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Biological Differentiation Part I

Biological Differentiation Part I. Dubai, United Arab Emirates January 19th, 2009 Prof. Joachim R. Kalden Director emeritus Dept. of Internal Medicine III Div. of Molecular Immunology Nikolaus-Fiebiger-Center University of Erlangen-Nuremberg. Overview. Pharmacology of TNF inhibitors

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Biological Differentiation Part I

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  1. Biological DifferentiationPart I Dubai, United Arab Emirates January 19th, 2009 Prof. Joachim R. Kalden Director emeritus Dept. of Internal Medicine III Div. of Molecular Immunology Nikolaus-Fiebiger-Center University of Erlangen-Nuremberg

  2. Overview • Pharmacology of TNF inhibitors • MOA of TNF inhibitors • Differences in latent TB among TNF inhibitors • Dose creep in biologics • Immunogenicity • 10 years safety data

  3. S S S S Structure of ENBREL S S S S S S CH3 CH2 Fc region of human IgG1 Extracellular domain of human p75 TNFR • Dimeric vs. monomeric sTNFR • Longer half-life • Higher affinity • More potent TNF- neutralizing activity (~1000X) Mohler KM et al, J Immunol 151:1548–1561, 1993

  4. Etanercept: Binds soluble and membrane TNF- and Lymphotoxin  (LT- ) with high affinity Competes with cell-surface TNF receptors (TNFRs) In vitro, does not lyse cells expressing membrane TNF- Neutralises TNF- activity Mechanism of action ENBREL® [package insert]. Seattle, WA; Immunex Corp. and Wyeth-Ayerst Laboratories, 2001.

  5. Inhibitors of TNF:Etanercept and the monoclonal antibodies

  6. TNF inhibitors Tracey et al. Pharmacology & Therapeutics 2008; 117: 244 – 79

  7. TNF inhibition: Differences in mechanisms of action • Soluble TNF receptors • Human TNF receptor linked to Fc portion of IgG • Bind soluble and cell-bound TNF and LT • Complement dependant cytotoxicity (significantly lower as MAb) • ADCC activity • TNF monoclonal antibodies • Chimeric and human versions • Variable (Fab) region binds to soluble and cell-bound TNF • Do not bind LT • Bind soluble and cell-bound TNF • Complement dependant cytotoxicity • ADCC activity • Induction of apoptosis and cell cycle arrest in trans-membrane TNFalpha expression

  8. Suggested reasons for differences in efficacy in Crohn’s disease related to MAb • Variations in tissue penetration • Stability of the immune complexes with TNF • Induction of apoptosis of both monocytes and T cells • Neutralisation of membrane TNF • Antibody-dependent cell-mediated cytotoxicity (ADCC) • Complement-dependent cytotoxicity (CDC) • Reverse signalling via mTNF • Interferring with granulomaformation Nesbitt et al. Inflamm Bowel Disease 2007; 13: 1323

  9. Binding of TNF

  10. Proposed cell binding model Kohno et al. ACR 2005

  11. Differences in binding characteristics * Drug:TNF ratio Adapted from Tracey et al. Pharmacology & Therapeutics 2008; 117: 244 – 79

  12. Neutralisation of sTNF* ETN CTZ IFX ADL *Measured by cytoxicity to L929 cells Nesbitt et al. Inflamm Bowel Disease 2007; 13: 1323

  13. Binding to tmTNF ETN CTZ IFX ADL IgG Fab’ PEG ETN, IFX, ADL and IgG detected with phycoerythrin-labeled anti-heavy and light chain polyclonal antiserum CTZ and Fab’ PEG detected with anti-Fab2 polyclonal antisera Nesbitt et al. Inflamm Bowel Disease 2007; 13: 1323

  14. ETN CTZ IFX ADL IgG Fab’ PEG Neutralisation of tmTNF Non-cleavable tmTNF-expressing NS0 clone 23 incubated with A549-Luc cells Nesbitt et al. Inflamm Bowel Disease 2007; 13: 1323

  15. Comparative stability of tmTNF binding: infliximab vs. etanercept None Infliximab Etanercept TNF A B 100 100 80 80 60 60 % Etanercept Bound % Infliximab Bound 40 40 20 20 0 0 0 20 40 60 80 100 120 0 20 40 60 80 100 120 Time of Incubation (min) Time of Incubation (min) Scallon B et al. J Pharmacol Exp Ther 2002; 301:418-26

  16. Summary

  17. Effects on mechanisms of immunity to TB

  18. The global problem of TB • The World Health Organisation (WHO) estimates that in 1999, there were 8.4 million new cases, up from 8.0 million in 1997 • Estimated nearly 2 million deaths from tuberculosis annually • Ranks second only to human immunodeficiency virus (HIV) infection as an infectious cause of death • 1.7 billion people, one third of the world's population, are thought to be infected with Mycobacterium tuberculosis • Developed countries are not protected from the ongoing epidemic of tuberculosis occurring in the poor countries of the world Jasmer et al. NEJM 2002; 347: 1860-66

  19. Host defence against TB Gardam et al. Lancet Infectious Diseases 2003; 3: 148 - 55

  20. Effects on T cell activation • Whole blood cultures of healthy tuberculin skin test + volunteers stimulated with TB culture filtrate antigen or PHA • T cell activation, apoptosis, necrosis, cytokine production, and gene expression profiles assessed • Whole blood cultures infected with TB H37Ra and growth assessed • TNF blockers were added at therapeutic concentrations • ETN also studied at a supratherapeutic concentration • Activation (CD69), apoptosis (annexin V), and necrosis (7AAD) were measured by flow cytometry • IFNγ and IL-10 measured by ELISA Saliu et al. J Infect Dis 2006

  21. Incidence of TB Is low in RA patients receiving etanercept therapy* *Majority of patients in combined analysis were white, female, and enrolled in RA studies Wajdula J et al. EULAR 2007

  22. Data from adalimumab trials* • 11,439 RA patients (14,544 patient-years [pt-yrs] of exposure) in North America and Europe • 3422 patients (5918.9 pt-yrs) North America • 8017 patients (8625.2 pt-yrs) Europe • Before screening 7 cases TB (534 pt-yrs exposure; 0.013/pt-yr) • After screening 27 cases TB (14,010 pt-yrs exposure; 0.0019/pt-yr) • 5 North America (rate 0.0008) • 22 Europe (rate 0.0027) • Ratio Europe to North America is 1:3.2 *Up to Dec 31 2004 Perez. EULAR 2005: OP 0093

  23. Rates of TB in France - RATIO • Case-control study found the following factors predictive of TB in multivariate analysis: • ADA vs. ETA HR: 10.05 [1.92-52.61], P=0.006 • IFX vs. ETA HR: 8.63 [1.38-53.78], P=0.02 • Estimated incidence of tuberculosis (per 100,000 pt/year) • French population 8.7 • TNFi treated patients 39.2 • IFX or ADA 71.5 • ETN 6.0 • This large national prospective study clearly shows that the risk of TB is higher with monoclonal antibodies than with the soluble receptor Tubach et al. Ann Rheum Dis 2008; 67(Suppl II):52; OP00143

  24. # cases 7 3 6 Exposure (pt-yrs) 534 3978 4447 TB Rates in Adalimumab Clinical Studies Post-screening Pre-screening Data on file: Through July 2003

  25. Possible reasons for differences in reactivation of latent TB and efficacy in CD • Divergent effects on control of intracellular TB growth • MAbs block T cell activation and IFNg production, while etanercept does not • Analysis of global gene expression by microarray shows differential effects of MAbs and ETN • ETN affects TH1 genes, MAbs TH2 • These differential effects are not due to T cell apoptosis, CDC or ADCC • CTZ does not induce apoptosis, CDC or ADCC but cases of TB have been reported during clinical trials in RA • Irreversible binding of mbTNF by MAbs, including CTZ, but not ETN may be important by reducing cell-to-cell signaling • The high rate of TB reactivation by the TNF MAbs may reflect their inhibition of both TNF and IFNg

  26. Summary of TB data • Cases of TB reported with all TNF-targeted therapies • Cases reported with ADL clinical trials, even with screening • Cases reported with CTZ in clinical trials • Screening for TB not undertaken with ETN clinical trials. Only 2 cases of TB reported • Registries report significantly lower rates of TB in patients treated with ETN than IFX or ADL

  27. Etanercept Infliximab # RA treated > 150 000 198 235 Pt-yrs exposure > 230 000 227 559 Pneumocystis carinii 4 14 Histoplasmosis 1 18 Listeriosis 3 16 Atypical mycobacteria 10 23 Aspergillus 5 14 Cytomegalovirus 5 9 Nocardia 2 -- Systemic Candidiasis 7 4 Coccidiodomycosis -- 4 Opportunistic Infections* * To August 2002 1. FDA Arthritis Advisory Committee Meeting Safety update on TNF alpha inhibitors. March 4, 2003 2.Keystone, Advances in Targeted Therapies V,April,2003 .

  28. Does dose escalation improve clinical efficacy?

  29. Why are we seeing dose increases with infliximab ? • Tachyphylaxis ? Anti-infliximab antibodies • Sub-optimal dosing • Concomitant meds: MTX, prednisone • Transient disease flares / Ease of dose increases • Pharmacokinetics

  30. Infliximab Dose in 1248 RA Patients After 1.5 Years • 56% had dose increases. Average dose of 5 mg/kg. • Comparable to reported literature • Montreal cohort of 85 patients 46 (54%) had dose increases Wolfe F, et al. Arthritis Rheum. 2003;48(9):S328.

  31. Does Increasing Dose of Infliximab Lead to Better Outcomes? • 124 Patients from STURE database • 44 patients treated with infliximab; dose increased from 3 mg/kg to 5–7 mg/kg q8 weeks • 44 patients treated with infliximab; dose maintained at 3 mg/kg • 36 patients treated with etanercept • Examined disease activity before and after dose increase Van Vollenvoven RF, et al. Ann Rheum Dis. 2004;63:426-30.

  32. DAS28 Scores Before and After Dose Escalation Van Vollenvoven RF, et al. Ann Rheum Dis. 2004;63:426-30.

  33. IMMUNOGENICITY HACA / HAHA

  34. Antibodies Anti-isotypic antibodies bind here Anti-idotype antibodies bind here Anti-allotypic antibodies bind here

  35. Incidence of Antibodies-to-Infliximab (ATI) - Maintenance Studies* Antibody-to-Infliximab (ATI) Status % of Pts with ATI % of Patients Inconclusive† % of Pts without ATI n=514 Week 72 n=258 Week 54 n=295 Week 102 ACCENT I CD ACCENT II CD ATTRACT RA Maintenance Studies *Patients. with evaluable samples †Patients with long-lasting serum concentrations of infliximab and never ATI (+) Integrated Safety Summary. Aug 09, 2002.

  36. Infusions with Infusion Reactions by Antibody-to-Infliximab(ATI) Status ACCENT I through week 542 ATTRACT through week 1021 Infusion Reactions Infusion Reactions Proportion of Infusions with Proportion of Infusions with Positive* 37 / 329 Inconclusive* 93 / 3092 Negative* 35 / 1224 Positive* 42 / 254 Inconclusive* 47 / 1470 Negative* 55 / 656 Antibody-to-Infliximab Status Antibody-to-Infliximab Status *patients with evaluable samples 1 Internal data, Centocor. 2 Lancet 2002; 359: 1541–49.

  37. HACA and Patterns of Infliximab Dosing 1P < 0.005, Group A vs. Group using two-tailed t-test. Haraoui et al, in press

  38. Probability of experiencing secondary loss of efficacy (%) 1 year 2 years 3 years 4 years 5 years 6 years etanercept 1.9 3.5 5.6 6.8 9.8 12.4 infliximab 1.4 5.4 11.4 16.8 21.5 27.5 adalimumab 4.4 11.8 Secondary Loss of Efficacy with TNF-antagonist: STURE Registry Conclusion: • Secondary loss of efficacy occurs to lesser degree with etanercept• Adalimumab data limited, some previous TNF treatment• Secondary loss of efficacy appear less during first years of treatment and greater with longer-term therapy Van Vollenhoven et al. SAT0198. EULAR 2006.

  39. 25% subjects adalimimab monotherapy and 11% of combination required dose escalation in the PREMIER1 study Adalimumab increasing starting dosepublished data 30% 25% 25% 20% 15% 13% 11% 10% 5% 0% PREMIER - PREMIER - Engel-Nitz et. Monotherapy Combination al EULAR 2007 Ferdinand C. et al, Arthritis & Rheumatism, Vol. 54, Jan. 2006

  40. THU0124 Safety and efficacy of over 10 years of continuous etanercept therapy in patients with rheumatoid arthritis in North America and Europe

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