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Optimising anti-TNF treatment using biosimilars

Practical Advice

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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. 

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Therapeutic drug monitoring (TDM) of anti-TNF products

Recent data highlights that TDM may more effectively optimise anti-TNF therapy efficacy, safety and cost compared with other treatment strategies. So, what is the evidence that TDM results in patients with gastroenterology, rheumatology or dermatology diseases remaining on anti-TNF therapy for longer?12

One study showed that the majority of patients with IBD that initiated an anti-TNF product, such as infliximab or adalimumab, had loss of response (58%), while 37% had a second loss of response.12 Data from the ACCENT1 trial showed that a large percentage (approximately 40%) of patients with CD treated with infliximab will lose response over time.13 A systematic review on loss of response in adult and pediatric patients with CD reported the mean percentage of patients who lost response over the course of a year to adalimumab was 18.2% among a total of 955 primary responders.14,15

For patients at risk of loss of response, TDM can play a preventative role. Through the monitoring of serum levels of anti-TNF products, using TDM, treatment can be intensified to ensure adequate drug exposure.16 Combination therapy with an immunosuppressive agent may also be considered to prevent anti-drug antibody formation.3 Treatment strategies should be tailored to the individual patient and desired therapeutic outcome. In a multicenter, retrospective study of 264 consecutive patients with IBD (167 with Crohn’s disease) receiving infliximab maintenance therapy the use of proactive TDM (optimisation of treatment prior to loss of response) compared with reactive TDM (performed after patient loss of response) was found to be associated with significantly better effectiveness and safety, as measured by greater durability on infliximab treatment, less need for IBD-related surgery and hospitalization, and less immunogenicity.17 For many patients who are monitored reactively, the monitoring has occurred too late to receive any kind of treatment optimization.17

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Figure 1, loss of response management algorithms for patients taking anti-TNF products.18 ATI, antibodies to infliximab; IFX, infliximab. 

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Cycling versus swapping of anti-TNF products

When patients experience failure with anti-TNF therapy the clinical guidelines recommend either cycling to a new therapeutic drug or switching to a new drug with a different mechanism of action, but which option is the most optimal?

Whilst a percentage of patients with CD or UC do not respond to induction therapy with anti-TNF therapy28,29 and some patients may experience a loss of response over time, or develop intolerance,30 anti-TNF product cycling can be an important and cost-effective treatment strategy with substantial benefit. For example, in a retrospective study of 5543 patients with UC and 7561 patients with CD a substantial proportion of patients required only one product of anti-TNF therapy throughout the 24-month follow-up, as the disease was effectively controlled by cycling of anti-TNF products and so did not require additional products.31 For the majority of cases, cycling to another anti-TNF product is associated with a response.

Other studies have shown that, overall, between one third and one half of patients do not respond to anti-TNF products, with a second product often prescribed when the first fails.31,32 Patients may benefit from being switched to another biosimilar with a different mechanism of action.31,33 For example, 40% of patients with UC who previously received infliximab responded well when switched to adalimumab and 21% of patients with CD who experienced intolerance or a loss of response to infliximab were able to achieve remission with adalimumab.31,33 There is no evidence that a single switch from an originator product to a biosimilar is associated with any significant risk or reduction in patient safety.34 It has also been argued that, at lower prices, cycling from infliximab to adalimumab may be more cost-effective. One study simulating the most cost effective position of vedolizumab among the available biologic drugs for the treatment of UC showed that when infliximab and adalimumab were offered at a 50% discounted price the incremental cost-effectiveness ratio of vedolizumab use in UC rose by $600,258.35

Amongst patients with rheumatology disease, anti-TNF product cycling is often first considered as a treatment strategy because it represents a lower cost option compared to switching mechanism of action and can provide successful therapeutic outcomes.36 For the majority of patients (92%) with anti-drug antibodies cycling to another anti-TNF product is associated with a response.36 A systematic review evaluating the effectiveness of anti-TNF product cycling versus switching in 4394 patients with RA concluded that both strategies are equally effective in terms of patient reported outcomes.37 Through TDM, patients with low serum product levels, due to the formation of anti-drug antibodies,36 may be identified that will most benefit from anti-TNF cycling – in particular, patients who have yet to receive a second anti-TNF product.

In some cases, largely dependent on the prices of products used in the analyses (list vs discounted prices), switching has been associated with higher treatment persistence and lower healthcare costs compared with anti-TNF product cycling.38 In one such study, a patient population of 581 (38.3%) mechanism of action switchers and 935 (61.7%) anti-TNF product cyclers were investigated with regards treatment persistence and cost per patient. Treatment persistence was significantly higher for switchers versus cyclers (47.7% versus 40.2%, P = 0.004) and when costs were divided by treatment persistence, costs per persistent patient were lower among switchers versus cyclers ($25,436 lower total RA-related cost and $25,999 lower medication costs).38 When assuming a discounted price (as is the case for biosimilars) the cost of cycling is likely to be much improved. Whilst there is debate about the benefits to switching out of class, given the lowered costs of anti-TNFs due to the arrival of biosimilars, cycling from one anti-TNF to another may be preferred.

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References

  1. Smeeding J, Malone DC, Ramchandani M, Stolshek B, Green L, Schneider P. Biosimilars: Considerations for payers. P T. 2019;44(2):54-63.
  2. 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
  3. 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
  4. CT-P13 FDA Advisory Committee Briefing Document CT-P13 (Infliximab Biosimilar) BRIEFING DOCUMENT FOR THE ARTHRITIS ADVISORY COMMITTEE.; 2016.
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. Mulleman D, Balsa A. Adalimumab concentration-based tapering strategy: as good as the recommended dosage. 2018;77(4). doi:10.1136/annrheumdis-2017-212376
  21. 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
  22. 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
  23. 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
  24. 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.
  25. Liau MM, Oon HH. Therapeutic drug monitoring of biologics in psoriasis. Biol Targets Ther. 2019;13:127-132. doi:10.2147/BTT.S188286
  26. 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
  27. 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
  28. 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
  29. 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.
  30. 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
  31. 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
  32. 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
  33. 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
  34. 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
  35. 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
  36. 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
  37. 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
  38. 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
  39. 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
  40. 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
  41. 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
  42. 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
  43. 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
  44. 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