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Anti-TNF biosimilars for rheumatic diseases: the key to early treatment?

Anti-TNFs in rheumatic diseases

Read time: 50 mins
Last updated:27th Apr 2022
Published:27th Apr 2022

Are you aware of key evidence behind regulatory approvals for tumour necrosis factor (TNF) inhibitor (anti-TNF) biosimilars, and how they may help to address unmet needs for patients with rheumatic disease? Read below to:

  • Learn more about the links between high treatment costs, unmet needs in rheumatic disease, and disease outcomes
  • Explore evidence for anti-TNFs in the early treatment of rheumatic diseases
  • Compare and contrast the development and approval process between biosimilars and their reference medicines, and decide for yourself whether anti-TNF biosimilars may help to address unmet needs in rheumatic diseases

Burden of rheumatic diseases

Rheumatic diseases are chronic inflammatory conditions affecting the joints, conferring a high burden of disease, negatively impacting patients’ health-related quality of life, and incurring high costs to individuals, society and healthcare systems1.

The emergence of biological disease-modifying anti-rheumatic drugs (bDMARDs) has contributed to improved clinical outcomes and greatly improved the treatment of rheumatic diseases2. Guidelines generally recommend bDMARDs as second-line treatment, after failure of conventional synthetic DMARDs (csDMARDs)3–9.

Unmet needs in managing rheumatic diseases

For patients with rheumatic disease, key unmet needs include early access to effective treatments that can limit disease progression and overall disease burden2,10 (Figure 1).

Anti-TNF_Fig_1.png

Figure 1. Key unmet needs in rheumatic diseases2,10–12(Adapted2).

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TNFα – a key therapeutic target in rheumatic diseases

As a pro-inflammatory and immunoregulatory cytokine, tumour necrosis factor alpha (TNFα) has an established role in the pathogenesis and progression of rheumatic, inflammatory and autoimmune diseases13–15. TNFα is therefore an important therapeutic target for treatment of rheumatoid arthritis (RA), ankylosing spondylitis (AS) and axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA)16 and other inflammatory conditions such as inflammatory bowel disease, plaque psoriasis, non-infectious uveitis and hidradenitis suppurativa13,15–17.

Anti-TNFs approved for rheumatic disease

Since anti-TNFs (TNF inhibitors) were the first biological disease-modifying antirheumatic drugs (bDMARDs) approved for treatment of rheumatoid arthritis18, other bDMARDs have been approved for various rheumatic disease indications, including those that target interleukin (IL) pathways (IL-6, IL-17, IL12/23)3,5,6,8, CTLA-4-Ig or CD205.

There are now five anti-TNFs approved for rheumatic and inflammatory disease indications across Europe and the US: adalimumab, certolizumab pegol, etanercept, infliximab and golimumab13 (Figure 2). These approvals were based on pivotal studies that demonstrated their efficacy in each indication for achieving and maintaining clinical response, and their well-characterised safety profiles19–23.

Anti-TNF_Fig_2.png

Figure 2. Timeline of first approvals* for anti-TNFs in rheumatic disease across the US and Europe24–35. *Year of first regulatory approval for each rheumatic disease indication, in either the US Food and Drug Administration or European Medicines Agency, whichever approval was first. AS, ankylosing spondylitis; JIA, juvenile idiopathic arthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; TNF, tumour necrosis factor.

Place in therapy for anti-TNFs in rheumatic diseases

In Europe, anti-TNFs are approved for second-line treatment (as either monotherapy or in combination with methotrexate) for RA, AS, JIA and PsA after an inadequate response to previous DMARD(s), and for first-line treatment of severe, active and progressive RA36–44. In contrast, the US FDA-approved indications for anti-TNFs in RA, AS, JIA and PsA do not require a prior inadequate response to DMARD(s)19–23.

According to European and US guidelines for RA, AS/AxSpA, JIA and PsA3–9, the place in therapy for anti-TNFs is generally consistent with that of other bDMARDs, as a second-line treatment option after failure of conventional synthetic DMARDS (csDMARDs). Although US guidelines for PsA and JIA and European guidelines for PsA also consider bDMARDs as a preferred first-line treatment option for certain patients with these conditions8,9, first-line use of anti-TNFs for both indications is considered off-label in Europe36–44.

Assessing treatment response in a timely manner, and adjusting treatment where necessary, is important to facilitate early disease control2,3

For RA, European Alliance of Associations for Rheumatology (EULAR, formerly the European League Against Rheumatism) recommends adjusting treatment if there is no improvement by at most 3 months after starting treatment, or if the target has not been reached by 6 months3. For those with poor prognostic factors (such as the presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), a bDMARD or a Janus kinase inhibitor should be initiated after failure to reach treatment target with the first csDMARD3. In the US, American College of Rheumatism (ACR) recommends re-evaluating treatment decisions within a minimum of 3 months based on efficacy and tolerability of the chosen DMARD(s)4.

Consistent with EULAR recommendations, csDMARD failure may be identified in patients with RA as early as 3 months after starting treatment, and biologic treatment may then be initiated for those with poor prognostic factors; however, inequities in access can impede initiation of bDMARDs in practice2,45. These inequities can arise due to treatment costs, strict reimbursement criteria and co-payment requirements2,11–13. Access to treatment may also be influenced by differences in bDMARD initiation thresholds and treatment traditions among rheumatologists, as well as region-specific economic considerations, previously suggested in association with variable market penetration and uptake of biologics observed across different regions within European countries45–47.

Key evidence for anti-TNFs in early treatment of rheumatic diseases

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About biosimilars

After the expiry of patents on reference biological disease-modifying antirheumatic drugs (bDMARDs), the emergence of biosimilars has helped to address the high cost burden of bDMARDs on patients and healthcare systems10,60. Biosimilars are medicines that are highly similar to another biological medicine (reference biologic) already on the market61. There may be minor differences between the biosimilar and the reference biologic due to natural biological variability and unique methods in the biomanufacturing process and, prior to regulatory approval, the manufacturer is required to demonstrate any differences are not clinically meaningful in terms of the biosimilar’s safety and efficacy61.

Biosimilar development, testing and approval

Biosimilars are required to have no clinically meaningful differences from their reference medicine in terms of safety and efficacy, and amino acid sequence and 3D structure (folding) must be the same as the reference medicine if the biosimilar active substance is a protein61,62

The development and approval process for biosimilars involves rigorous comparative analytical and clinical testing against their reference medicines1,10,60. For European Medicines Agency (EMA) and US Food and Drug Administration (FDA) regulatory approvals, a stepwise, totality of evidence approach is required, based on head-to-head analytical, non-clinical and clinical studies of the biosimilar against the reference medicine1,60 (Figure 3). These studies are required to demonstrate high similarity of the biosimilar to the reference medicine in terms of chemical structure, biological function, efficacy, safety and immunogenicity1,61. Previous data on the safety and effectiveness for the reference medicine is also considered as part of this process62.

Anti-TNF_Fig_3.png

Figure 3. Requirements for approval of biosimilars versus reference medicines (including reference biologics) in Europe and the US1,60–63(Adapted61). PD, pharmacodynamics; PK, pharmacokinetics; RM, reference medicine.

Extrapolation of biosimilars to further indications

After biosimilarity has been demonstrated61, the quality, safety and efficacy profile for a biosimilar in one therapeutic indication may be approved for extrapolation into other indications of the reference medicine (i.e. reference biologic)60–62. Extrapolation is considered on a case-by-case basis, if adequate justification can be provided by the sponsor60–62.

Extrapolation is a well-established scientific principle routinely used to approve manufacturing changes to biological medicines with several approved indications, whereby clinical trials are not repeated for all indications61

Extrapolation of data to other indications must be supported by scientific evidence generated in robust comparability studies (quality, non-clinical and clinical), considering aspects such as the biosimilar’s mechanism of action, the relevance of the study population and clinical setting, and immunogenicity data61. However, patent protection and exclusivity periods of reference biologics in certain countries can complicate extrapolation of biosimilars to wider indications60.

Interchangeability of biosimilars with reference medicines

Some biosimilars may be designated as ‘interchangeable’ by the FDA, in which case they may be substituted for the reference biologic without the involvement of the prescriber (i.e. at the pharmacy level)64. To receive this designation, further evaluation and testing are required to demonstrate that an interchangeable product is expected to produce the same clinical result as the reference biologic in any given patient64.

In Europe, interchangeability refers to exchanging one medicine for another medicine that is expected to have the same clinical effect, which may involve a prescriber switching medicines or substitution at pharmacies without consulting the prescriber61. Decisions on whether biosimilars and original products can be exchanged or substituted are regulated at the individual country level65. The European Alliance of Associations for Rheumatology (EULAR) consensus statement notes reference biologics and biosimilars should not be interchangeable with each other in pharmacies, unless they are produced using a manufacturing process that runs under identical conditions and are considered bioidentical65.

Safety monitoring of biosimilars and reference biologics

As with their reference biologics, appropriate pharmacovigilance and ongoing safety monitoring are required for biosimilars1,61. To enable effective pharmacovigilance, specific and unique naming requirements exist for all biological products in both Europe and the US61,66–68.

Of more than 50 biosimilars approved in the European Union to date, none has been withdrawn or suspended for reasons of safety or efficacy
European Medicines Agency, 201961

Anti-TNF biosimilars for rheumatic diseases

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