Exposure-Response Relationship of Certolizumab Pegol and Achievement of Low Disease Activity and Remission in Patients With Rheumatoid Arthritis

Stéphane Paul, Hubert Marotte, Arthur Kavanaugh, Philippe Goupille, Tore K Kvien, Marc de Longueville, Denis Mulleman, William J Sandborn, Niels Vande Casteele, Stéphane Paul, Hubert Marotte, Arthur Kavanaugh, Philippe Goupille, Tore K Kvien, Marc de Longueville, Denis Mulleman, William J Sandborn, Niels Vande Casteele

Abstract

Anti-tumor necrosis factor (anti-TNF) drugs are often prescribed for the treatment of rheumatoid arthritis (RA) and other immune-mediated inflammatory diseases. Although this treatment has been shown to be effective in many patients, up to 40% of patients do not achieve disease control. Drug concentration in plasma may be a factor affecting the observed variability in therapeutic response. In this study, we aimed to identify the plasma concentrations of the anti-TNF certolizumab pegol (CZP), associated with improvement in disease activity in patients with RA. Data were pooled from three randomized, controlled clinical trials with a combined total of 1,935 patients analyzed. Clinical outcomes of low disease activity (LDA) and remission were defined as Disease Activity Score in 28 joints with C-reactive protein (DAS28(CRP)) ≤ 2.7 and < 2.3, respectively. Quartile analysis results indicated that there may be an exposure-response relationship between CZP concentration and LDA/remission outcomes at weeks 12 and 24; the association was strongest for LDA (P < 0.05). Receiver operating characteristic (ROC) analysis showed that CZP concentrations ≥ 28.0 μg/ml at week 12, and ≥ 17.6 μg/ml at week 24, were associated with a greater likelihood of achieving LDA/remission outcomes. Although confirmatory studies are warranted to define the optimal CZP therapeutic range at weeks 12 and 24, these data indicate that CZP concentrations may be associated with improvement of disease activity.

Trial registration: ClinicalTrials.gov NCT00152386 NCT00160602 NCT00175877 NCT00160641 NCT01500278.

Conflict of interest statement

S.P. is on the scientific board of Theradiag. H.M. has received grants, personal fees, and nonfinancial support from Pfizer, AbbVie, Nordic Pharma, MSD, UCB, Sanofi, and Novartis; and personal fees and nonfinancial support from BMS; and personal fees from Roche Chugai, Janssen, Biogen, and Biogaran (all outside of the submitted work). A.K. has received grants from Abbott, Amgen, Bristol‐Myers Squibb, Pfizer, Roche, Janssen, and UCB. P.G. has received grants/consultancy payments from Abbvie, Amgen, Biogen, Celgene, Chugai, Janssen‐Cilag, Lilly, MSD, Nordic Pharma, Novartis, Pfizer, Sanofi, and UCB. T.K.K. has received speaking and/or consulting fees from AbbVie, Biogen, Celltrion, Egis, Eli Lilly, Hikma, MSD, Mylan, Novartis, Oktal, Orion Pharma, Hospira/Pfizer, Roche, Sandoz, Sanofi, and UCB, as well as research funding received for Diakonhjemmet Hospital from AbbVie, BMS, MSD, Pfizer, Roche, and UCB. M.d.L. is a former employee of UCB Pharma. D.M. has served as a consultant for Pfizer, Novartis, UCB, and Grifols, and has received grants from NGO Lions Club‒Tours Val de France. W.J.S. has received research grants from AbbVie, Amgen, Atlantic Healthcare, Celgene/Receptos, Eli Lilly, Genentech, Gilead Sciences, Janssen, and Takeda, as well as consulting fees from AbbVie, Allergan, Amgen, Boehringer Ingelheim, Celgene, Conatus, Cosmo, Eli Lilly, Escalier Biosciences, Ferring, Genentech, Gilead, Gossamer Bio, Janssen, Miraca Life Sciences, Nivalis Therapeutics, Novartis Nutrition Science Partners, Oppilan Pharma, Otsuka, Paul Hastings, Pfizer, Precision IBD, Progenity, Prometheus Laboratories, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust (HART)), Salix, Shire, Seres Therapeutics, Sigmoid Biotechnologies, Takeda, Tigenix, Tillotts Pharma, UCB Pharma, and Vivelix, and stock options from Escalier Biosciences, Gossamer Bio, Oppilan Pharma, Precision IBD, Progenity, Ritter Pharmaceuticals. N.V.C. has received grant/research support from R‐Biopharm, Takeda, and UCB, and has served as a consultant for Janssen, Pfizer, Progenity, Prometheus, Takeda, and UCB.

© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Exposure‒response curve of CZP vs. change from baseline in DAS28(CRP) at weeks 12 and 24. (a) RAPID1 and RAPID2 (n = 1,479). (b) EXXELERATE (n = 456). Patients’ CZP concentrations were grouped to the nearest 5 μg/ml; the number of patients is shown next to each data point. Error bars correspond to 95% confidence intervals. For data points corresponding to < 10 patients, confidence intervals are not shown. Patients with CZP concentration > 100 μg/ml were excluded from the analysis (RAPID1 and RAPID2 only; excluded patients: 26 of 1,438 at week 12 and 22 of 1,087 at week 24). CI, confidence interval; CZP, certolizumab pegol; ΔDAS28(CRP), change from baseline in Disease Activity Score 28‐joint assessment with C‐reactive protein.
Figure 2
Figure 2
CZP concentration quartile analyses of DAS28(CRP) remission or LDA. (a) Week 12 DAS28(CRP) LDA. (b) Week 24 DAS28(CRP) LDA. (c) Week 12 DAS28(CRP) remission. (d) Week 24 DAS28(CRP) remission. Patients were grouped according to CZP concentration (μg/ml) quartile, as detailed on the X axis. Note that disease activity in the original EXXELERATE publication was reported as DAS28(ESR).45 CZP, certolizumab pegol; DAS28(CRP), Disease Activity Score 28‐joint assessment with C‐reactive protein; ESR, erythrocyte sedimentation rate; LDA, low disease activity.

References

    1. Baert, F. et al Influence of immunogenicity on the long‐term efficacy of infliximab in Crohn's disease. N. Engl. J. Med. 348, 601–608 (2003).
    1. Bandres Ciga, S. et al An examination of the mechanisms involved in secondary clinical failure to adalimumab or etanercept in inflammatory arthropathies. J. Clin. Rheumatol. 21, 115–119 (2015).
    1. Bartelds, G.M. et al Clinical response to adalimumab: relationship to anti‐adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann. Rheum. Dis. 66, 921–926 (2007).
    1. de Vries, M.K. et al Inefficacy of infliximab in ankylosing spondylitis is correlated with antibody formation. Ann. Rheum. Dis. 66, 133–134 (2007).
    1. Garces, S. , Demengeot, J. & Benito‐Garcia, E. The immunogenicity of anti‐TNF therapy in immune‐mediated inflammatory diseases: a systematic review of the literature with a meta‐analysis. Ann. Rheum. Dis. 72, 1947–1955 (2013).
    1. Ordas, I. , Feagan, B.G. & Sandborn, W.J. Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 10, 1079–1087; quiz e85–6 (2012).
    1. Jamnitski, A. et al Patients non‐responding to etanercept obtain lower etanercept concentrations compared with responding patients. Ann. Rheum. Dis. 71, 88–91 (2012).
    1. Karmiris, K. et al Influence of trough serum levels and immunogenicity on long‐term outcome of adalimumab therapy in Crohn's disease. Gastroenterology 137, 1628–1640 (2009).
    1. Lee, H. , Kimko, H.C. , Rogge, M. , Wang, D. , Nestorov, I. & Peck, C.C. Population pharmacokinetic and pharmacodynamic modeling of etanercept using logistic regression analysis. Clin. Pharmacol. Ther. 73, 348–365 (2003).
    1. Mazor, Y. et al P517 evaluating adalimumab drug and antibody levels as predictors of clinical and laboratory response in Crohn's disease patients. J. Crohns. Colitis 7, S217‐S (2013).
    1. Pouw, M.F. et al Key findings towards optimising adalimumab treatment: the concentration‐effect curve. Ann. Rheum. Dis. 74, 513–518 (2015).
    1. St Clair, E.W. et al The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double‐blind, placebo‐controlled trial. Arthritis Rheum. 46, 1451–1459 (2002).
    1. Van Moerkercke, W. et al S31 Mucosal healing in Crohn's disease is associated with high infliximab trough levels. J. Crohns Colitis Suppl. 4, 30–31 (2010).
    1. Wolbink, G.J. et al Relationship between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical response to infliximab treatment in patients with rheumatoid arthritis. Ann. Rheum. Dis. 64, 704–707 (2005).
    1. Kennedy, N.A. et al Predictors of anti‐TNF treatment failure in anti‐TNF‐naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study. Lancet Gastroenterol. Hepatol. 4, 341–353 (2019).
    1. EMA . CIMZIA® (Certolizumab pegol) Annex 1: summary of product characteristics. (2019). <>.
    1. Gecse, K.B. et al Efficacy and safety of the biosimilar infliximab CT‐P13 treatment in inflammatory bowel diseases: a prospective, multicentre, nationwide cohort. J. Crohns. Colitis. 10, 133–140 (2016).
    1. van Schouwenburg, P.A. et al Adalimumab elicits a restricted anti‐idiotypic antibody response in autoimmune patients resulting in functional neutralisation. Ann. Rheum. Dis. 72, 104–109 (2013).
    1. Niccoli, L. et al Personalization of biologic therapy in patients with rheumatoid arthritis: less frequently accounted choice‐driving variables. Ther. Clin. Risk Manag. 14, 2097–2111 (2018).
    1. Aarden, L. , Ruuls, S.R. & Wolbink, G. Immunogenicity of anti‐tumor necrosis factor antibodies‐toward improved methods of anti‐antibody measurement. Curr. Opin. Immunol. 20, 431–435 (2008).
    1. van der Laken, C.J. et al Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti‐infliximab in responders and non‐responders to therapy for rheumatoid arthritis. Ann. Rheum. Dis. 66, 253–256 (2007).
    1. Wade, J.R. et al Population pharmacokinetic analysis of certolizumab pegol in patients with Crohn's disease. J. Clin. Pharmacol. 55, 866–874 (2015).
    1. EMA . HUMIRA® (Adalimumab) Annex 1: summary of product characteristics (2019). <>.
    1. EMA . ENBREL® (Etanercept) Annex 1: summary of product characteristics (2019). <>.
    1. EMA . SIMPONI® (Golimumab) Annex 1: summary of product characteristics (2019). <>.
    1. E MA . REMICADE® (Infliximab) Annex 1: summary of product characteristics (2019). <>.
    1. Brandse, J.F. et al Pharmacokinetic features and presence of antidrug antibodies associate with response to infliximab induction therapy in patients with moderate to severe ulcerative colitis. Clin. Gastroenterol. Hepatol. 14, 251–258.e2 (2016).
    1. Fasanmade, A.A. et al Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur. J. Clin. Pharmacol. 65, 251–258.e1–2 (2009).
    1. Gecse, K.B. , Vegh, Z. & Lakatos, P.L. Optimizing biological therapy in Crohn's disease. Expert. Rev. Gastroenterol. Hepatol. 10, 37–45 (2016).
    1. Mulleman, D. , Ducourau, E. , Paintaud, G. , Ternant, D. , Watier, H. & Goupille, P. Should anti‐TNF‐alpha drug levels and/or anti‐drug antibodies be assayed in patients treated for rheumatoid arthritis? Joint Bone Spine 79, 109–112 (2012).
    1. Vande Casteele, N. et al Exposure–response relationship of certolizumab pegol induction and maintenance therapy in patients with Crohn's disease. Aliment. Pharmacol. Ther. 47, 229–237 (2018).
    1. Vande Casteele, N. et al Accounting for pharmacokinetic variability of certolizumab pegol in patients with Crohn's disease. Clin. Pharmacokinet. 56, 1513–1523 (2017).
    1. Wang, W. , Leu, J. , Watson, R. , Xu, Z. & Zhou, H. Investigation of the mechanism of therapeutic protein‐drug interaction between methotrexate and golimumab, an anti‐TNFalpha monoclonal antibody. Aaps J. 20, 63 (2018).
    1. Ternant, D. , Bejan‐Angoulvant, T. , Passot, C. , Mulleman, D. & Paintaud, G. Clinical pharmacokinetics and pharmacodynamics of monoclonal antibodies approved to treat rheumatoid arthritis. Clin. Pharmacokinet. 54, 1107–1123 (2015).
    1. Papamichael, K. et al Proactive therapeutic drug monitoring of adalimumab is associated with better long‐term outcomes compared to standard of care in patients with inflammatory bowel disease. J. Crohns. Colitis. 13, 976–981. (2019).
    1. Hsieh, T.‐Y. et al Drug trough levels predict therapeutic responses to dose reduction of adalimumab for rheumatoid arthritis patients during 24 weeks of follow‐up. Rheumatology 55, 143–148 (2016).
    1. European Crohn's and Colitis Organisation . ECCO e‐Guide on biologics: anti‐TNFs in Crohn's disease (last reviewed: 1 October 2016) <>. Accessed January 16, 2018.
    1. Feuerstein, J.D. et al American Gastroenterological Association Institute Guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology 153, 827–34 (2017).
    1. Medina, F. , Plasencia, C. , Goupille, P. , Ternant, D. , Balsa, A. & Mulleman, D. Current practice for therapeutic drug monitoring of biopharmaceuticals in rheumatoid arthritis. Ther. Drug. Monit. 39, 364–369 (2017).
    1. Grossberg, L.B. , Papamichael, K. , Feuerstein, J.D. , Siegel, C.A. , Ullman, T.A. & Cheifetz, A.S. A Survey study of gastroenterologists' attitudes and barriers toward therapeutic drug monitoring of anti‐TNF therapy in inflammatory bowel disease. Inflamm. Bowel. Dis. 24, 191–197 (2017).
    1. Keystone, E. et al Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty‐two‐week, phase III, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study. Arthritis. Rheum. 58, 3319–3329 (2008).
    1. Keystone, E. et al Long‐term safety and efficacy of certolizumab pegol in combination with methotrexate in the treatment of rheumatoid arthritis: 5‐year results from the RAPID 1 trial and open‐label extension. Ann. Rheum. Dis. 73, 2094–2100 (2014).
    1. Smolen, J. et al Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann. Rheum. Dis. 68, 797–804 (2009).
    1. Smolen, J.S. et al Certolizumab pegol plus methotrexate 5‐year results from the rheumatoid arthritis prevention of structural damage (RAPID) 2 randomized controlled trial and long‐term extension in rheumatoid arthritis patients. Arthritis. Res. Ther. 17, 245 (2015).
    1. Smolen, J.S. et al Head‐to‐head comparison of certolizumab pegol versus adalimumab in rheumatoid arthritis: 2‐year efficacy and safety results from the randomised EXXELERATE study. Lancet 388, 2763–2764 (2016).
    1. FDA . CIMZIA® (Certolizumab pegol) Prescribing Information. 2019. <>.
    1. ICH Quality Guidelines ‐ validation of analytical procedures <>. Last accessed September 2016.
    1. Inoue, E. , Yamanaka, H. , Hara, M. , Tomatsu, T. & Kamatani, N. Comparison of Disease Activity Score (DAS)28‐ erythrocyte sedimentation rate and DAS28‐ C‐reactive protein threshold values. Ann. Rheum. Dis. 66, 407–409 (2007).
    1. Gehin, J. et al SAT0261 Certolizumab pegol serum levels ≥20 mg/l are associated with treatment response in patients with axial spondyloarthritis. Data from the NOR‐DMARD study. Ann. Rheum. Dis. 77, A994 (2018).
    1. Gehin, J. et al SAT0185 Certolizumab pegol serum levels ≥20 mg/l are associated with improvement in DAS28 in rheumatoid arthritis patients. Data from the NOR‐DMARD study. Ann. Rheum. Dis. 77, A953 (2018).
    1. Singh, J.A. et al 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 68, 1–26 (2016).
    1. Smolen, J.S. et al EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease‐modifying antirheumatic drugs: 2013 update. Ann. Rheum. Dis. 73, 492–509 (2014).
    1. Dénarié, D. , Rinaudo‐Gaujous, M. , Thomas, T. , Paul, S. & Marotte, H. Methotrexate reduced TNF bioactivity in rheumatoid arthritis patients treated with infliximab. Mediat. Inflamm. 2017, 3708250 (2017).
    1. Maser, E.A. , Villela, R. , Silverberg, M.S. & Greenberg, G.R. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease. Clin. Gastroenterol. Hepatol. 4, 1248–1254 (2006).
    1. Paul, S. et al Therapeutic drug monitoring of infliximab and mucosal healing in inflammatory bowel disease: a prospective study. Inflamm. Bowel. Dis. 19, 2568–2576 (2013).
    1. Yamada, A. , Sono, K. , Hosoe, N. , Takada, N. & Suzuki, Y. Monitoring functional serum antitumor necrosis factor antibody level in Crohn's disease patients who maintained and those who lost response to anti‐TNF. Inflamm. Bowel. Dis. 16, 1898–1904 (2010).
    1. Bornstein, G. , Lidar, M. , Langevitz, P. , Fardman, A. , Ben‐Zvi, I. & Grossman, C. The prevalence and clinical effect of immunogenicity of TNF‐alpha blockers in patients with axial spondyloarthritis. Clin. Exp. Rheumatol. 36, 228–232 (2018).
    1. Patil, A. et al Anti‐drug antibodies and low serum trough infliximab levels correlate with disease activity measures in spondyloarthritis patients on an as‐needed infliximab treatment. Int. J. Rheum. Dis. (2019).
    1. Gehin, J. et al FRI0645 Anti‐drug antibodies to certolizumab pegol are associated with low drug levels and reduced clinical response at 3 months in patients with inflammatory joint diseases. Data from the NOR‐DMARD study. Ann. Rheum. Dis. 77, A844 (2018).
    1. van Schouwenburg, P.A. , Rispens, T. & Wolbink, G.J. Immunogenicity of anti‐TNF biologic therapies for rheumatoid arthritis. Nat. Rev. Rheumatol. 9, 164–172 (2013).
    1. Berenbaum, F.Early et al non‐response to certolizumab pegol in rheumatoid arthritis predicts treatment failure at one year. Data from a randomised phase III clinical trial. Joint Bone Spine 85, 59–64 (2018).
    1. Curtis, J.R. , Herrem, C. , Ndlovu, N. , O'Brien, C. & Yazici, Y. A somatization comorbidity phenotype impacts response to therapy in rheumatoid arthritis: post‐hoc results from the certolizumab pegol phase 4 PREDICT trial. Arthritis. Res. Ther. 19, 215 (2017).
    1. Weinblatt, M.E. et al Twenty‐eight‐week results from the REALISTIC phase IIIb randomized trial: efficacy, safety and predictability of response to certolizumab pegol in a diverse rheumatoid arthritis population. Arthritis. Res. Ther. 17, 325 (2015).
    1. Mulleman, D. & Balsa, A. Adalimumab concentration‐based tapering strategy: as good as the recommended dosage. Ann. Rheum. Dis. 77, 473–475 (2018).
    1. Joh, D.Y. et al Inkjet‐printed point‐of‐care immunoassay on a nanoscale polymer brush enables subpicomolar detection of analytes in blood. Proc. Natl. Acad. Sci. USA 114, E7054‐e62 (2017).
    1. Meneghello, A. , Tartaggia, S. , Alvau, M.D. , Polo, F. & Toffoli, G. Biosensing technologies for therapeutic drug monitoring. Curr. Med. Chem. 25, 4354–4377 (2017).
    1. Van Stappen, T. et al Rapid test for infliximab drug concentration allows immediate dose adaptation. Clin. Transl. Gastroenterol. 7, e206 (2016).
    1. Dreesen, E. , Bossuyt, P. , Mulleman, D. , Gils, A. & Pascual‐Salcedo, D. Practical recommendations for the use of therapeutic drug monitoring of biopharmaceuticals in inflammatory diseases. Clin. Pharmacol 9, 101–111 (2017).

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