TNF Inhibitors: Lessons From Immunogenicity Edward Keystone, MD, FRCP(C) Professor of Medicine University of Toronto Toronto, Canada Edward Keystone, MD FRCP(C) Disclosures Sources of Funding for Research: Abbott Laboratories; Amgen Inc.; AstraZeneca Pharmaceuticals LP; Baylis Medical; Bristol-Myers Squibb; F. Hoffmann-La Roche Inc; Janssen Inc, Lilly Pharmaceuticals, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, Sanofi-Aventis, UCB. Consulting Agreements/Advisory Board Membership: Abbott Laboratories; AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company; F. Hoffmann-La Roche Inc; Genentech Inc; Jannsen Inc, Lilly Pharmaceuticals; Merck, Nycomed, Pfizer Pharmaceuticals, UCB; Speaker Honoraria Agreements: Abbott Laboratories; Astrazeneca LP; Bristol-Myers Squibb Canada; F. Hoffmann-La Roche Inc.; Janssen Inc.; Pfizer Pharmaceuticals; UCB; Amgen Financial Interests/Stock Ownership: None Discussion of Off-Label, Investigational, or Experimental Drug Use: None Revised May 2013
Outline Targets of Immunogenicity Factors Affecting Immunogenicity Clinical Implications Proposed Treatment Algorithm 2007
Etanercept (Enbrel ) Three classes of TNF antagonists: Fusion proteins, Antibodies, Pegylated Fab Fragments Receptor Infliximab (Remicade ) Fab Adalimumab (Humira ) Fab Golimumab Certolizumab pegol (Cimzia ) Fab IgG1 Fc IgG1 Fc IgG1 Fc PEG Recombinant receptor/fc fusion protein Monoclon al antibody PEGylated Fab fragment 40 kda PEG (2 20 kda) Weir N, Athwal D, et al. Therapy. 2006;3:535-45 Anti-Drug Antibodies Are Increased In All TNFis Managed Healthcare Training Audience Date 1.9.13 Company Confidential 2013
Antidrug Antibodies (ADAb) to TNF-Specific Neutralising Agents In Chronic Inflammatory Diseases: A Real Issue, A Clinical Perspective Vincent FB et al. Ann Rheum Dis 2012;0:1-9 Managed Healthcare Training Audience Date 1.9.13 Company Confidential 2013 INFLIXIMAB: Incidence, Clinical And Biological Associations Of Anti-drug Antibodies = 6-61% Vincent FB et al. Ann Rheum Dis 2012 Managed Healthcare Training Audience Date 1.9.13 Company Confidential 2013 8
ADALIMUMAB: Incidence, Clinical And Biological Associations Of Anti-drug Antibodies In The Literature = 0.04-87% Vincent FB et al. Ann Rheum Dis 2012 Managed Healthcare Training Audience Date 1.9.13 Company Confidential 2013 ETANERCEPT: Incidence, Clinical And Biological Associations Of Anti-drug Antibodies = 0-18% Vincent FB et al. Ann Rheum Dis 2012 Managed Healthcare Training Audience Date 1.9.13 Company Confidential 2013
CERTOLIZUMAB: Incidence, Clinical & Biological Associations of anti-drug Antibodies = 3-25% Vincent FB et al. Ann Rheum Dis 2012 Managed Healthcare Training Audience Date 1.9.13 Company Confidential 2013 GOLIMUMAB: Incidence, Clinical & Biological Associations of anti-drug Antibodies = 0-7.2% Vincent FB et al. Ann Rheum Dis 2012 Managed Healthcare Training Audience Date 1.9.13 Company Confidential 2013
Take Home Message Anti-Drug Abs observed with all TNFis: in RA and non-ra disorders variable between TNFis Anti-Drug Abs inversely correlated with: serum trough level clinical response MTX use Anti-Drug Abs correlated with A/Es: mainly infusion reactions Managed Healthcare Training Audience Date 1.9.13 Company Confidential 2013 Factors Related to Immunogenicity & Its Detection Factors Contributing to Immunogenicity Dose, frequency, duration and route of administration 1 Concomitant medication 2 Genetics, immune and nutritional status of the patient 1 Antibody isotype 1 IgG1, IgG2, IgG3, IgG4 Function of the therapeutic target 1 Size and complexity of the therapeutic agent 1 Factors Contributing to the Detection of Anti-drug Antibody Clearance rate of the immunecomplex 1 Presence of soluble drug 1 Type of detection assay 1 Timing of antibody determination 1 antibody titer 2 1. Cassinotti A, et al. Inflamm Bowel Dis. 2009;15:1264-1275. 2. Hermeling S, et al. Pharm Res. 2004;21:897-903.
Positive Interpretation of Results Positive for antibodies regardless of drug levels Negative Negative for antibodies Undetectable drug levels Inconclusive Negative for antibodies Detectable drug levels Important Limitations Regarding Immunogenicity Information Data on antibody development and immunogenicity are highly dependent on the sensitivity and specificity of the assay Interpretation requires information about drug levels at the time of sampling Very few assays in the public domain For these reasons, comparison of the incidence of antibodies between products may be misleading.
Practical Clinical Implications of Anti-Drug Abs Impact on safety Impact on efficacy Impact on TNFi dose escalation Impact on switching strategies Impact on Safety
Proportion of Infusions with Infusion Reactions Proportion of Infusions with Infusion Reactions Safety - Infusions with Infusion Reactions by Antibody-to-Infliximab (ATI) Status ATTRACT through week 102 1 ACCENT I through week 54 2 50 50 40 40 30 30 20 10 0 11 3 3 20 10 0 16 3 8 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 2 Lancet 2002; 359: 1541 49. Take Home Message Anti-drug Ab increase the risk of infusion reactions with TNFi s
Impact on Efficacy The Immunogenicity Of anti-tnf Therapy : A Systemic Review Of The Literature With A Meta-analysis Garces S, Demenegeot J and Benito-Garcia E. Ann Rheum Dis 2012; 0:1-9. doi:10.1136/annrheumdis-2012-20220
Effect of Anti-Drug Ab Positivity on a TNF Response Garces S et al. Ann Rheum Dis 2012; 0:1-9. doi:10.1136/annrheumdis-2012-20220 Clinical Characteristics To Address Effect Of Anti-Drug Abs On Drug Response & The Effect Of Immunosuppression On Anti-Drug Ab Detection Garces S et al. Ann Rheum Dis 2012; 0:1-9. doi:10.1136/annrheumdis-2012-20220
Take Home Message The Effect Of Anti-drug Abs On The TNFi Response Is Influenced By. MTX Rheumatoid Arthritis vs other diseases Initiation of higher biologic dose? Antidrug Antibodies : Association With Disease Activity and Treatment Failure During Long-term Follow-up Bartelds et al, JAMA, April 2013, Vol 305, No. 4, pp1460-1468
Effect of anti-adalimumab Abs on Overall Pt Dropout & Dropout Due to Rx Failure Bartelds, Geertje et al, JAMA, April 2013, Vol 305, No. 4, pp1460-1468 Effect of anti-adalimumab Abs on Sustained Disease Activity & Remission Bartelds, Geertje et al, JAMA, April 2013, Vol 305, No. 4, pp1460-1468
Take Home Message Anti- Drug Abs increased dropout rate as a consequence of loss of efficacy. Anti- Drug Abs reduced sustainability of LDAS and remission Effect of Serum TNFi Levels on Clinical Outcomes
CRP < 5mg/dL (% of patients) Complete Endoscopic Remission (% of patients) Remisssion (% of patients) Endoscopic Improvement >75% (% of patients) Effect of SerumTrough Levels of Infliximab in Crohn s Disease @ 52 wks 100 80 82 100 80 88 MSH, Toronto 60 40 20 0 100 90 80 70 60 50 40 30 20 10 0 76 Remission CRP P<0.001 6 P<0.001 32 60 40 20 0 100 80 60 40 20 Trough Serum Infliximab Detectable 0 P<0.001 33 Endoscopic improvement 47 P=0.03 19 Complete endoscopic remission Undetectable Maser EA et al. Clin Gastroenterol Hepatol 2006;4:1248-54 Anti-adalimumab Antibodies & Serum Adalimumab Concentrations In RA Bartelds GM et al., Ann Rheum Dis 2007; 66:921-926
Serum Trough Levels Of Adalimumab In Psoriasis Adalimumab Trough Concentrations per PASI Response Level P < 0.001 P = 0.001 P = 0.006 3* 4* Lecluse LLA, et al. Arch Dermatol. 2010;146(2):127-132 Serum Trough Levels of Infliximab In Ankylosing Spondylitis Serum Trough Infliximab Level for Responders and Non-Responders P=0.018 De Vries MK, et al. Ann Rheum Dis. 2007;66:1252-1254
Levels Of Etanercept In Ankylosing Spondylitis Etanercept Levels for ASAS Responders and Non-Responders De Vries MK, et al. Ann Rheum Dis. 2009;68:531-535 Take Home Message Serum trough levels of inflixmab & adalimumab affect clinical outcomes in RA and non-ra conditions. Trough levels of etanercept do not affect clinical outcomes in AS.
Subjects with a response Impact of Anti-Drug Abs On TNFi Dose Escalation Clinical Outcomes in Crohn s Disease Mayo Clinic 100 Detectable ATI 100 Subtherapeutic IFX 75 p<0.004 75 p<0.016 50 50 25 25 0 n=17 n=12 n=29 n=6 0 Increase IFX Change Anti- TNF Response to test Increase IFX Change Anti- TNF Response to test Afif et al. Am J Gastroenterol. 2010; 105(5):1133-1139.
Take Home Message Dose escalation is useful in patients with a subtherapeutic dose of a TNFi Dose escalation unhelpful in patients with detectable anti-drug Abs and therapeutic trough levels BUT.. Some reports show dose escalation can boost immune response with increased infusion reactions While other reports show decrease in anti-dug Abs and improved drug response More studies warranted. Impact of Anti-Drug Abs on TNFi Switching
Anti-Infliximab and Anti-Adalimumab Antibodies in Relation to Response to Adalimumab in Infliximab Switchers and Anti-TNF Naïve Patients Study Design Observational cohort study of 235 patients all treated with adalimumab 22% had previously been treated with infliximab switchers 78% were anti-tnf naive Bartelds GM, et al. Ann Rheum Dis. 2010;69:817-821 Anti-ADA status, n (%) Total populati on (N=235) Δ DAS28* all 1.6 ± 1.5 Δ DAS28* anti-ada (-) Δ DAS28* anti-ada (+) Anti-TNF naïve patients (n=183) INF switcher s (n=52) INF switcher s with anti-inf (n=33) INF switcher s w/out anti-inf (n=19) 46 (20) 32 (18) 14 (27) 11 (33) 3 (16) 1.8 ± 1.4* 0.6 ± 1.3 Results Frequency of Anti-Adalimumab (a-ada) Antibodies and Clinical Response After 28 Weeks of Adalimumab Treatment 1.7 ± 1.5 2.0 ± 1.4* 0.6 ± 1.3 1.1 ± 1.4 1.3 ± 1.3* 0.5 ± 1.4 1.2 ± 1.3 1.6 ± 1.1* 0.4 ± 1.4 0.9 ± 1.4 0.9 ± 1.4 NS 0.7 ± 1.4 Bartelds GM, et al. Ann Rheum Dis. 2010;69:817-821
Results & Conclusion Increased likelihood of anti-ada Ab in patients with anti-inf Ab (rapid metabolizers with low serum drug concentrations?) ADA switchers after INF without a-inf Abs had a reduced response. ADA switchers after INF with a-inf Ab had a good response These results have implications for choice of biologic in TNFi-IRs The Presence Or Absence Of Antibodies To Infliximab Or Adalimumab Determines The Outcome Of Switching To Etanercept Jamnitski Anna et al Ann Rheum Dis 2011; 70:284-2898. doi:10.1136
Results Improvement in DAS28 in TNF Naïve Patients vs Switchers P=0.001 P=0.743 P=0.017 Jamnitski A, et al. Ann Rheum Dis. 2011;70(2):284-288 Implications of anti-drug Abs to Biologic Switching If anti-drug Abs present to first TNFi consider a second TNFi But possible increase in anti-drug Abs to second TNFi (Bartelds et al) If no anti-drug Ab to first TNFi. consider a biologic with a different MOA (i.e. a non-tnfi)
Nice Thought, But There is no comparative data on the response of a second TNFi to that of a biologic with a different MOA in the presence or absence of anti-drug Abs to the first TNFi!
Take Home Message Serum trough levels of TNFi may be helpful in treatment decisions to dose escalate or switch TNFis Anti-drug levels may be helpful in treatment decisions to switch to another TNFi or a non- TNFi biologic. Can one construct an algorithm for monitoring serum &/or anti-drug Ab in TNFi failures? Of Course
Algorithm For Monitoring Serum TNFi Levels & Anti-Drug Abs & in Patients with Failure of a-tnf Therapy Vincent, Fabien et al., Ann Rheum Dis 2012; 0: 1-14.doi:10.1136/annrheumdis 2012-202545 Although Immunogenicity May Help Explain Clinical Outcomes, Its Role In Clinical Practice Remains Unclear. More Prospective Data Is Needed!
Thank You! Results & Conclusions Response to etanercept did not differ between patients who were anti-tnf naïve and switchers with anti-biologic antibodies to the previous TNFi However, switchers without anti-biologic antibodies to the previous TNFi had a diminished response;? Non TNF-dependent Jamnitski A, et al. Ann Rheum Dis. 2011;70(2):284-288
Effect of Serum Trough Levels of Adalimumab in Plaque Psoriasis Study Design Prospective observational study cohort of 29 patients with psoriasis starting a regimen of adalimumab 40mg every other week after an initial dose of 80 mg Patients who had inadequate response could be dosed weekly Lecluse LLA, et al. Arch Dermatol. 2010;146(2):127-132 Serum Trough Levels of Infliximab in Ankylosing Spondylitis Study Design Prospective clinical trial of 38 patients with AS treated with infliximab 5mg/kg every 6 weeks De Vries MK, et al. Ann Rheum Dis. 2007;66:1252-1254
Effect of Serum Trough Levels of Etanercept in Ankylosing Spondylitis Study Design 53 consecutive patients with AS treated with etanercept 25 mg twice weekly Sera collected at baseline, 3 and 6 months De Vries MK, et al. Ann Rheum Dis. 2009;68:531-535 Results Percentage of Patients With and Without ATI Fulfilling ASAS-20 Response Criteria De Vries MK, et al. Ann Rheum Dis. 2007;66:1252-1254
But. Before Routine Screening International consensus for further studies of impact of a-drug Abs and drug concentration Standardization of drug concentration detection methods Definition of cut-off values for defining presence of anti- Drug Abs Definition of therapeutic range of concentration for each TNFi