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Optimising anti-TNF treatment using biosimilars

Efficacy & Safety

Read time: 20 mins
Last updated:10th Nov 2020
Published:7th Aug 2020

Efficacy and Safety of Biosimilars

The costs of anti-TNF products are often high, placing a financial burden on the healthcare system and at times limiting the access to these products.1 As an alternative, anti-TNF biosimilars enable earlier and wider access to appropriate therapy without the financial burden associated with the reference product.2 But does the efficacy and safety data for anti-TNF biosimilar treatments support their use in the treatment of key gastroenterology, rheumatology, and dermatology conditions? 

There has been a lack of confidence amongst HCPs to prescribe biosimilars largely stemming from concerns regarding extrapolation and the lack of clinical data for biosimilars in their relevant indication. Additionally, patients have been reluctant to accept biosimilars in the past - highlighting the need for patient education and effective communication from informed medical professionals, confident in the reasoning behind their choice of biosimilar.3

Fortunately, there appears to be a shift in attitudes since recent real-world data has provided a wealth of data supporting the effectiveness and safety of biosimilars in many indications, for example, inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC).4 HCPs are increasingly recognising that biosimilars expand access to therapy, greatly impacting the care they can provide their patients. For example, a key role in changing attitudes around biosimilars in IBD was the potential to significantly decrease complications like strictures or perforations in early CD.5

With additional data confirming the safety and efficacy of biosimilars (over and above the data required for approval), confidence and comfort in using biosimilars should increase in both HCPs and patients alike.6 In general, the evidence acquired over ten years of clinical experience shows that biosimilars approved through the EMA can be used as safely and effectively in all their approved indications as other biological medicines. Furthermore, of more than 50 biosimilars approved in the EU to date, none have been withdrawn or suspended for reasons of safety or efficacy.7  

In IBD specifically, the first biosimilar to be FDA-approved for CD and UC (and for all the indications of the reference product infliximab) was CT-P13. While the only controlled clinical studies of this biosimilar were carried out in ankylosing spondylitis (AS) (phase 1) and rheumatoid arthritis (RA) (phase 3), the approval to extrapolate to IBD was supported by the non-clinical data supporting similarity across different potential mechanisms of action, pharmacokinetics, immunogenicity, and toxicity data.8 As data has emerged from a number of studies examining the use of biosimilars in IBD confidence has increased in the safety and effectiveness of biosimilars in this group of patients. 

The NOR-SWITCH trial was a double-blind, non-inferiority study of patients (with various IMIDs) receiving the reference drug infliximab who were randomly assigned to either continue this treatment or switch to CT-P13. The study showed non-inferiority between the biosimilar and the reference biologic, and that there were no significant differences in serum drug concentrations or the occurrence of anti-drug antibodies.9 Further investigation in CD patients naïve to biological therapy also reported non-inferiority of CT-P13 to infliximab with no notable differences between groups for faecal calprotectin, C-reactive protein, anti-drug antibodies, pharmacokinetics, safety, or the number of patients in clinical remission at one year.1

A recent observational study demonstrating real-world data indicated the effectiveness of CT-P13 is equivalent to that of the reference product infliximab (for infliximab-naïve patients with CD) and that no differences in safety outcomes were observed.10 Interim analyses from an observational study of patients with IBD treated with SB2 reported that the efficacy and safety of SB2 appears to be overall similar to those reported for the reference product (infliximab) and the biosimilar CT-P13.11 Additionally, a prospective, observational cohort study of CD and UC patients that switched from infliximab originator to biosimilar SB2 in 2017 were followed-up for 18-months. Median disease activity, CRP levels, trough levels, anti-drug antibodies, and adverse events were reported, and the study concluded that switching from infliximab to SB2 was not associated with an increase in disease activity and no clinically meaningful changes in trough levels or immunogenicity were identified. SB2 was well tolerated in a real-life setting.12

Table 18, Further selected studies and guidelines pertinent to the use of biosimilars in IBD are listed below. 


Biosimilars used to treat rheumatology diseases also show excellent efficacy and safety in comparison to their reference products with CT-P13 investigated as a treatment for multiple rheumatology conditions including RA and AS. The two main studies from these investigations were the PLANETRA study (RA)13 and the PLANETAS study (AS)14. Both studies reported comparable safety, efficacy, and immunogenicity of CT-P13 to infliximab and both extension studies reported that clinical efficacy was similar in patients in the maintenance (continued CT-P13) and switch groups (switched from reference biologic to CT-P13).13,15,16

Comparable efficacy and safety of SB2 compared with infliximab has also been reported in patients with RA, with no clinically relevant immunogenicity or treatment-emergent issues after switching from the reference product.17 SB5 has also been shown to have equivalent efficacy and comparable safety results to that of the reference adalimumab in patients with moderate-to-severe RA,18 with evidence that SB5 was well tolerated over 1 year and that switching from the reference product to SB5 had no treatment-emergent issues.19


Graph 113, American College of Rheumatology (ACR) response rates over time from the PLANETRA study. ACR20, ACR50 and ACR70 denote the ACR 20%, 50% and 70% improvement criteria, respectively. CT-P13 compared with RP (denotes reference product infliximab) at Week 14, 30 and 54. 



Graph 217, incidence of immunogenicity during transition period.

*Patients having at least one positive ADA result during the last transition-extension period among all patients regardless of prior ADA results up to week 54. † Patients having at least one positive ADA result during the transition period among patients with overall negative ADA results up to week 54.

In dermatological indications, a 2018 study examined the safety, efficacy and time to discontinuation of a number of biologics (adalimumab, etanercept, infliximab, secukinumab, and ustekinumab) in patients with moderate-to-severe psoriasis. The authors also compared originators etanercept with biosimilar, and infliximab with biosimilar, reporting that switching from originator to biosimilar had no significant impact on the time to discontinuation; in addition, the safety profiles were comparable. 20 The EGALITY study – a randomised, double-blind study comparing GP2015, an etanercept biosimilar, to the originator, demonstrated equivalent efficacy, comparable safety and immunogenicity in patients with moderate-to-severe chronic plaque-type psoriasis.21 Additionally, Gerdes et al evaluated the effects of repeated switching between GP2015 and the originator and reported no effects in the short term on clinical data of doing so. 22

The evidence of the safety and efficacy of biosimilars compared with their reference products in gastroenterology, rheumatology, and dermatology should instil ever more confidence in HCPs to prescribe them and, armed with such knowledge, HCPs can help put their patients at ease with using them. This can have a significant impact on adherence and reduce the risk of nocebo effects.4

The adoption of biosimilars early in the course of treatment can improve the health outcomes of the patient population overall. Importantly, the use of biosimilars reduces the need to reply on expensive branded biologics, and compounds traditionally used in the onset of IMIDs. They also increase market competition bringing the cost of the reference biologics down, resulting in the overall reduction in cost of treatment, expanding not only the number of patients who can access early biologic treatment, but increasing the number of treatment options available for HCPs to offer their patients. Biosimilars increase access and options to timely, life-changing treatment.

Disease Burden and Comorbidities

IMIDs are associated with a high disease burden and significantly reduced QoL. But how do comorbidities and undertreatment contribute to the overall high disease burden across gastroenterology, rheumatology, and dermatology conditions?

The burden of disease in IBD patients can be wide-ranging and variable due to the chronic and unpredictable nature of the disease. The symptoms of IBD are often painful and embarrassing leading individuals to develop many daily concerns, such as bowel control, bowel urgency, pain management, and fatigue. Longer-term concerns such as treatment options, the prospect of surgery, the development of cancer, and the personal financial burden due to reduced working hours (absenteeism), all contribute to the significant psychosocial burden of the disease, and the well-documented decrease in the quality of life (QoL) when compared to healthy individuals.23

Rates of anxiety and depression are higher in patients with IBD compared to healthy controls (anxiety; 19.1% vs. 9.6%, depression; 21.2% vs. 13.4%, respectively).23 This is also true for children with IBD, where higher rates of depressive and anxiety disorders are found compared to children with other chronic diseases and it typically correlates with disease activity.24 Further, the effect of proinflammatory cytokines on the brain, sleep disturbance, and corticosteroids are thought to contribute to the overall decrease in mental health.24

IBD can also have a significant impact on young patients because of the effects on their growth and bone health, micronutrient deficiencies, and colon cancer risk.24 For instance, 40% of children with CD will suffer from growth failure with 19% achieving a height 8 cm shorter than expected. This stunted growth is multifactorial but the use of corticosteroids and cytokine-induced growth hormone resistance have been implicated. Bone metabolism abnormalities are also an issue, and factors such as malnutrition, delayed puberty, decreased physical activity, and malabsorption contribute. However, chronic inflammation itself may exert the most profound effects placing patients at risk of fracture as they age. Chronic inflammation is also a contributing factor to the increased risk of developing colon cancer, highlighting the importance of effective and timely treatment to combat chronic inflammation, and ensure children with IBD achieve optimum adult bone mass, reduce the risk of colon cancer, and reduce the overall burden of disease.25

Other comorbidities have been associated with IBD activity such as coronary artery disease, where there is an increased risk in IBD patients compared with controls. Importantly, the classic risk factors such as hypertension, diabetes, dyslipidemia, and obesity were not related to this increase, but to an increase in white blood cell counts and a possible association with IBD activity.26 Metabolic syndrome and IBD have also been pathophysiologically linked with similarities in inadequate immune response and chronic inflammation.26 It has also been shown that fatigue, although multifactorial, increases in prevalence with increased disease activity. Patients with active disease report higher rates of fatigue (60–80%) than patients in clinical remission (20–40%), and it has been suggested that proinflammatory cytokines can act on the brain inducing symptoms that resemble sickness behaviour. Fatigue is a common complaint among patients, with a large negative impact on QoL and therefore it is very important to manage this comorbidity effectively.26

With such links between increased disease activity and chronic inflammation to an increase in the burden of disease, reduced QoL, and the prevalence of comorbidities (especially in younger patients), timely and effective disease control is paramount. 


Figure 226, comorbidities in IBD

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Seizing the window of opportunity 

Earlier access to anti-TNF treatment could reduce disease burden and improve QoL. Is early adoption of biosimilars in clinical practice the answer?

The underuse of biologics is an issue in gastroenterology, rheumatology, and dermatology despite the evidence that biologics offer effective treatment in all indications.  For example, patterns of biologic prescribing for CD in Europe vary from 8–33%, similar variations were seen for RA, and only 20% of patients with moderate-to-severe PsO were prescribed biologics in Europe and North America. The reasons for underuse are complex and country specific, however, in countries where biologics are less affordable, eligibility criteria tend to be more restrictive and the most common reason for dermatologists to not initiate or maintain a biologic is cost.4

Cost-savings from the introduction of biosimilars therefore offer improved patient access, and in turn, improved clinical outcomes. Moreover, there is increasing evidence that introducing biologics at an earlier disease stage can help avoid costly care associated with IMIDs such as hospitalisations or surgery - providing further long-term savings.4

For example, a 2016 study in patients with CD reported that initiation of infliximab or adalimumab within the first 2 years of diagnosis reduced the rate of surgery (5.7% vs. 30.7%) and secondary loss of response (45.3% vs. 67.2%) requiring dose escalation.39 Earlier initiation of <1 year has also been reported to achieve improved long-term clinical outcomes.40 Indeed, obtaining early and sustained deep remission (biological, clinical and complete mucosal healing) - the treat-to-target concept, by the early employment of biologics will be a key concept in the management of CD moving forward.41 


Figure 442, targeting early CD and achieving sustained deep remission. 

Similar findings are reported in the area of rheumatology.  The available data to date consistently reports that early diagnosis, prompt treatment, and early remission of RA has the ability to change the course of the disease. The demonstrated window of opportunity to attain sustained and long-term benefits clinically, functionally and radiographically is reported to be in the first 12 weeks from disease onset.43

Traditionally, DMARDs are used in the treatment of RA, however, evidence is also mounting that treatment with biologics early in the course of RA is highly effective in improving clinical symptoms, physical function, and slowing radiographic progression.44 Results from the COMET study demonstrated a significantly greater proportion of patients achieved remission and low disease activity when treated with etanercept less than 4 months since diagnosis.45 Such data implies a critical window early in disease when the benefits of anti-TNF therapy may be disproportionately greater.

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