Unlocking the Value of Anti-TNF Biosimilars: Reducing Disease Burden and Improving Outcomes in Chronic Immune-Mediated Inflammatory Diseases: A Narrative Review.

Immune-mediated inflammatory diseases (IMIDs) are chronic conditions that create a significant disease burden on millions of patients while adding a major financial burden to societies and healthcare systems. The introduction of biologic medicines has contributed majorly to improving the clinical outcomes of IMIDs and as such these modalities have gained first- or second-line positions in a wide range of treatment guidelines from different international clinical societies. However, the high cost of these biologics traditionally limited their accessibility and delayed their initiation, leaving millions of patients with unmet medical needs for a more affordable and sustainable solution. The introduction of cost-efficient biosimilar anti-TNFs within Europe since 2013 has allowed more patients with IMIDs to access biologic therapies earlier and for longer, potentially altering the course of the disease into a milder phenotype and reducing the long-term disease burden. This review provides the latest evidence for the impact of biosimilars on patient outcomes and demonstrates their clinical value beyond a reduction in price.

Key Summary Points

Introduction

Immune-mediated inflammatory diseases (IMIDs) are chronic conditions that share common pathophysiological pathways and include rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis (PsO) [1]. Globally, IMIDs have an incidence of 5–7% [2] and patients can often have multiple inflammatory-driven conditions at any one time [1]. Thus, IMIDs cause a large burden to patients, physicians and societies [1, 3–5].

The introduction of biologic drugs more than 2 decades ago revolutionized treatment across a number of IMIDs within rheumatology, dermatology and gastroenterology [6-9]. Key trials of biological therapies showed a large impact in reducing disease burden for the majority of patients [10-13]. This impressive efficacy, alongside manageable side effect profiles [14, 15], and improvements in patients’ quality of life [16-18] led to biologics being recommended for use within society guidelines [19-30].

While biologics undoubtedly have a positive clinical impact, they are associated with high costs [31-33]. One report noted that out of an estimated global drug budget of US$1 trillion in 2018, innovative biologics account for 29% (US$296 billion) [34]. Another report found that, in the US market, spending on biologics totaled US$125 billion in 2018, a 50% increase since 2014 [35]. These high costs create new clinical unmet needs that disadvantage patients and healthcare professionals (HCPs) (Fig. 1). The arrival of biosimilars introduced lower cost biologics to the market, reducing healthcare spend and allowing subsequent savings to be reinvested into healthcare services [36-41]. Numerous modeling studies have predicted large-scale cost savings across Europe following biosimilar market entry (Table 1), which are now being realized [42]. However, the benefits of biosimilars reach beyond cost alone and can impact the unmet clinical needs associated with biologics. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Fig. 1

Unmet clinical needs created by high costs of biological therapies in IMIDs

Table 1

Potential savings as a result of biosimilar introduction within the EU

References	Country	Therapy area	Biosimilars	Model	Projected saving	Additional patients treated
Aladul et al. [125]	UK	Rheumatology Gastroenterology	Adalimumab Etanercept Infliximab	Budget impact model using retrospective market shares of biologics in rheumatology and gastroenterology	£44 million over next 3 years
Jha et al. [126]	Belgium Germany Italy Netherlands UK	Rheumatology Gastroenterology Dermatology	Infliximab	Budget impact model with a 1-year time horizon	€25.79–77.37 million depending on country and price discount	1960–7561 across all five countries
Brodszky et al. [127]	Bulgaria Czech Republic Hungary Poland Romania Slovakia	Crohn’s disease	Infliximab	3-year, prevalence-based budget impact analysis	Scenario 1: interchanging not allowed: €8 million Scenario 2: interchanging allowed in 80% patients: ca. €17 million
Lee et al. [128]	28 EU countries*	Breast cancer Gastric cancer	Trastuzumab	Budget impact model with time horizon of 1–5 years	€0.91–2.27 billion over 5 years depending on scenario In the first year only budget savings ranged from €58 million to €136 million	3503–7078
Gulacsi et al. [129]	28 EU countries*	Rheumatology Cancer	Rituximab	3-year base-case scenario	Base-case scenario (biosimilar uptake 30%, cost 70% of originator): €90 million Second scenario (biosimilar uptake 50%): €150 million	Over 3 years projected budget savings were €570 million equating to 47,695 additional patients able to access rituximab

*Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, UK

Access to Treatment

While biologics are highly effective in treating IMIDs their high cost leads to their underutilization in many countries because of access restrictions [36, 39, 43–45]. A cross-sectional study across 46 European countries showed that many countries limited access through reimbursement criteria that were stricter than national and international guidelines [45]. In ten countries biologics were not reimbursed at all, and within the other 36 where at least one biologic was reimbursed, significant differences in eligibility criteria existed (requirement for more treatment failures, increased disease activity). Another study determined that while 32% of the total RA population in the European region is eligible for biologic treatment as defined by European League Against Rheumatism (EULAR) guidelines, only 59% of this population remain eligible following the application of national reimbursement criteria (range 13–86%) [39]. Furthermore, in some EU countries patients must make high co-payments that may lead to further inequities in the use of biologicals [46].

The introduction of cost-effective biosimilars across a wide range of therapeutic areas, including IMIDs, has lowered cost and increased the ability of patients to access biologic treatment [42]. Biosimilars to granulocyte colony-stimulating factor (GCSF) were the first biosimilars marketed. Following their introduction across Europe the cost of GCSF treatment decreased on average by 28%, while the uptake increased, although it varied greatly from country to country increasing from 50% to 200% in Belgium, Demark, Ireland and the Netherlands to 300–1600% in Poland, Romania, Slovakia and Slovenia in 2014 compared with year of biosimilar entry (2008) [47]. In Sweden, the introduction of biosimilar filgrastim reduced costs and resulted in a fivefold increase in GCSF uptake [48]. Finally, a recent review noted that the reduced costs and increased access that biosimilar pegfilgrastim affords could allow countries to switch from the shorter-acting filgrastim, improving adherence and enabling patients to receive their full chemotherapy treatment, without dose delays or reduced dose intensities, improving patient outcomes [49].

The same effects have been observed for anti-TNF biosimilars. Using data from the Swedish Rheumatology Quality Register, Di Giuseppe et al. [50] showed that introduction of biosimilars to infliximab (IFX) and etanercept (ETN) resulted in an increase of the total number of ongoing treatments (originator + biosimilar) during the study period from more than 125 patients/month before to more than 165 patients/month following the introduction of biosimilars. Similarly, Razanskaite et al. [51] demonstrated that at the same time that costs were reduced following IFX biosimilar introduction, the number of treatments went up from a maximum of 100,000 vials/month to 140,000 vials/month.

Earlier Treatment

It is generally accepted that IMIDs should be treated effectively as early as possible to modify the natural progression of the disease, preventing target organ damage and limiting the occurrence and worsening of comorbid diseases—the so-called window of opportunity [52-56]. Delays in the assessment and treatment of patients with RA are associated with higher risks of not achieving remission, joint destructions and radiographic progression [57, 58]. Conversely, in a meta-analysis of 12 studies within RA, early treatment with disease-modifying anti-rheumatic drugs (DMARDs) led to a significant 33% reduction in joint damage compared with patients treated later in the course of their disease [59]. These benefits of early treatment were observed for up to 5 years, and patients with aggressive disease (as measured by radiographic progression at baseline) appeared to derive more benefit than patients with less-aggressive disease. Benefits of earlier treatment have also been shown with biologics [60-68]. Earlier intervention with biologic treatment (IFX + MTX) provided higher short- and long-term remission rates in patients with Crohn’s disease (CD) compared with conventional treatment without increasing serious adverse events [62]. In an analysis of health claims data from the USA, patients who received anti-TNF therapy early in their disease course (30 days within the first prescription for CD—the ‘top down’ approach) experienced lower risks of concomitant corticosteroid use, anti-TNF dose escalation, discontinuation/switch of anti-TNF therapy, and CD-related surgery up to 24 months post therapy initiation compared with the ‘step-up’ approach (5-ASA ± corticosteroids before starting anti-TNFs) [65]. In a recent systematic review and meta-analysis of 47 publications totaling 18,471 patients with CD, early treatment with biologics was associated with higher rates of clinical remission (OR 2.10, p < 0.00001) or mucosal healing (OR 2.37, p < 0.00001) and lower relapse rates (OR 0.31, p = 0.003) compared with later treatment in both clinical trial and real-world settings [67].

Despite the rationale and evidence for the earlier treatment of patients, the ‘step-up’ strategy remains widely used in clinical practice, delaying the introduction of effective biological DMARDs (bDMARDs), resulting in long-term damage and disease burden. In addition, the majority of international guidelines restrict the use of biologics to the second line, following a ‘top-up’ approach, starting with a conventional DMARD before moving onto a bDMARD once disease progresses or does not respond to therapy [19–21, 24, 26, 28–30, 69]. A further complication is that guidelines are often not followed in clinical practice [70-72]. Furthermore, the health economic data that reimbursement criteria are based upon may not be up to date, leading to misalignment between policy and practice [73, 74]. Introducing biologics earlier in the disease course may reduce morbidity, hospitalizations and surgical interventions, therefore reducing disease burden and potentially reducing long-term costs [53, 54, 75–78].

The introduction of biosimilars could reduce the cost of therapy, allowing patients to be treated earlier in their disease course and more in line with guideline recommendations [36, 64]. In 2016 the National Institute for Health and Care Excellence (NICE) provided a technology appraisal on the use of biologic drugs in RA (TA375) [73]. It concluded that biologics could only be used in RA patients with severe disease who had not responded to intensive therapy with combinations of DMARDs. NICE determined that biologic use could not be recommended at that time in patients with moderate disease as the incremental cost-effectiveness ratio (ICER) for this group of patients was £10,000 higher than that for those with severe disease [73]. However, in January 2019, NICE took the decision to initiate a review of their recommendations within TA375 for patients with moderate disease because more cost-effective biosimilar versions of adalimumab, ETN and rituximab had become available that would improve the affordability of biologic treatment in patients with moderate disease [74]. Final recommendations are still pending. Availability of biosimilars has also had an impact on society guidelines. In the most recent EULAR guidelines on the use of DMARDs in patients with RA [27] the task force updated their recommendation from biologics being ‘considered’ to ‘should be added’ to conventional synthetic DMARDs (csDMARDs) for patients with poor prognostic factors. The guidelines also note that some members of the task force suggested applying a similar recommendation for patients who do not exhibit poor prognostic factors, but there was not sufficient support for this within the task force.

Achievement and Maintenance of Remission

The principle of treat-to-target (T2T) has been successful in different therapeutic areas including hypertension [79] and diabetes [80], and is aimed at achieving a prompt and effective control of the disease process that is then maintained over time [70, 81]. Current guidelines and recommendations for IMIDs also recommend a treat-to-target approach [69, 82–84]. The value of such an approach is better patient outcomes in both the short and long term, which in addition to remission includes reductions in comorbidities and cardiovascular risk, as well as improvements in quality of life and productivity [81, 85–90]. However, several studies have shown that the practices outlined in guidelines do not translate well into the clinic with low rates of adherence to recommendations [70, 91–94]. Reasons for non-adherence include lack of awareness of guidelines, individual physician beliefs and financial and cost issues [91-93], including access to the relevant treatments as outlined earlier in the review. Several studies have shown that RA patients with moderate-to-severe disease receive biologics on a less frequent basis than recommended in guidelines (7–55%) [92, 93, 95] and also patients with more severe disease are more likely to be non-adherent to treatment [92].

While biologics have proven highly effective in inducing remission in patients with IMIDs [96-98] they have also been shown to be effective in maintaining remission [96, 99, 100]. However, the financial burden of biologic drugs has led to investigations of whether bDMARD therapy can be tapered or stopped in patients who have been in remission for a significant period of time [101, 102]. While some patients in remission can become biologic or drug free, stopping or tapering biological therapy in patients with IMIDs increases the risk of flares and relapse for a significant proportion of patients [103-112]. In one study 184 patients with moderate-to-severe psoriasis were retrospectively followed after clinical trials they had participated in had ended [107]. The study showed that 86% of patients required systemic treatment 12 months after biologic withdrawal, and biologics were reinitiated in 77% of patients by 3 years post withdrawal. In an interim analysis of a randomized controlled trial of patients with RA (n = 101) in stable remission, over half of patients remained in remission following reduction in or stopping of csDMARD or bDMARD therapy [106]. However, one-third of patients relapsed with both tapering (OR = 5.74, p < 0.05) and stopping therapy (OR = 8.78, p < 0.01), which were significantly predictive of relapse in a multivariate logistical regression analysis. In a UK-based observational study relapse rates following withdrawal of anti-TNF therapy in patients with IBD were ca. 40% and ca. 50% at 1 year and 2 years post withdrawal for both CD and ulcerative colitis (UC) cohorts. A systematic review and meta-analysis by the same group confirmed 1-year relapse rates of ca. 40%. Reinitiation of anti-TNF therapy was successful in the majority of patients. Thus, while dose-reducing strategies can be successful for a subset of patients, they expose others to increased disease burden and reduced quality of life. Possible prognostic factors are being investigated to allow the identification of which patients are at higher risk of relapse following treatment withdrawal/tapering [110, 113–116]. Younger age at diagnosis and more extensive and aggressive disease are indicators for continued therapy [113].

The more cost-effective nature of biosimilars will allow patients to be treated to target and then to be maintained on the most ideal regimen based on their risk factors and personal needs. Patients deemed to be at risk of relapse can remain on therapy when in remission or experiencing low-disease activity, thus improving outcomes and reducing clinical and personal burden.

Disease Burden

As described earlier, IMIDs share common inflammatory pathways [1] and therefore it might be assumed that having one IMID might make a person more prone to other inflammatory diseases. This is indeed the case. In a systematic review and meta-analysis of 25 publications, Schieir et al. [117] noted an increased risk of myocardial infarction (MI) across IMIDs with a 69% increased risk in RA and a 41% increased risk in psoriatic arthritis. These risks remained following adjustment for more traditional risk factors for MI. Increased cardiovascular risk has also been noted in patients with PsO [118]. The presence of one IMID also puts patients at higher risk of other IMIDs. A recent retrospective matched cohort study showed that the presence of one IMID puts patients at 5–62% increased risk of developing an additional IMID and at 3–75% increased risk of another two IMIDs [119]. Patients with IBD have been noted to be at higher risk of developing psoriasis, RA, ankylosing spondylitis (AS), multiple sclerosis (MS) and asthma [120-123]. Conversely the risk of IBD is increased in patients with PsO [118]. In two large studies (one EU, one US) approximately 22% of patients with IBD had at least one other immune-mediated disease [121, 123]. The presence of another IMID increases disease burden by increasing the risk of surgery and decreasing disease-specific and general physical quality of life [121, 123]. However, treatment of the primary IMID with anti-TNFα therapies reduces the risk and impact of secondary IMIDs, therefore further reducing the burden on the patient [2, 121, 124]. Patients with IBD treated with infliximab had a 50% reduced risk of developing secondary IMIDs [121], while the risk of MI in patients with PsO was also reduced 50% by the use of anti-TNFα inhibitors for 2 months or longer [124].

Conclusions

Along the course of the last 2 decades, TNF inhibitors, particularly etanercept, infliximab and adalimumab, have revolutionized the management of chronic immune-mediated inflammatory diseases; however, their relatively high cost prevented healthcare systems from exploiting their full clinical benefit.

The introduction of anti-TNF biosimilars into clinical practice continues to have a large impact on the sustainability of global healthcare. As more real-world evidence on their use is accruing, it is also clear that the impact of anti-TNF biosimilars expands beyond that of cost reduction alone and can increase patients’ access to these essential biological therapies and positively influence the course of their disease [36, 50, 51]. This includes the opportunity to realize clinical goals such as early initiation of biological treatment, treating to target, continuing treatment to maintain remission or low disease activity and reducing disease burden. However, for the true benefit of biosimilar anti-TNFs to be realized, the right environment needs to be created, one where high-quality biosimilars are approved expeditiously, competition for a given originator is optimized and the switching of patients onto biosimilars is properly enabled. All of these actions will result in maximum cost savings [125], which can then be reinvested into patient care.

Acceptance of anti-TNF biosimilars across healthcare system stakeholders would allow more equitable access to these highly effective and cost-sensitive therapies and enable optimized management of chronic IMIDs.

Over the past 2 decades anti-tumour necrosis factor (TNF) biologics have revolutionized the management of chronic immune-mediated inflammatory diseases, but their relatively high cost has created unequal access for patients to these effective treatments and compromised therapeutic goals

In addition to their positive impact on the sustainability of global healthcare, current evidence clearly shows that anti-TNF biosimilars are having an impact beyond cost reduction alone—increasing access to these essential biological therapies, improving patients’ outcomes and reducing disease burden

However, all patients need to be able to take advantage of the full spectrum of benefits that biosimilars bring, which can be achieved by expeditious approvals, optimized market competition, and prompt and appropriate switching