The Pharmacology of TNF Inhibitors J. Cush

The Pharmacology of TNF Inhibitors Clinical Investigator Consultant/Lecturer  Amgen/Wyeth  Centocor  NIH (GAIT)  LaJolla Pharmaceuticals  ISIS  Genentech/IDEC  Aventis Aventis Centocor Amgen/Immunex Wyeth-Ayerst Pharmacia Abbott Astra Zeneca Cytokine Inhibitors: Current Indications Enbrel Target RA TNF Yes Remicade TNF Yes Humira TNF Yes Kineret IL-1 Yes Crohns - Yes Clinical Trials Clinical Trials - JRA Yes Clinical Trials Clinical Trials Psoriatic arthritis Ankylosing Spondylitis Yes Clinical Trials - - Yes Clinical Trials Clinical Trials - Kavanaugh A, Cohen S, Cush J Inhibitors of tumor necrosis factor (TNF) in Rheumatoid Arthritis: Will that dog hunt? J Rheumatol 1998;25:2049 Global Safety and Efficacy of Etanercept in RA Klareskog, L, Moreland L, Cohen S. ACR 2002 Discontinuations 100 % Remaining on Study ~80% Early RA (U.S.) Advanced RA (U.S.) Advanced RA (Europe) 80 60 40 Reason: Loss of efficacy 8 % Adverse event 9 % Patient decision 5 % Protocol issues 2 % Lost to follow up 1 % Other 3% Total 29% 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 20 0 Months DMARD Durability in RA Patients 1.0 Estimated Continuation 0.8 0.6 0.4 0.2 0 Azathioprine (n = 56) Hydroxychloroqui ne(n = 228) Methotrexate (n = 253) Oral gold (n = 84) Parenteral gold (n = 269) Penicillamine (n = 193) 0 10 20 30 Months 40 50 60 Pincus T, et al. J Rheumatol. 1992;19:1885–1894. Withdrawal of Methotrexate and Prednisone Change at 3 Years *paired-rank sum` test (n=68) MTX 20 17.6 p<0.001* 10 Prednisone p<0.001 6.4 15 10 9.3 Mean Predinsone dose (mg/d) Mean MTX dose (mg/wk) 5 2.3 5 0 0 Baseline Year 3 Baseline Year 3 Increased Decreased or D/C Discontinued Methotrexate 3% 68% 39% Prednisone 3% 85% 59% TNF Antagonists: Other Indications and Clinical Investigations Confirmed Efficacy in Trials ► ► Under Investigation ► ► ► ► Crohn’s disease Spondyloarthropathies Psoriatic arthritis Psoriasis Vasculitis: Wegener’s, GCA, PAN Scleroderma Graft-versus-host disease Inflammatory myositis Ankylosing spondylitis ► ► ► ► ► ► ► ► ► ► Interstitial lung disease Sjögren’s syndrome Inflammatory eye and ear disease Asthma Hepatitis C Sarcoidosis Behçet’s syndrome Pyoderma gangrenosum Juvenile rheumatoid arthritis Adult Still’s disease Psoriatic Arthritis: Improved Skin Lesions Baseline 12 Weeks Elbow of patient 577; 50% improvement in target lesion. Nail Responses with Etanercept Baseline Week 2 Week 8 Week 12 Cytokine Signaling Pathways Involved in RA RF Plasma cell IL-4 IL-6 IL-10 IL-4 IL-10 Th0 IFNg Interferon g IL-12 B cell Th2 Macrophage Synovium CD4 + T cell CD11 CD69 OPGL CD69CD11 TNF IL-1 IL-6 Osteoclast Fibroblast Chondrocyte Production of metalloproteinases and other effector molecules Migration of polymorphonuclear cells Erosion of bone and cartilage Choy EH, Panayi GS. N Engl J Med. 2001;344:907– 916. Anti-nflammatory -i Proinflammatory TGFb MMPs TIMPs IL-1Ra sIL-1RII IL-1 Ra MAb to IL-6R MAb to TNF IL-1, TNF GM-CSF, IFNg IL-6, IL-8 IL-15, IL-16 IL-17, IL-18 sTNFR, IL-4, IL-10 IL-11, IL-13, IL-18 BP Autoimmune diseases Adapted from Arend WP. Arthritis Rheum. 2001;45:101– 106. Key Actions Attributed to TNF TNF (VEGF) Inhibition of Cytokines Normal interaction Inflammator y cytokine Neutralization of cytokines Monoclonal antibody Cytokin e receptor Inflammator y signal Soluble receptor No signal Receptor blockade Monoclonal antibody Receptor antagonist No signal Activation of anti-inflammatory pathways Antiinflammatory cytokine Suppression of inflammatory cytokines Adapted with permission from Choy EH, Panayi GS. N Engl J Med. 2001;344:907–916. TNF Antagonists etanercept infliximab adalimumab nerelimomab CDP-571 afelimomab Murine sequences CDP PEG Human sequences Evolution of TNF Blocking Therapies Characteristic Class Etanercept (ENBREL) sTNFR Infliximab (REMICADE) TNF MAb Adalimumab (HUMIRA™) TNF MAb Construct Recombinant fusion protein 4 days TNF/LT Chimeric MAb Recombinant human MAb 10–20 days TNF Half-life Binding target 8–10 days TNF Administration 25 mg SC Twice weekly 3–10 mg/kg IV with MTX Every 4–8 weeks 40 mg SC Every other week* *Some patients not taking concomitant MTX may derive additional benefit from increasing the dosing frequency of adalimumab to 40 mg every week Synthesis and Actions of TNF Chimeric A2 (cA2) Monoclonal Antibody Infliximab Mouse (Binding Site for TNF) Human (IgG) k  Chimeric (mouse/human) IgG1 monoclonal antibody k  Binds to TNF with high affinity and specificity Knight DM, et al. Mol Immunol. 1993; 30(16):1443-53. Mechanisms for Antibody Neutralization of TNF Effect of Anti-TNF Antibody on Established Collagen-Induced Arthritis in Mice Effect on Clinical Progression * p < 0.05 vs. control Indicates injections Adapted from Williams RO, et al. Proc Natl Acad Sci. Inhibitory Effect of Infliximab on Synovial Cell IL-1 Production Brennan FM, et al. Lancet. 1989; ii:244-47. Haworth C, et al. Eur J Immunol. 1991; 21:2575-79. Butler D, et al. Eur Cytokine Network. 1995; 6:225-30. Infliximab (Anti-TNF mAb) in Patients with Active RA Serum VEGF and Serum E-selectin Paleolog EM, et al. Arthritis Rheum. 1995; 38 (suppl.):Abstract S757. Binding Characteristics: TNF Inhibitors Etanercept Association Rate (Ka) Dissociation Rate (Kd) Affinity Constants (Ka) Infliximab Adalimumab 5 M-1 Sec7.9 x 106 M-1 Sec- 1.4 x 106 M-1 Sec-1 1.9 x 10 1 1 2.4 x 10-4 Sec-1 33.9 x 109 M-1 2.7 x 10-4 Sec-1 5.8 x 109 M-1 8.8 x 10-5 Sec-1 2.2 x 109 M-1 Infliximab IV: 9.5 Day Half-Life Percent of Maximum Serum Concentration at Steady State 120 100 80 % 60 40 20 0 55-fold Variation 0 1.81% 60 120 Days 180 240 Dosed every 8 weeks Adalimumab SQ: 14 Day HalfLife Percent of Maximum Serum Concentration at Steady State 150 1.5-fold Variation % 100 50 0 0 14 28 Days 42 56 Dosed every 2 weeks Etanercept SQ: 4.8 Day Half-Life Percent of Maximum Serum Concentration at Steady State 150 1.5-fold Variation % 100 50 0 0 30 Days 60 Dosed twice a week Safety Considerations With Biologics ► Serious infections infections (TB) ► Opportunistic ► Malignancies ► Demyelination ► Hematologic abnormalities ► Administration ► Congestive reactions and lupus heart failure ► Autoantibodies TOTAL Opportunistic Infections # Exposed M. Tuberculosis (%US/%EU) Extrapulmonary/miliary Pneumocystis carnii Histoplasmosis* Listeriosis Atypical mycobacteria Etanercept 130,000 38 (32/68) 52% 4 1 2 10 Infliximab 365,000 277 (31/69) 30-45% 38 30 28 26 Adalimumab 2468 13 (23/77) 40% 3 1 Aspergillus Cytomegalovirus Systemic Candidiasis Others 5 5 7 Crypto3, sporo1 24 16 13 Cocci 13 2 Nocardia 1 TB arises in 10% of patients infected ► 1/3 of world infected with m.Tbc ► Many patients develop latent Tb harboring dormant by viable tubercle bacilli ► Nitric oxide & TNF (less so IL-1) play an essential role: activation of macrophages and granuloma formation resulting in containment of persistent Tb infection ► Animal models, TNF inhibition fatal reactivation of latent Tb ► TNF deficient mice: resistant to endotoxin, succeptable to Candida albicans, Listeria monocytogenes, M. TB ► Anti-TNF therapy is anti-granulomatous therapy!  (Tbc cases, Sarcoid, Wegeners, pyoderma gangr., etc) ► Active TNF and Mycobacterial Infection Tbc – Differences between TNF inhibitors Infliximab Pharmacokinetic(1/2 life) 210 hrs Etanercept 102 hrs Off Rate Lymphotoxin inhibition Apoptosis Cell Lysis in vitro Age > 65 yrs Slow None Yes Fast Yes No Yes 42 % No <25% Dose escalation 1/3  dose >90% 1.6 vials per week Tuberculosis & TNF Antagonists should be evaluated for latent TB infection with a tuberculin skin test prior to initiation of TNF antagonist therapy1 ► Obtain CXR? Not Routinely advocated in USA  If PPD positive  If Signs/Sxs present  Recent/known TB Contact ► Patients latent TB: initiate INH prior to or with TNF inhibitor therapy ► If active TB infection, treat 4 drugs, delay intiation of TNF inhibitor therapy 1Furst, ► If et al, Ann Rheum Dis, 2002;61:(Suppl II):ii-ii7 TNF Inhibitors & Antibody Formation ► ► ► ► ► ► Infliximab Etanercept ANA 22,43,63% 11% dsDNA 8,14,10,16 4,7,9,15% Ab to Rx HACA 8.3,17,25,50% < 1% Drug-induced lupus 4 pts (0.2%) 4 pts + Etiology ? IL-10? HACA: directed against murine component  Crohns; 13% HACA+ > more likely to have infusion rxn  Lower HACA levels: MTX, 6MP, AZA; higher dose (10mg) Maini’99 1mg 3mg 10mg HACA -MTX 53% 21% 7% +MTX 15% 7% 0% Safety Considerations: Immunogenicity Anti-Drug Antibodies During RA Clinical Trials % of Patients Developing Anti-drug Antibodies Etanercept Infliximab Adalimumab Anakinra 5 10 5 1 FDA Arthritis Advisory Committee meeting. August 17, 2001. Safety Issue: Administration Reactions Incidence D/C Injection-site reactions Etanercept Anakinra Adalimumab Infusion reactions 37% 71% 18.5% <2% 7% 0.3% Infliximab 22% 1.9% Enbrel® (etanercept) [package insert]. 2002; Remicade ® (infliximab) [package insert]. 2002; Kineret™ (anakinra) [package insert]. 2002; Keystone E et al. Ann Rheum Dis. 2001;60 (suppl 1):67. [Abstract]; van de Putte LBA et al. Ann Rheum Dis. 2002;61(suppl 1):168. [Abstract]; Schiff M et al. Ann Rheum Dis. 2002;61(suppl 1):169. [Abstract] Autoantibodies and TNF Inhibitors ANA (+) dsDNA(+) RA Etanercept Infliximab Adalimumab ►Safe Drug-induced lupus 0 4 6 1 30-40% 11% 62% 12.9% 0-4% 15% 15% 5.6% ►PreScreen/Monitoring ANA & dsDNA Not Necessary! to use TNF inhibitors in ANA+ RA patients with lupus like patients (Thalidomide used in LE) ►Caution Most adverse events have beenidentified in RA and Crohn’s patients. The frequency of these events in AS & SpA has not been studied. ► Use: RCT* = 5068; Worldwide post-marketing+ > 515,000 patients ► Safety Concerns With TNF Inhibitors Etanercept Infliximab Adalimumab Serious infections* Tuberculosis+ Lymphoma* New MS/Optic neuritis 0.04/pt-yr 0.03/pt-yr 38 + 9 0.04/pt-yr 13* 10 277 + 4 17/11+$ <2% 15% 4 pts + 21/34 + 1.9% 15% 4 pts+ 1/1* ND CHF+ 3 clinical trials (2E, 1I) were d/c for lack effect; dose related hosp/death D/C for Admin. Rxn* (+)dsDNA* Drug induced Lupus 0.3% 5.7% 1 pt.* The TNF Market are that 10-20% of patients are on TNF inhibitors ► Infliximab Sales grew by >316% from 1999 to 2000 ► Feb 2002 15% of etanercept Rxs by PCP ► 2003 TNF inhibitors on the market in 2003  Infliximab, etanercept, adalimumab ► Estimates Market = $21 Billion ► Current Market ~ $2 Billion ► 2004 Market Estimated @ $4 billion in sales ► Potential Decision Making and Newly Released Drugs Discomfort Comfort Safety Efficacy QOL Less Data More Data TNF Inhibitors Characteristic Etanercept Infliximab Adalimumab Class Construct sTNFR TNF mAb TNF mAb Recombinant Chimeric MAb Recombinant fusion protein human MAb 4 days TNF LT Half-life Binding target 8–10 days TNF 10–20 days TNF Administration Exposure SC BIW 43 mos 230,000 IV q 8 wk 55 mos 365,000 SC EOW 6 mos ~40,000 Comparison of New Agents Etanercept Administration Half-life Indications ACR20 ACR70 *Practice20 Infliximab q4-8 wk IV with MTX 210 hrs RA, Crohns 42-80% 10% >90% Anakinra QD, SC 5.9 hr RA 38-49% 10% ?? Arava PO 15-18d RA 50-52% 15% 60* BIW, SC 102 hrs RA, JRA, ERA 60-73% 10-15% >90% *Born Again RA? Costs 60-75% $15,436 60-75% $13940-30287 (5%) $12,800 5% $2938 TNF Antagonists: Relative Contraindications ► SLE ► Multiple ► Current sclerosis, optic neuritis active serious infections infections ► Chronic/recurrent ► Immunosuppression ► History of TB or positive PPD (untreated) heart failure ► Congestive