Sarzi puttini piercarlo i nuovi inibitori del tnf torino gennaio 2011_14° convegno patologia immune e maPresentation Transcript
I nuovi inibitori del TNF-α Piercarlo Sarzi-PuttiniL Sacco University Hospital Via GB Grassi 74, MIlano
The Journal of Immunology, 2010, 185: 791–794.
BackgroundIn the early 1980s, rheumatoid arthritis (RA), adisease affecting ~1% of the populationworldwide, was a major clinical problem.Twenty-five years later, RA is far from curable,but it is much more manageable, less crippling,and less lethal.Research in immunology has had time to bearfruit and yield clinical benefit, resulting inreduced disease activity and progression.
Cellular processes involved in the pathogenesis of rheumatoid arthritisAtzeni F, Sarzi-Puttini P - Current Opinion in Investigational Drugs 2009 10(11):1204-1211
Innate immunity Acquired immunity TNF-α, IL-1 and IL-6 regulation (non specific) (specific) of innate and acquired immunityHepatic acute Phase response Th2 ResponseAlbumin response T Lymphocyte IL-4Glyconeogenesis IL-10Gluconeogenesis and Amino Acid intake IL-13 Il-1 IL-12 IL-18 CNS Responses Th1 Response Fever TNF-α IL-1 Myalgias Altered sleep behavior macrophage TNF-α Anorexia IL-1 HPA activity IL-2 IL-6 IL-12 IL-18 Somatic tissue response TNF-α IFN-γ Muscle proteolysis Adypocyte Lipolysis Inflammation Immunological responses Cytotoxic response Macrophage activation T lymphocyte or NK Cells Release of Neutrophils Trace mineral redistribution
Induction of Prothrombotic endothelial adhesion action molecules Autocrine activation and differentiation macrophage factor TNF-α Defence againtsGrowth factor intracellular pathogens Comitogen for Induces other Regulates T and B cells cytokines haematopoiesis
TNFαCitochina pro-infiammatoria rilasciata da: monociti attivati macrofagi T-linfocitiIl TNFα si lega a 2 recettori espressi daalcuni tipi di cellule: il recettore TNF p55 edil recettore TNF p75
α Trasduzione del segnale di TNF-α TNF-R1 TNF-R2PC FAN SM PC-PLC SODD TRIP nSMase CK-1 FLIP MADD Ceramide I-TRAF DAG ? ? TRAF 2 TRAF1 TRADD MAPK TRAF2 ASK1 cIAPPKC RIP aSMase FADD SM A20 RAIDO NIK MKKs PLA2 Casp-8 Casp-2 Ceramide κ NF-κB ? ? α β IKKα/IKKβ JNK Apoptosi Apoptosi κ IκB Degradazione c-Jun Apoptosi Attivazione di JNK κ NF-κB p50/p65 κ geni NF-κB-dipendenti
Key Actions Attributed to TNF-a in inflammation
IntroduzioneGli antagonisti del tumor necrosis factor (TNF)-αhanno determinato un nuovo standard terapeutico peril trattamento dell’artrite reumatoide (AR) e di altrepatologie reumatiche.L’utilizzo di qualunque agente farmacologico che alterila funzione immunitaria aumenta la possibilità dideterminati effetti collaterali, quali, per esempio,infezioni e neoplasie
Biologic DMARDs: TNF AntagonistsApproved CompoundChimeric anti-TNF-α mAb Infliximab IgG1TNF-receptor p75 IgG1 Etanercept IgG1 constructFully human anti-TNF-α mAb Adalimumab IgG1Pegylated humanized anti-TNF-α Fab-fragment CertolizumabFully human anti-TNF-α mAb Golimumab Human Mouse Synthetic element Polyethylene glycol
Pathogenesis of rheumatoid arthritis APC MHC+ Co-stimulation CD80/86 antigen TCR modulation CD28 Activated T cellCytokine inhibition• Anti-TNF Activated RANK-L TNF Activated B-cell depletion macrophage IFN-γ IL- B cell• Anti-IL-1R •Anti-CD20 2• Anti-IL-6R IL-6 TNF IL-1 Autoantibodies, e.g. RF IL-6 RANK Osteoclast Chondrocyte MMPs Inflammation and destruction Choy EHS et al. N Engl J Med 2001
Quali modificazioni nel nostrocomportamento clinico individuale edelle raccomandazioni dettate delladelle società scientifiche hannoindotto l’avvento dei farmaci biologici ?
Yesterday’s Approach to Treating RA has Hidden Consequences– Control pain and inflammation– Respond to joint damage only after it is grossly evident Inflammation Destruction Erosions on X-ray Start of Begin Tx Time Start of Start of Timesymptoms symptoms damage
Today’s Goals in RA Treatment Reduce Inflammation AND Prevent Joint Damage – Treat early – Minimize disease activity – Strive for remission – Prevent destruction Non-intensiveInflammation Destruction therapy Intensive therapy Start of Time Start of Start of Timesymptoms symptoms damage
Recommandations for treating RA from an international task forceWhile remission should be a clear target, based on available evidence low diseaseactivity may be an acceptable alternative therapeutic goal, particularly in establishedlong-standing diseaseAn ACR/EULAR initiative on defining remission is currently ongoing Smolen et al. ARD online March 9th 2010 doi: 10.1136/ard.2009.123919
Classification criteria for RA (Scores for A–D ≥6/10 for classification of definite RA)A. Joint involvement (swelling, tenderness or synovitis) 1 large joint 0 2−10 large joints 1 1−3 small joints (with or without involvement of large joints) 2 4−10 small joints (with or without involvement of large joints) 3 >10 joints (at least one small joint) 5B. Serology (at least 1 test result is needed for classification) Negative RF and negative ACPA (anti-CCP) 0 Low-positive RF or low-positive ACPA 2 High-positive RF or high-positive ACPA 3C. Acute-phase reactants (at least 1 test result is needed for classification) Normal CRP and normal ESR 0 Abnormal CRP or normal ESR 1D. Duration of symptoms <6 weeks 0 ≥6 weeks 1 Aletaha D et al. Ann Rheum Dis 2010;69:1580-1588.
EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease- modifying antirheumatic drugsJosef S Smolen, Robert Landewé, Ferdinand C Breedveld, Maxime Dougados, Paul Emery, Cecile Gaujoux-Viala, Simone Gorter, Rachel Knevel, Jackie Nam, Monika Schoels, Daniel Aletaha, Maya Buch, Laure Gossec, Tom Huizinga, Johannes W J W Bijlsma, Gerd Burmester, Bernard Combe, Maurizio Cutolo, Cem Gabay, Juan Gomez-Reino, Marios Kouloumas, Tore K Kvien, Emilio Martin-Mola, Iain McInnes, Karel Pavelka, Piet van Riel, Marieke Scholte, David L Scott, Tuulikki Sokka, Guido Valesini, Ronald van Vollenhoven, Kevin L Winthrop, John Wong, Angela Zink, Désirée van der Heijde [Austria, Czech Republic, Finland,France, Germany, Italy, Spain, Sweden, Switzerland, The Netherlands, UK, USA] Smolen JS et al. Ann Rheum Dis 2010;69:964-975.
EULAR Algorithm: RA management Phase II* Treatment target is clinical remission, or if remission is unlikely to be achievable, at least low disease activity Smolen JS et al. Ann Rheum Dis 2010;69:964-975.
EULAR Algorithm: RA management Phase III* Treatment target is clinical remission, or if remission is unlikely to be achievable, at least low disease activity Smolen JS et al. Ann Rheum Dis 2010;69:964-975.
EULAR Algorithm: RA management Phase III* Treatment target is clinical remission, or if remission is unlikely to be achievable, at least low disease activity Smolen JS et al. Ann Rheum Dis 2010;69:964-975.
Unmet need in pazienti trattati con antiTNF Terapia Gold standard antiTNF + MTX Non tutti i pazienti beneficiano del trattamento Unmet Medical Need Inibitore TNF + MTX Solo antiTNF Solo MTX ACR 70＝70％ miglioramento in: •Attività globale della malattia - paziente •Attività globale della malattia - medico •Percezione del paziente del dolore (Breedveld et al, 2006) •Disabilità fisica •Fase acuta di reazione – PCR,VES
Strategie terapeutiche per pazienti TNF-IR TNF- Nessuna indicazione ufficiale approvata Indicazione approvata in Pazienti in TNF-IR Adalimumab Cambiare TNF cycling meccanismo d’azione oInfliximab Etanercept
Quali le caratteristiche di nuovi farmaci anti- anti- TNF ?• Stessi meccanismi d’azione e funzioni effettrici dei farmaci anti-TNF esistenti (miglioramento delle tecniche di produzione del mAb)• Stessa specificità, ma maggiore affinità• Ridotta immunogenicità• Miglioramento della risposta clinica (maggior e percentuale di remissione o LDA)• Minori effetti collaterali• Minori costi
Systematic review and meta-analysis of 21 randomized, placebo-controlled trials (eight adalimumab, seven infliximab, sixetanercept).Adults with RA who received ADA (1524 patients), IFN (1116patients), ETN (1029 patients), or placebo (2834 patients) with orwithout concomitant methotrexate in all groups.
Efficacy and Safety of anti-TNF• ADA and ETN demonstrated greater efficacy results than did infliximab for short-term treatment (12-30 weeks).• For treatments longer than 1 year, ADA seemed to be more effective than ETN, whereas infliximab seemed to have a decrease in its efficacy
Safety results, whenanalyzed separately, werenot statistically significantamong the anti–TNF drugs; Withdrawals due to adverse events were higher in IFN-treated patients than in ADA- treated patients, whereas in patients who received etanercept, these withdrawals were not statistically significant compared with placebo
Certolizumab Pegolscientific background
LPSRC approvato giugno 2010 CZP-SCT- 007157 32Therapeutic indication from the Summary of ProductCharacteristics (SmPC):Cimzia®, in combination with methotrexate (MTX), is indicatedfor the treatment of moderate to severe, active rheumatoidarthritis (RA) in adult patients when the response to disease-modifying antirheumatic drugs (DMARDs) including MTX, hasbeen inadequate. Cimzia® can be given as monotherapy incase of intolerance to MTX or when continued treatment withMTX is inappropriate.Posology from SmPC:The recommended starting dose of Cimzia® for adult patientswith RA is 400 mg (as 2 injections of 200 mg each on one day)at weeks 0, 2 and 4, followed by a maintenance dose of 200 mgevery 2 weeks. MTX should be continued during treatmentwith Cimzia® where appropriate.
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 33 Structure of Certolizumab Pegol (CZP) Fab′ CZP is the only PEGylated anti-TNF Site-specific PEGylation results in: Designed half life of ~14 days Enhanced penetration of CZP into inflamed tissue (in animal models) PEG No Fc region May avoid potential Fc-mediated effects PEGylated such as CDC or ADCC Fab′ fragment 40 kDa PEG (2x20 kDa) Chapman A, et al. Nature Biotech. 1999;17:780-3 Weir N, Athwal D, et al. Therapy. 2006;3:535-45
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 34 Three different approaches to TNF inhibition: Fusion proteins, Antibodies, Pegylated Fab′ Fragments Certolizumab Etanercept Infliximab Adalimumab pegol (Enbrel®) (Remicade®) (Humira®) (Cimzia®) Receptor Fab Fab′ IgG1 IgG1 Fc Fc PEG PEGylated Recombinant Fab′ fragment receptor/Fc fusion Monoclonal 40 kDa PEG protein antibody (2×20 kDa) Weir N, Athwal D, et al. Therapy. 2006;3:535-45
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 35 Potential advantages of PEGylation May improve the pharmacokinetics of PEGylated molecules are well hydrated therapeutic agents.1 May improve bioavailability.1 May enhance penetration and retention of macromolecules into various diseased tissues.1,2 May reduce immunogenicity of some proteins (at this time this has not been shown for certolizumab pegol) (1,3) http://www.nektar.com/platform_technologies.html 1. Chapman et al., Adv Drug Deliv Rev 2002;54:531-545 2. Palframan R. Ann Rheum Dis 2007; 66 (Suppl): A117 3. Harris et al., Clin. Pharmacokinet 2005;44:331-347
LPSRC approvato giugno 2010 CZP-SCT- 007157 36The effect of PEGylation on the half-life of Fc-free Fab′ PEGylation extended the half-life of Fab′ Concentration (% injected dose / gram of blood) 10 1 Fab Fv Fc 0.1 0.01 IgG Fab- Fab-PEG SH Fab Fab′ 0.001 hinge 0 25 50 75 100 125 150 Time (hr) human murineData obtained in animal model Chapman AP, Adv Drug Deliv Rev 2002; 54:531-545
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 37 Imaging CZP Distribution in Inflamed and Normal Tissue in Vivo Normal tissue Diseased tissue Image Min = -4.4803e-05 Max = 0.00065361 efficiency 5 5 4 4 3 3 2 2 -4 -4 10 10 8 8 7 7 6 6 ROI 1=2.3231e-05 ROI 2=1.5441e-05 5 5 ROI 1=4.25e-05 ROI 2=0.00010276 4 4 Color Bar Min = 3.268e-05 Max = 0.00053026 Color Bar Min = 3.268e-05 fluor sub Max = 0.00053026 flat-fielded cosmic • Mice with active arthritis and normal mice administered 2 mg/kg dye-labeled CZP • Imaging and peripheral blood samples taken over the following 24-h period Palframan R et al. Journal Imm. Meth.2009;348:36-41
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 38 Ratio of Level of Anti-TNF Between Normal and Inflamed Tissue in an Animal Model 5 Certolizumab Pegol-Alexa680 *** Adalimumab-Alexa680 Ratio inflammed: normal tissue 4 ** *** 3 *** NS 2 1 0 0 3 6 9 12 15 18 21 24 26 Time (h) *p<0.05, **p<0.01, ***p<0.001 (certolizumab pegol-Alexa680 vs adalimumab-Alexa680) Adattato da Palframan A. J Immunol Methods 348 (2009) 36–41
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 39 Formation of Immune Complexes TNF TNF TNF TNF Certolizumab pegol + TNF-a Antibodies + TNF-a • “Monovalent” • “Bivalent” • No immune complex • Large immune complexes formation are formed Taylor PC., Curr Opin Pharmacol 2010, 10:1–8 Henry et al, Gastroenterology 2007; 132: A-231 (No. S1609)
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 40 RAPID: Study Designs n=636 CZP 400 mg every 2 weeks + MTX Adult patients with active n=639 400 mg, 0, 2, 4 wk CZP 200 mg every 2 weeks + MTX RA on treatment 2:2:1 n=326 Placebo + MTX Week 16 mandatory escape* Open-Label Extension Study RAPID 1 ACR20 mTSS change Co-primary endpoints (lyophilized) 0 16 24 52 OLE RAPID 2 ACR20 (liquid) Primary endpoint 0 16 24 * Patients who failed to respond (ACR 20) at both Weeks 12 and 14 were designated as treatment failures, were withdrawn and had the option entering into an open-label extension study at Week 16. X-rays were taken at withdrawal Keystone et al., Arthritis Rheum. 2008;58(11):3319-29 Smolen et al., Ann Rheum Dis. 2008 Nov 17 (Epub ahead of print) Mease et al., Int. J. Clin. Rheumatol. 2009; 4(3): 253-266
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 41 Significant Improvement in Signs and Symptoms over the first 12 wks of Therapy (RAPID 1: ACR 20 and 50 response rates) 80 80 ** 63,8 ACR 50 (% of Patients) ACR 20 (% of Patients) 60 ** 54,2 60 ** 43,6 40 ** 40 ** 32,9 33,5 ** ** 25,7 22,9 ** 18,3 20 16 20 12,6 15,3 * 9 8,1 4,4 6,1 6,6 5,6 2 2,5 3,5 0 0 wk 1 wk 2 wk 4 wk 8 wk 12 wk 1 wk 2 wk 4 wk 8 wk 12 Placebo + MTX Q2W (n = 199) CZP 200 mg + MTX Q2W (n = 393) *p ≤ 0.05 versus placebo **p < 0.001 versus placebo Adapted from Keystone E, et al. Ann Rheum Dis 2007; 66(Suppl II): 55
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 42 Rapid and Sustained Improvement in Signs and Symptoms With CZP in RAPID 1 80 ACR20 Patients (%) 60 ACR50 40 ACR70 20 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks CZP 200mg + MTX vs. Placebo ACR20: p<0.001 at weeks 1 to 52 ACR50: p<0.01 at week 2; p<0.001 at weeks 4 to 52 CZP 200mg + MTX Q2W (n=393) ACR70: p≤0.05 at week 4; p≤0.01 at week 6 and 8; Placebo + MTX Q2W (n=199) p<0.001 at weeks 10 to 52 Keystone et al. Arthritis Rheum. 2008;58(11):3319-29
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 43 OLE Study Design and Patient Disposition RAPID 1 Open-label Extension CZP 400mg Q2W + MTX CZP 400mg Q2W + MTX n=390a n=274c n=265d n=246e Completers CZP 400mg CZP 200mg Q2W + MTX CZP 400mg Q2W + MTX Wk 0,2,4 n=393a n=255c n=243d n=216e PBO + MTX CZP 400mg Q2W + MTX n=199a n=43c n=41d n=38e Withdrawers (Wk 16) 400 mg n=74b n=66d n=51e 200 mg n=91b n=86d CZP 400mg Q2W + MTX n=61e PBO n=137b n=135d n=106e 0 16 52 100 Weeks aRAPID 1 ITT population bpatients who withdrew from RAPID 1 at Week 16/per protocol selection cpatients who completed RAPID 1 dpatients who entered the OLE epatients remaining in the OLE at Week 100 from RAPID 1 baseline. Keystone et al., Poster Presentation THU0196, EULAR2009
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 44 Efficacy and Safety of CZP + MTX: 3 Year Data - Results RAPID 2 Open-Label Extension Wk24 Wk92a CZP 200 mg Q2W + MTX CZP 400 mg Q2W + MTX CZP 200 mg Q2W + MTX CZP 400 mg Q2W + MTX CZP 400 mg Q2W + MTX CZP 200 mg Q2W + MTX Figure 1. Figure 1. Patients Responding (%) ACR20 Observeda ACR 20/50/70 response rates ACR50 in CZP completers over 3 years Week 148: ACR70 CZP 200 mg EOW + MTX, n=100; CZP 200 mg EOW + MTX, n=106 Weeks Figure 2. Figure 2. DAS28 scores in CZP completers over 3 years (LOCF) a CZP dose decreased per protocol after ≥6 months in the OLECompleters population only JS Smolen et al. EULAR 2010
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 45 ACR Responder Rates at Week 24 (ITT) RAPID 1 RAPID 2 Combination Therapy Combination Therapy 80 80 * 60,8 * * 57,6 Percent Responders (%) 58,8 60 60 * 57,3 * 39,9 40 * 37,1 * 40 * 33,1 32,5 * * 20,6 21,4 † 20 20 † 13,6 15,9 7,6 10,6 8,7 3 3,1 0,8 0 0 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70RAPID 1 RAPID 2 *Significantly different from placebo, * p < 0.001; †p ≤ 0.01 Placebo + MTX (n=199) Placebo + MTX (n=127) CZP 200 mg + MTX (n=393) CZP 200 mg + MTX (n=246) Patients who withdrew or used rescue medication were considered non-responders CZP 400 mg + MTX (n=390) CZP 400 mg + MTX (n=246) Mease et al., Int. J. Clin. Rheumatol. 2009; 4(3): 253-266
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 46 RAPID 1: ACR Responder Rates at Week 52 (ITT Population) 60 * * 54,9 Placebo + MTX (n=199) 53,1 Percent Responders (%) CZP 200mg + MTX (n=393) CZP 400mg + MTX (n=390) 50 * * 39,9 40 38 30 * * 23,2 21,2 20 13,1 10 7,6 3,5 0 ACR20 ACR50 ACR70 *Significantly different from placebo, p < 0.001 Keystone et al., Arthritis Rheum. 2008;58(11):3319-29 Patients who withdrew or used rescue medication were considered non-responders Keystone EC, et al. EULAR 2008, Paris, #THU0157
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 47 Change From Baseline in mTSS, ES, and JSN 3.5 RAPID 1 RAPID 2 3.5 Placebo + MTX (n=199) Placebo + MTX (n=127) 3.0 2.8 3.0 Mean Change From Baseline Mean Change From Baseline CZP 200 mg + MTX (n=393) CZP 200 mg + MTX (n=246) CZP 400 mg + MTX (n=390) CZP 400 mg + MTX (n=246) 2.5 2.5 2.0 2.0 1.5 1.5 1.4 1.5 1.2 1.0 1.0 † 0.7 * 0.4 † 0.5 † 0.5 0.5 0.4 † * * 0.2 † 0.2 0.1 * 0.2 * 0.1 * 0.1 † 0 0.0 -0.4 -0.3 -0.1 0.0 -0.5 mTSS Erosion JSN mTSS Erosion JSN Week 52 Week 24 *p<0.001 versus placebo. *p<0.001 versus placebo. †p≤0.006 versus placebo. †p≤0.005 versus placebo. Keystone et al., Arthritis Rheum. 2008;58(11):3319-29 ITT/LinExt population. Smolen et al., Ann Rheum Dis. 2008 Nov 17 (Epub ahead of print)
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 48 RAPID 1 and 2: Safety Data Overview Adverse events reported to date by patients receiving CZP are consistent with the mechanism of action and route of administration for anti-TNF-α agents There was a low incidence of drop-outs due to adverse events No new unexpected safety signals have been identified to date during these trials The complete safety profile of CZP will be based on the pooled analysis of all the clinical studies Keystone et al., Arthritis Rheum. 2008;58(11):3319-29 Smolen et al., Ann Rheum Dis. 2008 Nov 17 (Epub ahead of print) Mease et al., Poster presentation (Abstract 941), ACR Congress 2007
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 49 A More Rapid Clinical Response Following Certolizumab Pegol Treatment is Associated with Better 52-Week Outcomes in Patients with Rheumatoid Arthritis Edward C Keystone, Jeffrey R Curtis, Roy Fleischmann, Philip Mease, Dinesh Khanna, Josef Smolen, Daniel E Furst, Geoffroy Coteur, Bernard Combe Keystone et al., Poster Presentation THU0163, EULAR2009
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 50 ACR20/50/70 responder rates at Week 52 by DAS28 1.2 response to CZP treatment 100 Week 12 responders (n=57) Week 6 responders (n=200) 81.5* 80 61.0* Patients (%) 60 56,1 40 36,8 37.0* 20 12,3 0 ACR20 ACR50 ACR70 * P < 0.01 vs Week 12 responders Keystone et al., Poster Presentation THU0163, EULAR2009
GPSRC INF 062 0908 CZPCom/CZP/2009/08 LPSRC approved November 2009 For Response to Unsolicited Questions Only 51 Assessment of Kinetics of Response on Long-term Outcomes- Authors’ Conclusions In patients with active RA, a more rapid response to treatment with CZP + MTX (at Wk 6) was associated with a higher probability of improved long-term response than a response at Wk 12/14. Rapid (Week 6) responders demonstrated: Significantly greater improvements in ACR20/50/70, pain relief, and improvements in physical function than the later (Week 12/14) responders. Keystone et al., Poster Presentation THU0163, EULAR2009
Infliximab, Adalimumab, and GolimumabIntended for training purposes only / Requires local regulatory review prior to external use Structures Evolution of Technology The difference in their variable domains and their CDRs is Infliximab primarily due Adalimumab the the different Golimumab technologies that were used to create the variable domain of each antibody Chimeric Phage Display Transgenic Baker D, et al. Rev Gastroenterol Dis. 2004;4(4):196-210.
Intended for training purposes only / Requires local regulatory review prior to external use More Human, Less Immunogenic? Immuno- Immunogenicity? genicity …omab …ximab …zumab …mumab Murine Chimeric Humanized Human Mouse origin Human origin Pendley et al. Curr Op Mol Therap 2003; 5: 172; Koren et al. Curr Pharm Biotech 2002; 3: 349
Evolution of Antibody R&D* Golimumab (Simponi) 2009 Transgenic human mAb‘s 1994 Lonberg et al.; 1994 Green et al. Phage Display synthetic mAb‘s 1990 McCafferty Adalimumab (Humira) 2002 CDR0-modified mAb‘s Trastuzumab (Herceptin) 1986 Jones et al. Palivizumab (Synagis) Gemtuzumab (Mylotarg) Alemtuzumab (Campath) Daclizumab(Zenapax) 1997 Omalizumab (Xolair) Efalizumab (Raptiva) Bevacizumab (Avastin) Chimeric recombinant mAb‘s 1984 Morrison et al. Rituximab (Rituxan) Basiliximab (Simulect) Abciximab (RheoPro) 1994 Infliximab (Remicade) Cetuximab (Erbitux)Murine monoclonal Ab‘s (mAb’s)1975 Koehler & Milstein Ibritumomab (Zevalin) Muromonab-CD3 (Orthoclone OKT3) 1986 Tositumomab (Bexxar) * adapted from: Nils Lonberg: Human antibodies from transgenic animals; Nat. Biotech. Sep 2005. Vol 23 No 9: 1117
Development of Human Antibodies UsingHuman Antibody Transgenic Mice For clarity, several intermediate steps are not shown. Mouse Ig genes deleted Hu Human Ig genes inserted Human antibody Normal mouse transgenic mouse Immunize with Immunize with antigen antigen IFX chimeric ADA human Mouse antibody Human antibody Lonberg et al. Nature Biotech 2005; 23(9): 1117 http://www.medarex.com/Development/Evolution.htm
Comparison of Affinities for TNF Overall mAb affinities for TNF: Shealy et al., epub 2010
Golimumab Stability/Solubility • Allows for a highly concentrated formulation: – Golimumab 100 mg/mL – Adalimumab 50 mg/mL – Infliximab 50 mg/mL – Etanercept 50 mg/mL • For SubQ agents allows for low injection volume: – Golimumab Monthly 0.5 cc – Adalimumab EOW 0.8 cc – Etanercept Weekly 1.0 cc HUMIRA (adalimumab) Prescribing Information, Abbott Laboratories. REMICADE® (infliximab) Prescribing Information, Centocor Inc. ENBREL® (etanercept) Prescribing Information, Amgen Inc. Golimumab, Data on File; Centocor Inc.
GLM: similar Half-life of other anti-TNF but different Dosing Interval TNF-blocker Half-life (days)* Dosing interval* Etanercept s.c. 3.5 - 5 q0.5-q1 wks Adalimumab s.c. 12 - 14# q1-q2 wks q1 in monotherapy Certolizumab s.c. appr. 14 q2 wks Golimumab s.c. 12 ± 3 once per month Infliximab i.v. 8 - 9.5 q6-q8 wks dep. on indication*Based on most recent EMEA approved SPCs (14OCT09 for both GLM and CZP). qX wks = every X weeks. #EMEA SPC mentions "approximately 2 weeks"
Multiple Factors Determine the Dosing Regimen of s.c. anti-TNFs Dosing Regimen = Net Biologic Effect of:• Half-life: The time required for the plasma level of a drug to fall to half of a certain measured level• Binding properties: Specificity (affinity) and tightness (avidity) of binding to the target cytokine TNFαα• Potency: The amount of drug necessary to α neutralize an equal amount of TNFα to produce a clinical effect• Protein stability/solubility: Stability of the molecule in solution
Golimumab Rheumatology Clinical Trials > 2,900 Patients in Phase III Indication Study Indication N GO-BEFORE T05 Active RA naive for MTX 637Rheumatoid GO-FORWARD T06 Active RA despite MTX 444 Arthritis GO-AFTER T11 Active RA w/previous anti-TNF(s) 461 GO-LIVE T12 Active RA despite MTX / IV inj. 643 Psoriatic Active PsA GO-REVEAL T08 356 ArthritisAnkylosing GO-RAISE T09 Active AS 405Spondylitis
Golimumab, a human antibody to TNF-α α given by monthly subcutaneous injections,in active rheumatoid arthritis despite methotrexate: the GO-FORWARD Study Keystone EC, Genovese MC, Klareskog L, Hsia EC, Hall T, Miranda PC, Pazdur J, Bae SC, Palmer W, Zrubek J, Wiekowski M, Visvanathan S, Wu Z, Rahmann MU Ann Rheum Dis. 2009;68:789–796
Co-Primary Endpoints• The proportion of patients achieving American College of Rheumatology Response criteria (ACR) 20 at Week 14• The improvement from baseline in Health Assessment Questionnaire (HAQ) at Week 24 Keystone E et al. Ann Rheum Dis 2009;68:789–796
GO-FORWARD: Study Design GO- Early escape if <20% Subjects with active RA despite MTX therapy (n=444) improvement in TJC and SJC Placebo GLM 100 mg GLM 50 mg GLM 100 mg(ethical reasons) + MTX + Placebo + MTX + MTXSQ injection n=133 n=133 n=89 n=89 Week 0 Week 4 Week 8 Blinded Blinded Blinded Blinded Week 12 Early Escape Early Escape Early Escape Early Escape Week 14* (Golimumab 50 mg) (MTX, baseline dose) (Golimumab 100 mg) (No Change) Week 16 Week 20 Week 24** Week 48: Co-primary Endpoints:Active, Blind *ACR 20 response at Week 14 Treatment **Change from baseline in HAQ at Week 24 Keystone E et al. Ann Rheum Dis 2009;68:789–796
GO-FORWARD: ACR Responses atGO-Week 14 Co-primary * * p< 0.001 * p< 0.01 end point # p< 0.05 ** * ** ** ** ** # * * Keystone E et al. Ann Rheum Dis 2009;68:789–796
Golimumab, A New Human Anti-TNF-Alpha MonoclonalAntibody, Subcutaneously Administered Every 4 Weeks in Patients with Active Rheumatoid Arthritis who werePreviously Treated with Anti-TNF-Alpha Agent(s): Results of the Randomized, Double-Blind, Placebo-Controlled (GO-AFTER) Study Smolen J et al. Lancet 2009; 374: 210-21
GO-AFTER: Study Design GO- Early escape if <20% α Patients with active RA and previously treated with TNFα inhibitor(s) improvement in TJC and SJC (n=461)(ethical reasons) Placebo q4 Golimumab 50 mg q4 Golimumab 100 mg q4SQ injection n=155 n=153 n=153 Week 0 Week 4 Week 8 Double-blinded Double-blinded Double-blinded Week 12 Early Escape Early Escape Early Escape Week 14* (Golimumab 50 mg) (Golimumab 100 mg) (No change) Week 16 Week 20 Week 24 Primary Endpoint: *ACR 20 response at Week 14 Stratification by investigational site and baseline MTX use Smolen J et al. Lancet 2009; 374: 210-21
GLM is efficacious in anti-TNF Experienced Pts anti-Regardless of Type, No. of anti-TNFs and Reason for anti-Discontinuation: GO-AFTER GO- Number of previous anti-TNFs Type of 1st anti-TNF: ADA, IFX, ETA ACR 20 at wk 14 wk 14 wk 24 Percent of Patients p=0.002 p=0.014 Reason for discontinuation ACR 20 at wk 14 Pts previously treated with ADA,Percent of Patients p<0.001 p=0.027 ETN or IFX responded to, and tolerated GLM, regardless of the type, number (1 or 2) or reason for discontinuation of prior anti-TNF therapy Smolen J et al. Lancet 2009; 374: 210-221
CNTO 148 T11 Proportion of ACR20 Responders at Week 14 by Sub-Groups Sub- Proportion of ACR20 Responders at Week 14 Odds Ratio and 95% CI Golimumab Odds Golimumab Combined vs. Placebo Placebo Combined Ratio (95% CI) p-value n (%) n (%)DMARD Yes 107 17.8 215 40 3 (1.8, 5.4) <0.0001 No 48 18.8 89 29.2 1.8 (0.8, 4.2) 0.1836No. of prior TNF inhibitor 1 90 -20 213 -38.5 2.5 (1.4, 4.5) 0.0021 2 44 -15.9 71 -38 3.2 (1.3, 8.3) 0.0141 3 21 -14.3 22 -13.6 0.9 (0.2, 5.3) 0.951Reason for discontinuationof prior TNF inhibitor 96 17.7 173 39.3 3 (1.6, 5.5) 0.0004 Lack of efficacy Non-efficacy related reasons 84 20.2 162 34 2 (1.1, 3.8) 0.0265 Placebo Golimumab Combined Better Better
GO-AFTER: ConclusionGO-• In patients with active RA who had received α anti-TNFα therapy – GLM significantly reduced RA signs and symptoms and improved physical function• Well-tolerated• First randomized study of a switch from a previous anti TNF alpha to second anti TNF alpha
Golimumab, Golimumab, a New, Human, TNF Alpha Antibody Administered SubcutaneouslyEvery 4 Weeks, in Ankylosing Spondylitis(AS): 24 Week Efficacy and Safety Results of Randomized, Placebo Controlled GO-RAISE Study GO- Inman et al. Arthritis Rheum 2008; 58(11): 3402-12
Golimumab, A New, Human, TNF-alpha TNF- antibody administered as a monthlysubcutaneous injection in psoriatic arthritis: 24-week efficacy and safety results of the 24- randomized,placebo- randomized,placebo-controlled GO-REVEAL study GO- Kavanaugh A et al. Arthritis & Rheum 2009; 60: 976-986
Can we compare with other anti TNFα trials? TNFα
Intended for training purposes only / Requires local regulatory review prior to external use ACR20 Response at Week 24 Compared with Other anti-TNFs anti- No head-to-head trials Golimumab Infliximab Etanercept Adalimumab (GO-BEFORE) (ASPIRE) (ERA) (PREMIER) Week 24 Week 221 6 months2 1 Year 3 100 ∆=13 ∆=11 ∆=7 ∆=10 80 73.0 Percent of Patients 72.0 62.0 65.0 63.0 61.0 58.0 60 49.0 40 20 p=0.011 p=0.001 p=NS p=0.022 0 Pbo GLM Pbo IFX MTX ETN MTX ADA 40 mg +MTX Combo + MTX Combo (n=217) 25 mg (n=257) eow + MTX (n=160) + MTX (n=245) + MTX 2x wk (n=268) (n=318) (n=648) (n=207) 1Data on File for ASPIRE; Centocor, Inc. 2Extracted from Bathon J, et al. N Engl J Med. 2000;343:1586-1593. 3Breedveld FC et al. Arthritis Rheum. 2006;54:26-37.
CNTO 148 T05Intended for training purposes only / Requires local regulatory review prior to external use Limitation of comparing studies : substantial and variable placebo effect MTX mono in MTX naive patients : no head to head comparison 100 This control panel show the 90 heterogeneous responsiveness of different patients’ populations 80 (J Smolen Lancet 2007; 370 : 1861-74) 75 70 63 60 53.6 49.4 50 46 43 40 32.1 29.4 28 30 21.2 19 20 15.6 10 0 T05 (24w) ASPIRE (54w) PREMIER (1y) TEMPO (52w) ACR20 ACR50 ACR70
GLM monotherapy 100 mg is equivalent to MTX alone for sign and symptoms This is consistent with ETN and ADA
Intended for training purposes only / Requires local regulatory review prior to external use Anti TNFα monotherapies versus TNFα combination with MTX ACR response at 52 weeks in TEMPO study - 100 *† 85 Percentage of Patients 76 *‡ 80 75 69 60 48 *‡ 43 43 40 24 19 20 0 ACR 20 ACR 50 ACR 70 MTX Etanercept MTX + Etanercept * p<0.01 vs. MTX † p<0.05 vs. ETA ‡ p<0.01 vs. ETA Klareskog L et al. Lancet 2004; 363: 675-81
Intended for training purposes only / Requires local regulatory review prior to external use Anti TNFα monotherapies versus TNFα combination with MTX ACR response at 1 year in PREMIER study - 100 * Percentage of Patients * 80 73 63 62 * 60 54 46 46 41 40 28 26 20 0 ACR 20 ACR 50 ACR 70 MTX Adalimumab MTX + Adalimumab * p<0.01 vs. MTX † p<0.05 vs. ETA ‡ p<0.01 vs. ETA Breedveld et al. Arthritis & Rheum 2006;54:26-37
ConclusionsBlockade of TNF has proved a highly successful therapeutic interventionin the treatment of certain IMIDs.There are currently five biologic therapies within this classThe most notable distinction with respect to efficacy and safety is thatetanercept is not efficacious in inflammatory bowel disease, and has alower association with TB reactivation than the mAbs.Various distinctions between mAbs, either chimeric or human in sequence, aPEGylated Fab0 fragment and an IgG1–TNFR2 fusion protein have beendescribed but the exact biologic and clinical relevance of these distinctionshas yet to be fully elucidated, however.Better understanding may permit future optimization of choice of biologicagent within class for an individual patient.