Therapeutic Drug Monitoring of Biosimilars in Autoimmune Diseases

Anti-TNF-alpha biologics have been proven to be effective treatments for autoimmune diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD)¹. Rising healthcare costs as well as patent expirations, however, have prompted the development of biosimilars, such as the infliximab biosimilar CT-P13¹. The introduction of these drugs also presents the need for a better understanding of potential differences in biosimilar immunogenicity, as well as safety and efficacy profiles in comparison to their predecessors. In addition, it is vital to develop methods for the therapeutic drug monitoring of biosimilars in autoimmune diseases to ensure complete patient care.

What are Biosimilars?

Biosimilars are biologics that are comparable to their reference product with respect to structure, efficacy, safety and quality². Due to the inherently variable nature of the biomanufacturing process, biosimilars will never be identical copies of their reference products². Unlike generics, however, any differences that may exist between a biosimilar and its reference product do not affect its safety or efficacy³.

What is Biosimilar Immunogenicity?

One of the main concerns with developing biosimilars is the potential for unexpected immunogenicity^4,5. Immunogenicity is characterized by the formation of anti-drug antibodies (ADAs) which can render a drug ineffective by interfering with the interaction between the drug and its target^4,5. TNF-alpha blockers such as infliximab and adalimumab are both well known for triggering immunogenicity responses. It is therefore hypothesized that their biosimilars may also promote immunogenicity⁶.

Factors Influencing Biosimilar Immunogenicity

Research on biologics and biosimilars indicates many different factors may lead to immunogenicity against biosimilars:

Infliximab Biosimilar CT-P13: Remsima^® and Inflectra^®

In 2015, the expiration of the Remicade^® patent in the European Union allowed for the development of the infliximab biosimilar CT-P13 [Remsima^® (Celltrion) and Inflectra^® (Hospira, Pfizer)]⁸. Like infliximab, CT-P13 is a chimeric murine monoclonal IgG1 antibody that acts as a TNF-alpha blocker. Extensive similarity testing and clinical trials resulted in the approval of Remsima^® and Inflectra^® for the treatment of RA and IBD in over 40 countries around the world including the U.S., Canada, and Japan^2,9,10.

CT-P13 and Rheumatoid Arthritis

CT-P13 was first investigated as a treatment for multiple rheumatic diseases including rheumatoid arthritis (RA) and ankylosing spondylitis (AS). The PLANETRA and PLANETAS clinical trials demonstrated that CT-P13 is comparable to infliximab in safety, efficacy, and immunogenicity when treating RA and AS^11,12,13.

CT-P13 and Inflammatory Bowel Disease

Data extrapolation from the rheumatic disease clinical trials led to the approval of CT-P13 to treat Crohn’s disease (CD) and ulcerative colitis (UC). A meta-analysis of observational studies investigating the safety and efficacy of Remsima^® and Inflectra^® for treating IBD further supports that CT-P13 exhibits the same safety and efficacy profile as infliximab¹. A meta-analysis reviewing the biosimilar demonstrated high rates of clinical response and low rates of adverse events¹. Furthermore, research shows that there is no significant difference between the development of ADAs towards infliximab or CT-P13^14,15. Therefore, these studies are strong evidence that CT-P13 and infliximab have comparable immunogenicity.

Therapeutic Drug Monitoring of Biosimilars in Autoimmune Diseases

Therapeutic drug monitoring (TDM) of biologics for IBD and RA has recently allowed for improved treatment plans and better clinical outcomes. With the approval of CT-P13, it is important to develop methods for therapeutic drug monitoring of biosimilars to improve clinical outcomes for individuals with RA and IBD¹⁵.

TDM Assays for Infliximab Biosimilars

Therapeutic drug monitoring assays provide a tool for measuring the drug level of CT-P13 (Remsima^® and Inflectra^®). The Infliximab Drug Level ELISA has been tested and shown to successfully cross-react with and accurately quantify levels of CT-P13. Cross-reactivity testing data can be found in our technical note: Therapeutic Drug Monitoring of Biosimilars.

CT-P13 drug level measurements can help research therapeutic biologic drug concentration optimization to understand how to avoid doses that are too low (ineffective) or too high (toxic).

The rising cost of healthcare and patent expirations for anti-TNF-alpha biologics for treating autoimmune diseases has prompted the development and fast-track approval of biosimilars such as the infliximab biosimilar CT-P13¹. However, concerns over biosimilar immunogenicity, safety, and efficacy have resulted in a need for assays that can help define the activity profile¹⁵. TDM assays that can cross-react with a biosimilar, such as the Infliximab Drug Level ELISA, can become part of the process for therapeutic drug monitoring of biosimilars in autoimmune diseases which may lead to better clinical outcomes.

The Infliximab Drug Level ELISA is Health Canada Licensed, and is For Research Use Only in the U.S.

References

1. Komaki et al. (2017). Systematic review with meta-analysis: the efficacy and safety of CT-P13, a biosimilar of anti-tumour necrosis factor-α agent (infliximab), in inflammatory bowel diseases. Aliment Pharmacol Ther. 45:1043–1057. doi:10.1111/apt.13990.
2. Jahnsen. (2016). Clinical experience with infliximab biosimilar Remsima (CT-P13) in inflammatory bowel disease patients. Therap Adv Gastroenterol. 2016 May;9(3):322–329. doi:10.1177/1756283X16636764. PMCID: PMC4830106 .
3. US Food and Drug Administration. (2016). Information on Biosimilars. www.fda.gov.
4. Brinks. (2013). Immunogenicity of biosimilar monoclonal antibodies. Generics and Biosimilars Initiative Journal. 2013;2(4):188-93. doi:10.5639/gabij.2013.0204.052.
5. Pineda et al. (2016). Assessing the Immunogenicity of Biopharmaceuticals. BioDrugs. 2016 Jun;30(3):195-206. doi:10.1007/s40259-016-0174-5. PMID: 27097915.
6. Moss et al. (2013). Review article: Immunogenicity of anti-TNF biologics in IBD – the role of patient, product and prescriber factors. Aliment Pharmacol Ther. 2013 Nov;38(10):1188-97. doi:10.1111/apt.12507. Epub 2013 Oct 3. PMID: 24118102.
7. Ben-Horin et al. (2015). The immunogenicity of biosimilar infliximab: Can we extrapolate the data across indications? Expert Rev Gastroenterol Hepatol. 2015;9 Suppl 1:27-34. doi:10.1586/17474124.2015.1091307. PMID: 26395532.
8. Derbyshire. (2016). Patent expiry dates for biologicals: 2016 update. Generics and Biosimilars Initiative Journal. 2017;6(1):27-30. doi:10.5639/gabij.2017.0601.006.
9. Jung et al. (2015). Physicochemical characterization of Remsima. MAbs. 2014;6(5):1163-77. doi:10.4161/mabs.32221. PMID: 25517302.
10. Celltrion. (2016). Corporate History Timeline. Celltrion.com.
11. Yoo et al. (2013). A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: The PLANETRA study. Ann Rheum Dis. 2013 Oct;72(10):1613–1620. doi:1136/annrheumdis-2012-203090. PMCID: PMC3786641.
12. Park et al. (2013). A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis. 2013 Oct; 72(10): 1605–1612. 10.1136/annrheumdis-2012-203091. PMCID: PMC3786643.
13. Yoo et al. (2015). Analysis of clinical trials of biosimilar infliximab (CT-P13) and comparison against historical clinical studies with the infliximab reference medicinal product. Expert Rev Clin Immunol. 2015;11 Suppl 1:S15-24. doi:10.1586/1744666X.2015.1090314. PMID: 26395833.
14. Ben-Horin et al. (2015). Cross-immunogenicity: Antibodies to infliximab in Remicade-treated patients with IBD similarly recognize the biosimilar Remsima. Gut. 2016 Jul;65(7):1132-8. doi:10.1136/gutjnl-2015-309290. PMID: 25897019.
15. Schulze et al. (2016). CT-P13 (Inflectra™, Remsima™) monitoring in patients with inflammatory bowel disease. Biologicals. 2016 Sep;44(5):463-6. doi:10.1016/j.biologicals.2016.06.011. PMID: 27435444.