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Optimising anti-TNF treatment using biosimilars

Clinical Practice

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Biosimilars in Clinical Practice - What are Biosimilars?

Biological medicines have revolutionised healthcare since their development in the 1980’s. Recently, biosimilars have established their place in the clinic, benefitting almost every stakeholder in the healthcare system. So what are biosimilars and how could they be important to your practice?1

A biosimilar is a medicine containing a version of the active substance of an already-approved biological medicine whose patent has expired (known as a reference product); a biosimilar is approved once it has been shown not to have any clinically meaningful differences in terms of quality, safety and efficacy from the reference product.2–5

As of January 2020, 70 biosimilars have been approved by the EMA and 26 by the US FDA.6,7 Biosimilars based on anti-TNF products such as adalimumab, etanercept, infliximab, and rituximab have been approved for the treatment of gastroenterology, rheumatic, and dermatological diseases. Anti-TNF biosimilars, reduce costs by offering a lower-cost treatment option and can potentially improve patient outcomes by providing more treatment options.8 The arrival of biosimilars has led to cost reductions that allow earlier access to effective treatments, leading to improved patient outcomes and QoL.8 For example, the development of biosimilars to TNF inhibitors such as etanercept and adalimumab for the treatment of psoriasis has led to significant improvements in health-related quality of life in patients.9

Biological molecules have more complex structures than small molecule medicines

Figure 1, Biological molecules have more complex structures than small molecule medicines.10 

Biosimilars are more costly and difficult to produce than generic versions of small-molecule drugs. It can take 5–10 years and an investment of $100–250 million to bring a biosimilar to market, compared with about 2 years and $1–10 million to develop a conventional generic.4

The manufacturer of an original biological medicine must demonstrate its safety and efficacy in clinical trials, in contrast, biosimilar development focuses on in-depth analyses to confirm that the biosimilar is highly similar to its reference product in terms of structure, composition, and in vitro activity.11 At least one clinical study is required to compare the pharmacokinetics of the reference product and biosimilar, and at least one randomised trial is required to demonstrate clinical equivalence.11 If a biosimilar has comparable safety and efficacy in one therapeutic indication to a reference product, then the data may be extrapolated to other indications already approved for the reference medicine.11,12 Consequently, a biosimilar may be approved in all indications for which the reference product has been approved without multiple clinical trials.11 Safety data are monitored and reported on a continuous basis according to rigorous pharmacovigilance regulations outlined by the EMA and US FDA.12,13

Interchangeability is a legal designation, which only exists in the US that indicates patients can expect the same outcome in terms of safety and efficacy with either a biosimilar or its reference product.12 In the EU, interchangeability is a scientific term meaning that a product can be safely switched.14 In the US it is a legal term which allows automatic substitution at the pharmacy level.14 This is slightly different to the term 'switching', which refers to the treatment decision made by a physician to switch patients treated with a reference product to a biosimilar. Substitution refers to a pharmacist substituting one prescribed reference product for a biosimilar without the need to consult a physician.15

Drug development comparison. The development processes for biologics and biosimilars are considerably more rigorous than the development process for small molecule generics

Figure 2, Drug development comparison. The development processes for biologics and biosimilars are considerably more rigorous than the development process for small molecule generics.16

It is estimated that in the UK the healthcare system can make substantial savings of £200 million to £300 million per year if patients are initiated on or switched to biosimilars.3 These savings can then be reinvested into other aspects of patient care to increase the number of health service staff, to increase funding for nurses and to maintain the quality of the social care system.17 As the number of treatment options increases, manufacturers reduce the prices of their products to increase market share and this in turn increases patient access to biologic medicines.18,19

Estimated cost savings by biologic class over a ten-year period from 2017 to 2026

Figure 3, Estimated cost savings by biologic class over a ten-year period from 2017 to 2026.20

The Health Economic Perspective

Biosimilars provide enormous benefits from a health economics perspective.21 But how do anti-TNF biosimilars in particular offer a great value proposition across gastroenterology, rheumatology and dermatology diseases?

Inflammatory bowel diseases including Crohn's disease and ulcerative colitis are chronic inflammatory disorders. In the UK, the incidence rates are currently estimated to be 150 per 100, 000 person-years for Crohn's disease and 10 per 100 000 person-years for ulcerative colitis.22,23

Increasing confidence in the safety profiles of biosimilars such as infliximab and adalimumab is leading to a shift in practice toward early implementation and treatment with biosimilars of patients at risk of early disease progression.24

The introduction of biosimilars for infliximab, for example, is expected to have a major impact on the cost profile of gastroenterology disease. A Dutch study reported that cost savings over 5 years could yield €493 million in total, predominantly determined by price reduction of anti-TNF therapy with physicians switching patients towards biosimilars.25

There are a high number of comorbidities linked to inflammatory conditions such as osteoporosis, cardiovascular disease, neuropsychological disorders and metabolic syndrome. Biosimilars offer patients greater access to treatment at an earlier stage which may prevent the emergence of comorbidities.26

Image representing gastro disease

Rheumatoid arthritis is a systemic autoimmune disorder that causes pain and swelling in multiple joints of the body. The global prevalence of rheumatoid arthritis is estimated at 0.24%.27 Other rheumatology disorders including ankylosing spondylitis and psoriatic arthritis have a global prevalence of 0.1–1.4% and 0.001–0.42%, respectively.28,29

Compared with 2016, the year before any etanercept or infliximab biosimilars were available, the price per treatment day across overall TNF inhibitor use decreased by 13% in the EU, and volume per treatment day increased by 19%. Biosimilars are available at a lower cost and are increasing the access to therapies for more patients.3

The introduction of biosimilars may widen access to biologic therapy and improve overall patient outcomes. Guidelines do not prioritise the use of any particular biosimilar and so the choice of biosimilar for any particular patient may come down to physician–patient judgement and should involve an informed decision-making process.30 There are a number of comorbidities linked to rheumatologic diseases in particular atherosclerosis and cardiovascular disease, which affect a high proportion of patients.31 Careful management of rheumatologic diseases is important for the prevention of comorbidities particularly amongst an ageing patient population.31 Providing patients with affordable treatment ultimately increases their access to medicine that can be started earlier and maintained longer in order to contribute to the prevention of comorbidities.5

Image representing rheumatology

Plaque psoriasis and hidradentitis suppurativa are chronic inflammatory diseases with a high prevalence globally, affecting up to 0.9–8.5% and 0.03–4% of the population, respectively.32,33 Recent estimates of the annual total and direct healthcare costs of moderate-to-severe psoriasis were $22,713 per patient and $13,731, respectively, in the USA and €1617–13,343 and €1314–8966 per patient-year, respectively, across France, Germany, Italy, and Spain.34

Dermatological diseases have been shown to have an effect on the mental health of patients, particularly those with plaque psoriasis and hidradentitis suppurativa.35,36 Comorbidities include depression, anxiety, and suicidal thoughts or behaviour. Treating the disease at an early stage can significantly increase the quality of life of the patient - something that biosimilars provide the opportunity to do.35

Image representing dermatological disease

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How can biosimilars be used in patients and what is the evidence to support their use?

It is widely acknowledged that provider education and acceptance of biosimilars is one of the factors critical to increasing uptake of biosimilars.37 Recently the concept of the nocebo effect has gained renewed interest as a result of introducing biosimilars in therapy; gaps in patients’ and HCPs’ awareness, understanding, and perception of biosimilars may contribute to the nocebo effect, reducing the clinical benefit of biosimilars.37 Apart from the contribution of particular psychological factors to nocebo effects (e.g., general drug sensitivity, negative drug effects in the past, anxiety, etc.), the neurobiological predictors of nocebo responses are not well understood.38 In some cases, patients have discontinued biosimilars, despite having no worsening of disease, after switching from reference products.37 Given the crucial contribution of the nocebo effect on clinical outcomes it is important that HCPs understand the scientific evidence behind biosimilar development and the biosimilar regulatory approval pathway.38 It is thought that when HCPs are confident in their biosimilar knowledge, they can help reduce the risk of nocebo effects and improve patient adherence.39

A systematic literature review identified an extensive body of evidence from retrospective and cohort studies including patients with gastroenterology disease reporting no significant difference in efficacy, safety, and immunogenicity when comparing patients switched to biosimilars compared with those treated continuously with reference products. Data from recent RWE and RCTs across gastroenterology, rheumatology and dermatology therapy areas shows that HCPs can be confident that there will be no differences in safety and efficacy when they prescribe biosimilars as an alternative to reference medicine. Not only data from RWE and RCTs but the continuing pharmacovigilance of biosimilars should also increase confidence of HCPs prescribing anti-TNF biosimilars.39

Summary of randomized controlled switching studies

Summary of randomized controlled switching studies (including open-label extensions).40 ACR: American College of Rheumatology; AS: ankylosing spondylitis; DB: double-blind; IBD: inflammatory bowel disease; OL: open-label; OLE: open-label extension; PsA: psoriatic arthritis; PsO: psoriasis; pts: patients; RA: rheumatoid arthritis; RCT: randomised controlled trial; RP: reference product; w: weeks. 

The infliximab biosimilars CT-P13 and SB2 have been studied extensively to determine their safety and efficacy in the treatment of inflammatory conditions. For example, a nationwide, observational study to evaluate the efficacy, safety, and immunogenicity of CT-P13 with IBD compared with reference infliximab, demonstrated that the effectiveness and safety of CT-P13 were in line with reference infliximab after a total of 195 patient years of follow-up.41 The effectiveness of the biosimilar was evaluated in 434 patients who received treatment for at least 8 weeks, using time-to-event methods for censored observations: 35 patients were primary failures (8.1%).41 After further 8, 16, and 24 weeks, the efficacy estimations were 95.7%, 86.4%, and 73.7% for naive, 97.2%, 85.2%, and 62.2% for pre-exposed, and 94.5%, 90.8%, and 78.9% for switch, respectively (log-rank P = 0.64).41

Regulatory approval for CT-P13 was supported with two RCTs in patients with rheumatoid arthritis and ankylosing spondylitis each of which incorporated a switching event and at least 1-year follow-up. Each study was followed by an open label extension where patients receiving reference infliximab were transitioned to CT-P13. Both studies demonstrated no clinically meaningful differences in safety and efficacy of CT-P13 compared to reference product.42,43

SB2 approval was supported by an RCT in which patients treated with reference product were switched to SB2 after 54 weeks and followed to 78 weeks. No changes were detected in safety or efficacy.44

Phase III confirmatory studies were conducted to support approval of GP2015 (biosimilar etanercept) and ABP-501 (biosimilar adalimumab) in patients with psoriasis. For both studies the safety and efficacy of the switched and non-switched arms were similar.45,46

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References - Biosimilars in Clinical Practice

  1. NRAS (2019) Paper on biosimilar medicines. Updated February 2019. Retrieved January 6, 2020 from: https://www.nras.org.uk/data/files/About%20RA/How%20is%20RA%20managed/NRAS%20revised%20position%20paper%20biosimilars%20Feb%202019.pdf
  2. Emery, P et al. (2015) A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis 76:51–57. http://dx.doi.org/10.1136/annrheumdis-2015-207613 https://doi.org/10.1136/annrheumdis-2015-207588
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