various diseases  Subtle differences in adverse event profiles (TB)  Monoclonal antibodies vs p75 TNF  receptor fusion protein  Dosage creep mAb  Differences between biologics: important research tools for inflammatory diseases  Structural/kinetic/biological differences between biologics  Differential efficacy in various diseases  Subtle differences in adverse event profiles (TB)  Monoclonal antibodies vs p75 TNF  receptor fusion protein  Dosage creep mAb  Differences between biologics: important research tools for inflammatory diseases

44 Don’t blame TNF  ……! Men die younger….

45

46

47

48

49 Go ahead…… Make my day…… Join the University of Liverpool Academic Rheumatology Unit!


Download ppt "Examining the Properties of Biologic Agents Robert J Moots, MD, PhD Professor of Rheumatology University of Liverpool, UK Robert J Moots, MD, PhD Professor."

Similar presentations


Ads by Google