Practical advice and considerations for the use of Biosimilars
Biosimilars offer health care practices large potential cost savings and the opportunity to widen patient access to treatment, but what are the different factors that are important to consider when prescribing biosimilars in gastroenterology, rheumatology and dermatology?1
One of the main factors for consideration when optimising a biologic and/or biosimilar dose regimen is potential loss of response over time, which is often attributed to increased drug clearance linked to anti-drug antibodies.2 One treatment strategy to optimise the effect of biologics or biosimilars is therapeutic drug monitoring (TDM), which uses drug concentration measurements to inform dose adjustments to ensure serum levels are maintained within a therapeutic range.3 For patients with Crohn’s disease (CD) and ulcerative colitis (UC), infliximab biosimilar dosing is based on body weight (5 mg/kg) starting with an induction phase at weeks 0, 2, and 6, followed by a maintenance phase (5 mg/kg every 8 weeks).4 However, there is substantial variability regarding drug exposure and treatment responses between patients who receive standard infliximab biosimilar doses. By using TDM, dosing levels can be adjusted so that infliximab serum levels are between 3 and 7 μg/ml, a range associated with optimal outcomes during maintenance treatment.3 There are, however, limitations to adjusting serum levels of infliximab due to approved dosing. Additionally, immunogenicity may not make dose adjustments beneficial.3
A key concern when prescribing biologics (including biosimilars) is immunogenicity. To prevent the formation of anti-drug antibodies, several treatment strategies can be implemented including systematic maintenance therapy, which is mainly true for infliximab, concomitant immunosuppression and prophylactic systemic steroids.5–7 One study of a cohort of 121 patients with rheumatic arthritis (RA) found that anti-drug antibodies were present in 17% of patients treated for 28 weeks with adalimumab and concomitant immunosuppressive agent (methotrexate) use was lower in the group with anti-drug antibodies (52% vs. 84%, P = 0.003).8 At 28 weeks, patients with RA that were responding to treatment were less likely to have anti-drug antibodies than those not responding (5% vs. 34%).8 With episodic infliximab therapy, immunosuppressive agents should be considered to decrease immunogenicity and secondary loss of response.9
If, following dose optimisation, the efficacy of an anti-TNF fades in a patient with initial response, a degree of flexibility is required in order to counteract the loss of response. Possible strategies include increasing drug exposure by decreasing the dosing interval or increasing the dose or switching to another product.9 Current guidelines advise a number of alternative systemic biologic therapies for moderate-to-severe psoriasis, as well as more conventional systemic therapies and ultraviolet treatment.10 When selecting the systemic treatment for patients with psoriasis, HCPs should consider the clinical criteria as well as the patient and product characteristics.10
Table 1, factors associated with loss of response to anti-TNF therapy.11 ANA, antinuclear antibodies; ATI, antibodies to infliximab; BMI, body mass index; CRP, c-reactive protein; WBC, white blood cell.
Recent data highlights that TDM may more effectively optimise anti-TNF therapy efficacy, safety and cost compared with other treatment strategies.
When patients experience failure with anti-TNF therapy the clinical guidelines recommend either cycling to a new therapeutic drug or switching to a
- Smeeding J, Malone DC, Ramchandani M, Stolshek B, Green L, Schneider P. Biosimilars: Considerations for payers. P T. 2019;44(2):54-63.
- Dotan I, Ron Y, Yanai H, et al. Patient Factors That Increase Infliximab Clearance and Shorten Half-life in Inflammatory Bowel Disease: A Population Pharmacokinetic Study. 2014. doi:10.1097/MIB.0000000000000212
- Strik AS, Berends SE, Löwenberg M. Expert Review of Clinical Pharmacology Therapeutic drug monitoring-based dosing of TNF inhibitors in inflammatory bowel disease: the way forward? Therapeutic drug monitoring-based dosing of TNF inhibitors in inflammatory bowel disease: the way forward? 2019. doi:10.1080/17512433.2019.1642745
- CT-P13 FDA Advisory Committee Briefing Document CT-P13 (Infliximab Biosimilar) BRIEFING DOCUMENT FOR THE ARTHRITIS ADVISORY COMMITTEE.; 2016.
- Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348(7):601-608. doi:10.1056/NEJMoa020888
- Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: A randomized controlled trial. Gastroenterology. 2003;124(4):917-924. doi:10.1053/gast.2003.50145
- Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastroenterol Hepatol. 2004;2(7):542-553. doi:10.1016/S1542-3565(04)00238-1
- Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Clinical response to adalimumab: Relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007;66(7):921-926. doi:10.1136/ard.2006.065615
- Van Assche G, Vermeire S, Rutgeerts P. Management of loss of response to anti-TNF drugs: Change the dose or change the drug? 2008. doi:10.1016/j.crohns.2008.05.011
- Nast A, Gisondi P, Ormerod AD, et al. European S3-Guidelines on the systemic treatment of psoriasis vulgaris - Update 2015 - Short version - EDF in cooperation with EADV and IPC. J Eur Acad Dermatology Venereol. 2015;29(12):2277-2294. doi:10.1111/jdv.13354
- Danese S, Fiorino G, Reinisch W. Review article: causative factors and the clinical management of patients with Crohn’s disease who lose response to anti-TNF-α therapy. Aliment Pharmacol Ther. 2011;34(1):1-10. doi:10.1111/j.1365-2036.2011.04679.x
- Sousa M, Silva AP, Rodrigues A, et al. P414 Loss of response to anti-TNF in inflammatory bowel disease in a Portuguese centre. J Crohn’s Colitis. 2018;12(supplement_1):S313-S314. doi:10.1093/ecco-jcc/jjx180.541
- Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: The ACCENT I randomised trial. Lancet. 2002;359(9317):1541-1549. doi:10.1016/S0140-6736(02)08512-4
- Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for Maintenance of Clinical Response and Remission in Patients With Crohn’s Disease: The CHARM Trial. Gastroenterology. 2007;132(1):52-65. doi:10.1053/j.gastro.2006.11.041
- Roda G, Jharap B, Neeraj N, Colombel J-F. Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management. Clin Transl Gastroenterol. 2016;7. doi:10.1038/ctg.2015.63
- Strik AS, Bots SJA, D’Haens G, Löwenberg M. Optimization of anti-TNF therapy in patients with Inflammatory Bowel Disease. Expert Rev Clin Pharmacol. 2016;9(3):429-439. doi:10.1586/17512433.2016.1133288
- Papamichael, K., Chachu, K. A., Vajravelu, R. K., Vaughn, B. P., Ni, J., Osterman, M. T., Cheifetz, A. S. Improved Long-term Outcomes of Patients With Inflammatory Bowel Disease Receiving Proactive Compared With Reactive Monitoring of Serum Concentrations of Infliximab. Clinical Gastroenterology and Hepatology, 2017;15(10), 1580–1588.e3. doi:10.1016/j.cgh.2017.03.031
- Scott FI, Lichtenstein GR. Therapeutic Drug Monitoring of Anti-TNF Therapy in Inflammatory Bowel Disease. Curr Treat Options Gastroenterol. 2014;12(1):59-75. doi:10.1007/s11938-013-0004-5
- Bartelds GM, Wijbrandts CA, Nurmohamed MT, Stapel S, Lems WF, Aarden L, Dijkmans BAC, Tak P, Wolbink GJ. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis 2007;66:921–926. doi: 10.1136/ard.2006.065615
- Mulleman D, Balsa A. Adalimumab concentration-based tapering strategy: as good as the recommended dosage. 2018;77(4). doi:10.1136/annrheumdis-2017-212376
- Vogelzang EH, Kneepkens EL, Nurmohamed MT, et al. Anti-adalimumab antibodies and adalimumab concentrations in psoriatic arthritis; an association with disease activity at 28 and 52 weeks of follow-up. Ann Rheum Dis. 2014;73(12):2178-2182. doi:10.1136/annrheumdis-2014-205554
- Ducourau E, Mulleman D, Paintaud G, et al. Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases. Arthritis Res Ther. 2011;13(3). doi:10.1186/ar3386
- L’ami MJ, Krieckaert CLM, Nurmohamed MT, et al. Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: An open-label, non-inferiority, randomised clinical trial. Ann Rheum Dis. 2018;77(4):484-487. doi:10.1136/annrheumdis-2017-211781
- l’ Ami MJ, Ruwaard J, Krieckaert CLM, Nurmohamed MT, van Vollenhoven RF, Rispens T & Wolbink GJ. Serum drug concentrations to optimize switching from adalimumab to etanercept in rheumatoid arthritis. SC J Rheum 2019 Jul;48(4):266-270. doi: 10.1080/03009742.2019.1577915. Epub 2019 Apr 23.
- Liau MM, Oon HH. Therapeutic drug monitoring of biologics in psoriasis. Biol Targets Ther. 2019;13:127-132. doi:10.2147/BTT.S188286
- Lecluse LLA, Driessen RJB, Spuls PI, et al. Extent and clinical consequences of antibody formation against adalimumab in patients with plaque psoriasis. Arch Dermatol. 2010;146(2):127-132. doi:10.1001/archdermatol.2009.347
- Mahil SK, Arkir Z, Richards G, Lewis CM, Barker JN, Smith CH. Predicting treatment response in psoriasis using serum levels of adalimumab and etanercept: a single-centre, cohort study. Br J Dermatol. 2013;169(2):306-313. doi:10.1111/bjd.12341
- Allez M, Karmiris K, Louis E, et al. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: Definitions, frequency and pharmacological aspects. J Crohn’s Colitis. 2010. doi:10.1016/j.crohns.2010.04.004
- Molnár T,Farkas K, Nyari T, Szepes Z, et al. Frequency and Predictors of Loss of Response to Infliximab or Adalimumab in Crohn’s Disease after One-Year Treatment Period-A Single Center Experience. Vol 21.; 2012. https://www.researchgate.net/publication/231212402. Accessed January 15, 2020.
- Gisbert JP, Panés J. Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am J Gastroenterol. 2009;104(3):760-767. doi:10.1038/ajg.2008.88
- Brady JE, Stott-Miller M, Mu G, Perera S. Treatment Patterns and Sequencing in Patients With Inflammatory Bowel Disease. Clin Ther. 2018;40(9):1509-1521.e5. doi:10.1016/j.clinthera.2018.07.013
- Lindsay JO, Armuzzi A, Gisbert JP, et al. Indicators of suboptimal tumor necrosis factor antagonist therapy in inflammatory bowel disease. Dig Liver Dis. 2017. doi:10.1016/j.dld.2017.07.010
- Peyrin-Biroulet L, Laclotte L, Roblin X, Bigard M-A. Adalimumab induction therapy for ulcerative colitis with intolerance or lost response to infliximab: An open-label study World J Gastroenterol. Apr 28, 2007; 13(16): 2328-2332. doi: 10.3748/wjg.v13.i16.2328
- Wiland P, Batko B, Brzosko M, et al. Biosimilar switching - current state of knowledge. Reumatologia. 2018;56(4):234–242. doi:10.5114/reum.2018.77975
- Frank I Scott, Michelle Luo, Yash Shah, Karen Lasch, Ravy K Vajravelu, Ronac Mamtani, Blair Fennimore, Mark E Gerich, James D Lewis, Identification of the most cost effective position of vedolizumab among the available biologic drugs for the treatment of ulcerative colitis, Journal of Crohn's and Colitis, , jjz212, https://doi.org/10.1093/ecco-jcc/jjz212
- Rubbert-Roth A, Zsuzsanna Szabó M, Kedves M, Nagy G, Atzeni F, Sarzi-Puttini P. Failure of anti-TNF treatment in patients with rheumatoid arthritis: The pros and cons of the early use of alternative biological agents Autoimmun Rev. 2019 Dec;18(12):102398. doi: 10.1016/j.autrev.2019.102398
- Lopez-Olivo M. A, Matusevich M, Cantor S.B, Pratt G, Suarez Almazor M.E. The comparative effectiveness of cycling tumour necrosis factor inhibitor (TNFI) versus swapping to a nontnfi on patient-reported functional ability of patients with rheumatoid arthritis. Annals of the Rheumatic Diseases 2018;77:196. https://ard.bmj.com/content/77/Suppl_2/196.1
- Chastek Chieh-I Chen Clare Proudfoot Shraddha Shinde Andreas Kuznik Wenhui Wei B. Treatment Persistence and Healthcare Costs Among Patients with Rheumatoid Arthritis Changing Biologics in the USA. doi:10.1007/s12325-017-0617-5
- Antoni C, Krueger GG, De Vlam K, et al. Infliximab improves signs and symptoms of psoriatic arthritis: Results of the IMPACT 2 trial. Ann Rheum Dis. 2005;64(8):1150-1157. doi:10.1136/ard.2004.032268
- Mease PJ, Goffe BS, Metz J, Vanderstoep A, Finck B, Bürge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: A randomised trial. Lancet. 2000;356(9227):385-390. doi:10.1016/S0140-6736(00)02530-7
- Mease PJ, Gladman DD, Ritchlin CT, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: Results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52(10):3279-3289. doi:10.1002/art.21306
- Mease PJ, Karki C, Liu M, et al. Discontinuation and switching patterns of tumour necrosis factor inhibitors (TNFis) in TNFi-naive and TNFi-experienced patients with psoriatic arthritis: An observational study from the US-based Corrona registry. RMD Open. 2019;5(1). doi:10.1136/rmdopen-2018-000880
- Kerdel F, Zaiac M. An evolution in switching therapy for psoriasis patients who fail to meet treatment goals. Dermatol Ther. 2015 Nov-Dec; 28(6): 390–403. doi: 10.1111/dth.12267
- Clunie G, McInnes IB, Barkham N, et al. Long-term effectiveness of tumour necrosis factor-α inhibitor treatment for psoriatic arthritis in the UK: a multicentre retrospective study. Rheumatol Adv Pract. 2018;2(2). doi:10.1093/rap/rky042
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