Biosimilar efficacy & safety

Introduction to the efficacy and safety of biosimilars

The costs of tumour necrosis factor alpha inhibitor (anti-TNF) products are often high, placing a financial burden on the healthcare system and at times limiting the access to these products¹. As an alternative, anti-TNF biosimilars enable earlier and wider access to appropriate therapy without the financial burden associated with the reference product². 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 healthcare professionals (HCP) 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 HCPs, confident in the reasoning behind their choice of biosimilar³.

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)^4-6.

The adoption of biosimilars early in the course of treatment can improve health outcomes⁷. Importantly, the use of biosimilars reduces the need to reply on expensive branded biologics, and compounds traditionally used in immune-mediated inflammatory diseases⁸. Biosimilars improve market competition, bringing the cost of the reference biologics down, resulting in 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 can offer patients⁸. Biosimilars can increase access and options to timely, potentially life-changing treatment⁸.

Healthcare professionals are recognising that biosimilars can expand patient access to therapy, resulting in improved care for patients⁴

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 CD⁹.

With additional data confirming the safety and efficacy of biosimilars (in addition to the data required for approval), confidence and comfort in using biosimilars should increase in both HCPs and patients alike¹⁰. In general, the evidence acquired over ten years of clinical experience shows that biosimilars approved through the European Medicines Agency (EMA) can be used as safely and effectively in all approved indications, as reference biological medicines⁸.  

Biosimilars for inflammatory bowel diseases

In IBD specifically, the first biosimilar to be FDA- and EMA-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 conducted 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^11,12. 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 patients⁵. 

The NOR-SWITCH trial was a double-blind, non-inferiority study of patients (with various immune-mediated inflammatory diseases [IMID]) 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 antibodies¹³. 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 year¹.

A more 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); no differences in safety outcomes were observed¹⁴. 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-P13¹⁵. 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, C-reactive protein (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 setting¹⁶.

Table 1 shows selected studies and guidelines pertinent to the use of biosimilars in IBD¹¹. 

Table 1. Studies and guidelines investigating biosimilars in inflammatory bowel disease (Adapted¹¹). CT-P13, Remsima^®; IBD, inflammatory bowel disease.

Biosimilars used to treat rheumatology diseases also show efficacy and safety in comparison to their reference products, with CT-P13 investigated as a treatment for multiple rheumatology conditions. The two main studies from these investigations were the PLANETRA study (rheumatoid arthritis)¹⁷  and the PLANETAS study (ankylosing spondylitis)¹⁸. Both studies reported comparable safety, efficacy, and immunogenicity of CT-P13 to infliximab; both extension studies reported clinical efficacy was similar in patients in the maintenance (continued CT-P13) and switch groups (switched from reference biologic to CT-P13) (Figure 1)^17,19,20.

Figure 1. American College of Rheumatology (ACR) response rates over time from the PLANETRA study (Adapted¹⁷). ACR20, ACR50 and ACR70 denote the ACR 20%, 50% and 70% improvement criteria, respectively. CT-P13 compared with RP (denotes reference product infliximab) at Weeks 14, 30, and 54. 

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 (Figure 2)²¹.  

Figure 2. Incidence of immunogenicity during transition period (Adapted²¹). *Patients having at least one positive anti-drug antibody (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.

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 RA²², with evidence that SB5 was well tolerated over 1 year, and that switching from the reference product to SB5 had no treatment-emergent issues²³. In an observational cohort study conducted in a tertiary IBD referral centre, switching from adalimumab originator to SB5 appeared effective and safe, following over 12 months of follow-up²⁴.

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 comparable²⁵. 

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 psoriasis²⁶. 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 so²⁷.

The evidence for the safety and efficacy of biosimilars, compared with their reference products in gastroenterology, rheumatology, and dermatology, could make healthcare professionals more confident in prescribing biosimilars

Biosimilar-to-biosimilar switching is a safe and effective clinical practice, although it is not covered in current health authority regulations or guidance²⁸. No reduction in effectiveness or increase in adverse events has been reported in biosimilar-to-biosimilar switching studies published before 2022²⁸.

The effects of biosimilars on patient adherence

Prescribing biosimilars can have a significant impact on adherence, and can reduce the risk of nocebo effects^4,29.

Dr Nick Kennedy (Consultant Gastroenterologist, Royal Devon and Exeter NHS Foundation Trust; Honorary Clinical Senior Lecturer, University of Exeter Medical School, UK) considers the main reasons patients can fail to adhere to their medication, including forgetfulness, fear of side effects, and a lack of understanding of negative effects. Learn the consequences of non-adherence and the benefits of open dialogue, and a good relationship with Inflammatory bowel disease nurses.

Dr Nick Kennedy reviews strategies for improving adherence in inflammatory bowel disease patients, such as educational leaflets, nursing teams, multidisciplinary care, apps and investigating the causes of poor adherence.

Dr Nick Kennedy highlights how alternative treatment regimens could positively impact patient adherence (e.g., patients who respond poorly to subcutaneous or intravenous therapy, or patients requiring complex multiple daily dosing).

Disease burden and comorbidities

Immune-mediated inflammatory diseases (IMID) are associated with a high disease burden, and significantly impaired quality of life (QoL)³⁰.

This section explores how comorbidities and undertreatment contribute to the overall high disease burden across gastroenterological, rheumatological, and dermatological conditions.

Inflammatory bowel disease: burden and comorbidities

Dr Nick Kennedy (Consultant Gastroenterologist, Royal Devon and Exeter NHS Foundation Trust; Honorary Clinical Senior Lecturer, University of Exeter Medical School, UK) describes the common symptoms of inflammatory bowel disease, and extraintestinal manifestations. Learn how treatment and surgery can impact on patients.

Figure 3. Comorbidities in inflammatory bowel disease (Adapted³¹). COPD, chronic obstructive pulmonary disease.

The burden of disease in inflammatory bowel disease (IBD) patients can be wide-ranging and variable due to the chronic and unpredictable nature of the disease³². The symptoms of IBD are often painful and associated with social stigma, leading some individuals to develop complications, such as bowel control, bowel urgency, pain management, or fatigue³².

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 QoL when compared to healthy individuals³³.

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)³³. 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 activity³⁴. Further, the effect of proinflammatory cytokines on the brain, sleep disturbance, and corticosteroids are thought to contribute to the overall decrease in mental health³⁴.

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 risk³⁴. For instance, 40% of children with CD will show 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 disease³⁵.

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 (Figure 3). Importantly, the classic risk factors such as hypertension, diabetes, dyslipidaemia, and obesity were not related to this increase, but to an increase in white blood cell counts, and a possible association with IBD activity³¹. 

Metabolic syndrome and IBD have also been linked with similarities in inadequate immune response and chronic inflammation³¹. 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 effectively³¹.

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.

Rheumatic disease: burden and comorbidities

In this short video, Professor Thomas Dörner (Charité University Hospitals, Berlin, Germany) outlines how patients are personally impacted by rheumatoid arthritis through loss of function, and loss of work. Professor Thomas Dörner considers the impact of coronavirus disease 2019 (COVID-19) on patient anxiety and the potential risks of immunosuppressive agents.

Rheumatology patients, such as those with rheumatoid arthritis (RA), are often faced with a variety of physical and mental hurdles that impact their daily activities and their overall participation in life^36,37. Pain, decreased physical function and capabilities, and overall decrease in general health result in an especially decreased health-related QoL (HR-QOL)^36,37. In addition, there is a negative impact on the mental health of patients, their role in society, and their social functioning abilities³⁸. Often, patients have to take substantial sick-leave from work, or leave work altogether. If the individual remains in work, there is often a loss of productivity. For rheumatology patients, disease activity is often a predictor of QoL, especially in ankylosing spondylitis (AS)³⁹. Extra-articular manifestations and comorbidities are also likely to increase the overall burden of disease⁴⁰.

Cardiovascular disease is common in patients with RA, where patients have a 60% increased risk of cardiovascular-related mortality⁴¹. While atherosclerosis is a common denominator, traditional risk factors such as age, gender, dyslipidaemia, hypertension, smoking, obesity and diabetes mellitus, and medications such as nonsteroidal anti-inflammatory drugs (NSAIDS), corticosteroids, disease-modifying anti-rheumatic drugs (DMARDS), together with inflammation, are the main factors increasing the risk in these patients (Figure 4)⁴².

Figure 4. Contributing risk factors for cardiovascular disease in rheumatology patients (Adapted⁴²). DMARD, disease-modifying anti-rheumatic drug; COXIB, selective cox-2 inhibitors; NSAID, non-steroidal anti-inflammatory drug.

Early treatment resulting in tight inflammation control and remission, is associated with improvement in cardiovascular risk and reduction of cardiovascular morbidity⁴². Patients should undergo routine cardiovascular risk assessment, and implementation of standard-of-care (SOC) pharmacological management of cardiovascular risk factors, as required³⁷. 

Other comorbidities in rheumatology patients include an increase in lymphoma risk by approximately two-fold, particularly in those with high disease activity and rheumatoid factor³⁷. Osteoporosis and changes in body composition (a decrease in lean body mass with a maintenance or increase in fat mass) both increase the risk of fractures in this cohort of patients. Cognitive impairment, along with depression and anxiety, are highly prevalent in patients with RA (as with other IMIDs), and are associated with poorer RA outcomes^37,41.

With patients surviving longer and as the number of comorbidities increases with age, more rheumatology patients will have an increasing number of comorbidities to manage^37,41

It is important to identify patients at risk for associated comorbidities in order to minimise underdiagnosis and undertreatment^37,43.

Plaque psoriasis: burden and comorbidities

In this video clip, Professor Tiago Torres (Department of Dermatology and Dermatology Research Unit, Centro Hospitalar do Porto, University of Porto, Portugal) describes why the concerns of biosimilars for the treatment of psoriasis are no longer justified, and how biosimilars can positively impact the course of this disease.

Plaque psoriasis (PsO) is associated with a significant disease burden, with an increase in disability caused by the physical symptoms as well as the social stigma due to the appearance of their skin^44-46. As a result, patients with PsO often experience a decrease in emotional and physical well-being, and poor QoL^44-46. A recent study highlighted that more than 70% of patients with moderate PsO reported a high burden of disease and impact on QoL⁴⁷.

Dermatological diseases also greatly impact the mental health of patients, particularly those with PsO. Common mental health comorbidities are depression, anxiety, and suicidal thoughts or behaviour, with evidence that depression and PsO share a common biological mechanism due to the elevated levels of pro-inflammatory cytokines in both conditions⁴⁸. 

Higher disease severity is linked to higher rates of depressive and anxious symptoms⁴⁹. Younger patients, those with genital lesions, female sex, and depressive symptoms are associated with lower mental QoL. Particular attention to women with genital or articular lesions is recommended for preventing future psychopathology⁴⁹.

Nontreatment and undertreatment of patients with psoriasis (and psoriatic arthritis) remains a significant problem^45,46,50. This information, combined with the mental health burden and suicidal behaviours of dermatological patients, reinforce the need for clinicians to provide timely, appropriate, and effective disease treatment, and incorporate appropriate screening for psychiatric comorbidities and mental health support for patients with PsO^45,46,51.

Hidradenitis suppurativa: burden and comorbidities

Dr Joana Cabete (Consultant in Dermatology and Venereology consultant at Santo António dos Capuchos Hospital, Centro Hospitalar de Lisboa Central, Portugal) details the burden of hidradenitis suppurativa on the patient.

Dr Joana Cabete summarises the unmet needs of hidradenitis suppurativa, including a vicious circle of inadequate treatment and the difficulties of accessing care.

Hidradenitis suppurativa (HS) can also be a highly debilitating disease in relation to patient’s psychosocial evaluation, with a moderate-to-severe adverse effect on patients' lives^52-54. Depression and anxiety are also highly prevalent in patients with HS (42.9% and 39%, respectively), and approximately 65% of patients report profound consequences on their sex life⁵². Suicide risk is also 2.5 times greater among patients with HS compared with the general population⁵².

Seizing the window of opportunity 

Dr Nick Kennedy (Consultant Gastroenterologist, Royal Devon and Exeter NHS Foundation Trust; Honorary Clinical Senior Lecturer, University of Exeter Medical School, UK) reviews the importance of patient risk stratification, access to effective treatments, multidisciplinary teamwork, and patient communication.

Earlier access to tumour necrosis factor alpha inhibitor (anti-TNF) treatment could reduce disease burden and improve quality of life (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 indications⁵⁵. For example, patterns of biologic prescribing for Crohn’s disease (CD) in Europe vary from 8–33%, similar variations were seen for rheumatoid arthritis (RA), and only 20% of patients with moderate-to-severe plaque psoriasis (PsO) were prescribed biologics in Europe and North America⁵⁵. 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 cost⁴.

Cost-savings from the introduction of biosimilars therefore offer improved patient access, and in turn, improved clinical outcomes^4,56. Moreover, there is increasing evidence that introducing biologics at an earlier disease stage can help avoid costly care associated with immune-mediated inflammatory diseases (IMID), such as hospitalisations or surgery, providing further long-term savings⁴.

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 escalation⁵⁷. Earlier initiation of <1 year has also been reported to achieve improved long-term clinical outcomes⁵⁸. 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 (Figure 5)⁵⁹.

Figure 5. Targeting early Crohn’s Disease and achieving sustained remission (Adapted⁶⁰). 

Similar findings are reported in the area of rheumatology⁶¹. Early diagnosis, prompt treatment, and early remission of RA can positively 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 onset⁶¹.

Traditionally, disease-modifying antirheumatic drugs (DMARD) are used in the treatment of RA. However, evidence is also mounting that treatment with biologics early in the course of RA is effective in improving clinical symptoms, physical function, and slowing radiographic progression⁶². 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 diagnosis⁶³.  Such data implies a critical window early in disease when the benefits of anti-TNF therapy may be disproportionately greater.

The underuse of biologics in patients with dermatological disease was demonstrated in a report showing only 20% of patients from Europe (France, Germany, Italy, Spain, and United Kingdom) and North America with moderate-to-severe PsO were receiving treatment with a biologic⁵⁵. Approximately 40% of dermatologists were conservative in their use of biologics despite being comfortable with prescribing them, and only half the number of dermatologists used biologics aggressively compared to rheumatologists. It was also reported that ~11% of dermatologists did not prescribe biologics at all, the main concerns being related to cost and long-term safety and tolerability⁶⁴.

Biosimilars as cost-effective therapeutic options can improve access to therapy, a key unmet need for patients with dermatological disease

With improved access to therapy comes the chance to treat patients earlier and therefore alleviate the impact of the disease. In a psoriatic arthritis study, an intensive and early treatment protocol was investigated versus standard care⁶⁴. The results of the study demonstrated that early treatment provided greater patient improvement in disease activity and reduction in joint damage than standard care⁶⁴.

Summary

The use of biologics and the determination of the optimum therapeutic window of opportunity in each indication, which mounting evidence suggests is early in the course of IMIDs, is possible if patients have timely and unrestricted access to such treatments. Biosimilars are uniquely placed for HCPs to offer their patients the most appropriate treatment, at the optimum time to ensure the best possible long-term disease outcomes, reductions in comorbidities, and a reduction of disease burden, particularly QoL.

Biosimilars publication highlights infographics

Read or download recent research on biosimilars in rheumatoid arthritis (RA) inflammatory bowel disease (IBD).

The infographics in this section summarise recent research on anti-tumour necrosis factor (TNF) biosimilars utilisation in RA and IBD in a concise and graphical manner.