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Optimising anti-TNF treatment using biosimilars Learning Zone

The future of immunology biosimilars

Last updated: 25th Jul 2023
Published: 13th Dec 2022
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Anti-TNF Treatment Using Biosimilars – Overview
In this section

Changes in the biosimilar therapy landscape

There are now more than 560 biosimilars of complex proteins in development worldwide, with clinical trials ongoing (see Figure 1)1.

The global biosimilars landscape

Figure 1: The global biosimilars landscape

While biosimilars are said to have comparable efficacy to their reference products, the terms “value-added medicines”, “biobetters” and “biosuperiors” have been used to describe products that offer improvements in clinical outcomes and drug pharmacology over their reference products2,3. For example, ‘insulin lispro’ was the first to receive FDA approval in 1996. CT-P13 subcutaneous (CT-P13 SC), an infliximab biosimilar, is another example of this, providing improved efficacy with its changes in formulation and administration compared to CT-P13 intravenous (CT-P13 IV)2.

Efficacy analyses from different patient population subgroups will be important for future biosimilar investigations, such as the extension PLANETRA and PLANETAS studies with CT-P134

Targets for rheumatoid arthritis

New therapies and treatment targets for RA continue to be developed including5:

  • Biological disease-modifying anti-rheumatic drugs (bDMARDs)
  • Cannabinoid therapies
  • T-cell, B-cell and monocyte/macrophage targeted treatments
  • Cell-based therapies
  • RNA therapeutics
  • Exosome-base therapies

Specifically, targets for RA modulating the immune response of an individual patients include6:

  • Target-specific DMARDs: JAK inhibitors
  • bDMARDs: (ig-CTLA-4, anti-IL6R, anti-TNFα, anti-CD20)

The bMARDS granulocyte-monocyte colony stimulating factor, transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) are also being investigated7.

Regarding biological DMARDs (bDMARDs), the efficacy of tocilizumab in RA treatments has encouraged research targeting the IL-6 pathway with new bDMARDs5. These are primarily inhibitors targeting IL6R (e.g. sarilumab), or the IL-6 cytokine (e.g. olokizumab, clazakizumab)5. Although drugs focused on such targets can be used to improve RA symptoms, not all people respond well.

A recent study demonstrated phenotypic plasticity of synovial fluid macrophages in vitro, in which with the presence of IFNγ an increased expression of PD-L1 and PD-L2 was observed8. It was suggested these could be future targets for treatment of RA as well8.

Alternative administration methods and future directions

Anti-TNF therapies are usually administrated either intravenously or subcutaneously, meaning higher doses are necessary, which in turn can lead to immunosuppression and other adverse events. Now, new types of anti-TNF therapy are in development to combat this9. For example, the following have been investigated9:

  • Anti-TNF-α-enriched microneedles
  • Rectal administration (infliximab)
  • Tablet coating (V565-adalimumab)
  • Anti-TNF-α loaded nanoparticles

New immunological therapies are being investigated alongside improvements in understanding RA immune mechanisms and differences in patient profiles, to ultimately improve patient outcomes

For an overview of IL-6 production, recent approvals of IL-6-tageted therapies and using IL-6 inhibitors in the management of rheumatoid arthritis, please view the following downloadable infographic.

Targeting interleukin-6 in inflammatory diseases

Download infographic here

IL-6 treatment in the last decade

Interleukin-6 (IL-6) is secreted by T cells and has a role in antibody production by B cells10. IL-6 receptor activation causes activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, in turn resulting in the production of inflammatory cytokines (Figure 1)10,11. Overproduction plays a role in the pathogenesis of many diseases11.

Cell signalling pathways and physiology of IL-6 in diseases

Figure 1. Cell signalling pathways and physiology of IL-6 in diseases (Adapted10). IL-6, interleukin 6; IL-6R, IL-6 receptor; JAK, Janus kinase; STAT, signal transducer and activator of transcription.

Over the last decade, IL-6 has become increasingly studied as a target for therapies in rheumatology, notably for rheumatoid arthritis10,12.

In recent years, IL-6 inhibitors tocilizumab, sarilumab and silutixumab have been approved for various conditions10,13:

  • Rheumatoid arthritis (RA)
    • 2017: sarilumab approved in the EU, USA and Japan
    • In Europe sarilumab and tocilizumab can be used in adult patients, who have had an inadequate response to, or intolerance to at least one DMARD14
  • Juvenile idiopathic arthritis (JIA), both polyarticular-course JIA (pJIA) and systematic JIA (sJIA)
  • Giant cell arteritis (GCA)
    • 2017: tocilizumab approved in the EU and USA
  • Adult-onset Still’s disease (ASOD)
    • 2019: tocilizumab approved in Japan
  • Takayasu arteritis
  • Castleman disease
    • 2014: siltuximab approved in the EU and USA
  • Cytokine release syndrome (CRS)
    • Tocilizumab approved in the US (2017), EU (2018) and Japan (2019)

View the infographic above for a full timeline of the approvals and clinical trials of IL-6 inhibitors.

Figure 2 shows some symptoms of disease IL-6 inhibitors can relieve, such as fever, fatigue, pain and join destruction among others.

The role of anti-IL-6 therapies on symptoms of diseases

Figure 2. The role of anti-IL-6 therapies on symptoms of diseases (Adapted10). sJIA, systematic juvenile idiopathic arthritis.

Another IL-6 inhibitor, satralizumab, is indicated for neuromyelitis optica spectrum disorder (NMOSD) and was approved in the USA, Japan and Switzerland in 202014,15.

Other future potential indications of anti-IL-6 therapeutics include10:

  • Uveitis
  • Thyroid eye disease
  • Neuromyelitis optica
  • Polymyalgia rheumatic (PMR)14
  • Graft-versus-host disease
  • Oncological indications
  • Depression
  • Schizophrenia
  • COVID-19 pneumonia

Covid-19 and IL-6 inhibitors

In July 2021, the World Health Organisation recommended the use of IL-6 receptor blockade in COVID-19 patients with severe symptoms14

Evidence suggests IL-6 is a main factor in COVID-19 hyperinflammation and therefore, IL-6 inhibitors may counteract this16. A meta-analysis of 10,930 patients hospitalised for COVID-19 in 27 trials reported that administration of IL-6 inhibitors in patients compared to those receiving usual care or placebo had an association with lower 28-day all-cause mortality (summary odds ratio, 0.86 [95% confidence interval, 0.79–0.95])17. However, use of IL-6 inhibitors for patients with non-severe COVID-19, or comorbid irreversible organ dysfunction or bacterial or fungal infections is less likely to be beneficial and may be associated with harm18.

Implementing IL-6 in clinical practice

The safety profile of IL-6 inhibitors is understood mainly from clinical trials of tocilizumab, sarilumab and real-world data from more than 1 million patients globally10. Serious infections, including serious bacterial infections, are the most commonly reported adverse events, which is consistent with expectations for a bDMARD treatment for RA10. Long-term data is in line with most short-term data10. Tociluzumab treatment has been associated with an increased risk of gastrointestinal perforations requiring hospitalisation when compared to other bDMARDs13.

Prior to initiation with an anti-IL-6 therapy, it is advised to screen for13:

  • Latent tuberculosis
  • Hepatitis B/C
  • Severe hepatic disease
  • A previous history of intestinal ulceration or diverticulitis (or suggestive symptoms)
  • Altered blood cell counts
  • Severe lipid disorder
  • A history of malignancies

Data of tocilizumab treatment in pregnant women reported preterm birth occurrence in around a third of patients13. This is similar to occurrence rates with anti-TNF agents and is likely due to the presence of higher disease activity in patients on biologic agents13.

A reliable biomarker for prediction of treatment response in many rheumatic diseases has yet to be identified10

However, some studies suggest low pre-treatment IL-6 levels or high pre-treatment CRP levels may be indicative of good treatment responses with tocilizumab13.

A study of tocilizumab for RA reported that low initial CRP, high health assessment questionnaire (HAQ) scores, fatigue, pain and prior bDMARD exposure were all predictors of treatment discontinuation14. Compared to csDMARD or adalimumab monotherapy, anti-IL-6 monotherapy produces larger improvements in patient reported outcomes14.

The evidence for the use of IL-6 inhibitors in clinical practice is growing, and future research could show potential for a wider range of conditions

References

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  2. Kim H, Alten R, Cummings F, Danese S, D’Haens G, Emery P, et al. Innovative approaches to biologic development on the trail of CT-P13: biosimilars, value-added medicines, and biobetters. mAbs. 2021;13(1):1868078.
  3. D'Amico F, Solitano V, Aletaha D, Hart A, Magro F, Selmi C, et al. Biobetters in patients with immune-mediated inflammatory disorders: An international Delphi consensus. Autoimmunity Reviews. 2021;20(7):102849.
  4. Kim H, Alten R, Avedano L, Dignass A, Gomollón F, Greveson K, et al. The Future of Biosimilars: Maximizing Benefits Across Immune-Mediated Inflammatory Diseases. Drugs. 2020;80(2):99-113.
  5. Ben Mrid R, Bouchmaa N, Ainani H, El Fatimy R, Malka G, Mazini L. Anti-rheumatoid drugs advancements: New insights into the molecular treatment of rheumatoid arthritis. Biomedicine & Pharmacotherapy. 2022;151:113126.
  6. Fonseca Peixoto R, Ewerton Maia Rodrigues C, Henrique de Sousa Palmeira P, Cézar Comberlang Queiroz Davis dos Santos F, Keesen de Souza Lima T, de Sousa Braz A. Immune hallmarks of rheumatoid arthritis management: A brief review. Cytokine. 2022;158:156007.
  7. Findeisen KE, Sewell J, Ostor AJ. Biological Therapies for Rheumatoid Arthritis: An Overview for the Clinician. Biologics: Targets and Therapy. 2021;Volume 15:343-352.
  8. Small A, Williams K, Ferrante A, Smith M, Proudman S, Weedon H, et al. Manipulation of B7 Family Member Expression Demonstrates Synovial Macrophage Plasticity and Possible Future Targets for Treatment of Rheumatoid Arthritis. Presented at the ACR Convergence 2021. Available at: https://acrabstracts.org/abstract/manipulation-of-b7-family-member-expression-demonstrates-synovial-macrophage-plasticity-and-possible-future-targets-for-treatment-of-rheumatoid-arthritis/. Accessed December 8, 2022.
  9. Evangelatos G, Bamias G, Kitas GD, Kollias G, Sfikakis PP. The second decade of anti-TNF-a therapy in clinical practice: new lessons and future directions in the COVID-19 era. Rheumatology International. 2022;42(9):1493-1511.
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  13. Kastrati K, Aletaha D, Burmester GR, Chwala E, Dejaco C, Dougados M, et al. A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases. RMD Open. 2022;8(2):e002359.
  14. Aletaha D, Kerschbaumer A, Kastrati K, Dejaco C, Dougados M, McInnes IB, et al. Consensus statement on blocking interleukin-6 receptor and interleukin-6 in inflammatory conditions: an update. Annals of the Rheumatic Diseases. 2022:annrheumdis-202.
  15. Heo Y-A. Satralizumab: First Approval. Drugs. 2020;80(14):1477-1482.
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