Practical advice on use of biosimilars

Practical advice and considerations for the use of biosimilars

In this short video, Professor Thomas Dörner (Charité University Hospitals, Berlin, Germany) summarises the current level of adoption of therapeutic drug monitoring (TDM) in rheumatology, its potential in the future, and the pragmatic argument for changing the therapeutic principle in non-responding patients.

Dr Joana Cabete (dermatology and venereology consultant at Santo António dos Capuchos Hospital, Centro Hospitalar de Lisboa Central, Portugal) reviews the TDM options available for hidradenitis suppurativa, including measuring the dose from blood samples, gaining experience from inflammatory bowel disease centres, and managing without TDM.

Dr Nick Kennedy (Consultant Gastroenterologist, Royal Devon and Exeter NHS Foundation Trust; Honorary Clinical Senior Lecturer, University of Exeter Medical School, UK) notes that gastroenterology has been ahead in the use of TDM, compared with other immune-mediated disease areas. The PANTS study supports a strong association between drug concentration and outcome, both in the short- and long-term.

Dr Nick Kennedy (Consultant Gastroenterologist, Royal Devon and Exeter NHS Foundation Trust; Honorary Clinical Senior Lecturer, University of Exeter Medical School, UK) summarises why reactive TDM is currently the standard of care for inflammatory bowel disease, and the scenarios in which proactive TDM may be useful. Learn the data that supports the clinical use of proactive TDM.

A key factor when optimising a biologic or biosimilar dose regimen is potential loss of response over time due to inadequate drug exposure^1,2

Loss of response to biologics and biosimilars is a major challenge with the use of these agents in the management of chronic inflammatory diseases². One study showed that the 58% of patients with inflammatory bowel disease (IBD) who commenced treatment with a tumour necrosis factor alpha inhibitor (anti-TNF), such as infliximab or adalimumab, had loss of response, while 37% had a second loss of response³. 

A systematic review of loss of response in adult and paediatric patients with Crohn’s disease (CD) reported the mean percentage of patients who lost response to adalimumab over the course of a year was 18.2% among a total of 955 primary responders⁴.

Possible mechanisms that may contribute to loss of response to biologics and biosimilars include the development of neutralising antibodies, alterations in drug metabolism, drug interactions, and patient characteristics, including genetic make-up (Table 1)⁵.

Table 1. Factors associated with loss of response to anti-TNF therapy (Adapted⁵).  ANA, antinuclear antibodies; ATI, antibodies to infliximab; BMI, body mass index; CRP, c-reactive protein; IgG, immunoglobulin; WBC, white blood cell.

One treatment strategy to optimise the effect of biologics or biosimilars is therapeutic drug monitoring (TDM), which uses drug concentration measurements to inform dose adjustments to ensure serum levels are maintained within a therapeutic range². 

For patients with Crohn’s disease (CD) or ulcerative colitis (UC), infliximab biosimilar dosing is based on body weight (5 mg/kg), starting with an induction phase at weeks 0, 2 and 6, followed by a maintenance phase (5–10 mg/kg every 8 weeks)⁶. This is also true for infliximab (reference drug)⁷. However, there is substantial variability regarding drug exposure and treatment responses among patients who receive standard infliximab biosimilar doses². By using TDM, dosing levels can be adjusted so that infliximab serum levels are between 3 and 7 μg/mL, a range associated with optimal outcomes during maintenance treatment². There are, however, limitations to adjusting serum levels of infliximab due to costs constraints².

A key concern when prescribing biologics (including biosimilars) is immunogenicity. To prevent the formation of anti-drug antibodies, several treatment strategies can be implemented, including systematic maintenance therapy, which is mainly true for infliximab, concomitant immunosuppression and prophylactic systemic steroids^8-10.

One study of a cohort of 121 patients with rheumatoid arthritis (RA) found that anti-drug antibodies were present in 17% of patients treated for 28 weeks with adalimumab¹¹. At 28 weeks, patients with RA who were responding to treatment were less likely to have anti-drug antibodies than those not responding (5% vs 34%; P=0.032)¹¹. Concomitant use of an immunosuppressive agent (methotrexate) was lower in the group with anti-drug antibodies (52% vs 84%; P=0.003)¹¹. With episodic infliximab therapy, immunosuppressive agents should be considered to decrease immunogenicity and secondary loss of response¹².

The incidence of anti-drug antibodies reported in the literature for patients with psoriasis treated with adalimumab ranged from 6.5% to 45%¹³.  It has been shown that the development of anti-drug antibodies is associated with lower adalimumab serum concentrations and, as a result, impaired treatment outcomes¹³.

Following dose optimisation, if the efficacy of an anti-TNF agent fades in a patient with initial response, a degree of flexibility is required to counteract the loss of response¹². Possible strategies include increasing drug exposure by decreasing the dosing interval or increasing the dose or switching to another agent¹². Current guidelines advise a number of alternative systemic biologic therapies for moderate-to-severe psoriasis, as well as more conventional systemic therapies and ultraviolet treatment¹⁴. When selecting the systemic treatment for patients with psoriasis, healthcare professionals (HCP) should consider the clinical criteria as well as the patient and product characteristics¹⁴.

Therapeutic drug monitoring of anti-TNF agents

Recent data highlight that therapeutic drug monitoring (TDM) may more effectively optimise the efficacy, safety and cost of tumour necrosis factor alpha (anti-TNF) therapy, compared with other treatment strategies. So, what is the evidence that TDM results in patients with gastrointestinal, rheumatological or dermatological diseases remaining on anti-TNF therapy for longer?

For patients at risk of loss of response, TDM can play a preventive role. By monitoring serum levels of anti-TNF agents using TDM, treatment can be intensified to ensure adequate drug exposure². Combination therapy with an immunosuppressive agent may also be considered to prevent anti-drug antibody formation². Treatment strategies should be tailored to the individual patient and desired therapeutic outcome².

In a multicentre, retrospective study of 264 consecutive patients with inflammatory bowel disease (IBD; 167 with Crohn’s disease) receiving infliximab maintenance therapy, the use of proactive TDM (optimisation of treatment prior to loss of response), compared with reactive TDM (performed after loss of response), was found to be associated with significantly better effectiveness and safety, as measured by greater durability on infliximab treatment, less need for IBD-related surgery and hospitalisation, and less immunogenicity¹⁵. For many patients who are monitored reactively, the monitoring has occurred too late to receive any kind of treatment optimisation¹⁵.

An algorithm for interpretation of TDM information for anti-TNFs is shown in Figure 1. According to this algorithm, if anti-drug antibodies are detected, switching to an alternative anti-TNF can be considered. If drug levels are adequate, swapping to an agent with a different mechanism of action may be preferable¹⁶.

Figure 1. Loss of response management algorithms for patients taking anti-TNF products (Adapted¹⁶). ATI, antibodies to infliximab; IFX, infliximab; TNF, tumour necrosis factor.

TDM use may also be considered, for a number of reasons, for patients with rheumatological disorders treated with anti-TNFs. There is a relationship between product concentration and clinical response, but only in responding patients, as this association is lacking in primary non-responders¹⁷. Low drug concentration may result in decreased efficacy and increased risk of anti-drug antibody formation, whereas high drug concentration may increase the risk of side effects^17,18.

For adalimumab, clinical improvement in patients with rheumatoid arthritis (RA) was found to increase with increasing serum concentrations, reaching a maximum at 5–8 µg/L. Serum concentrations >8 µg/L did not produce any further benefit, suggesting overexposure at higher concentrations¹⁹.

A subsequent open-label, randomised trial was conducted to investigate whether overexposure could be reduced by increasing the dosing interval of adalimumab Patients with RA who had trough levels >8 µg/L were randomly assigned to a prolonged dosing interval of 3 weeks or to the standard 2-week interval²⁰. The strategy to increase the dosing interval was not inferior to the conservative strategy over 28 weeks²⁰. This study illustrates the benefits of TDM to ensure optimal serum concentrations that maintain disease control without overexposure, which not only increases the risk of side effects, but also incurs unnecessary costs²⁰. The same group also conducted a study of TDM with biologics in immune-mediated inflammatory diseases, using TDM to optimise the selection of a second anti-TNF product following loss of response²¹.

There is increasing evidence that TDM is also a valuable tool for clinical decision-making in the treatment of moderate-to-severe psoriasis¹³. TDM informs dose adjustments in patients with low drug concentrations, monitoring of adherence and assessment of patients who lose response to biosimilars¹³. 

Effective implementation of TDM requires reliable methods for quantifying serum levels of drug and anti-drug antibodies, evidence-based guidelines and prediction tools, and personalised medicine whereby optimal dosing can be defined on an individual basis¹⁷. An algorithm for TDM in chronic plaque psoriasis is shown in Table 2.

Table 2. Therapeutic drug monitoring algorithm in chronic plaque psoriasis (Adapted¹³).

Cycling to another anti-TNF, or swapping to an agent with a different mechanism of action

Dr Nick Kennedy (Consultant Gastroenterologist, Royal Devon and Exeter NHS Foundation Trust; Honorary Clinical Senior Lecturer, University of Exeter Medical School, UK) examines cycling (switching) to another tumour necrosis factor alpha inhibitor (anti-TNF), compared with swapping to an agent with a different mechanism of action (MoA).

Options for patients who have an inadequate response to an anti-TNF agent include cycling (switching) to a different anti-TNF or swapping to a drug with a different MoA^22,23. But which option is optimal?

A percentage of patients with Crohn’s disease (CD) or ulcerative colitis (UC) do not respond to induction therapy with anti-TNFs ^7,24,25, and some patients may experience a loss of response over time or develop intolerance^7,25,26. Studies have shown that, overall, between one-third and one-half of patients do not respond to anti-TNFs, with a second agent often prescribed when the first fails²⁷. Similarly, 30-40% of patients with rheumatoid arthritis discontinue treatment with anti-TNFs because of an inadequate primary response, loss of response or intolerance²³. For these patients, anti-TNF cycling can be an important and cost-effective treatment strategy with substantial benefit^22,23,25.

If an anti-TNF fails to produce a response, cycling or switching to an alternative anti-TNF might also be expected to fail, given that it has the same mechanism of action. However, studies have shown that cycling can be effective. For example, one study found that after failure of an anti-TNF, 40% of patients with inflammatory bowel disease (IBD) achieved remission with an alternative anti-TNF²⁸. Another study showed that 21% of patients with CD who experienced intolerance or a loss of response to infliximab were able to achieve remission with adalimumab²⁹.  There is no evidence that a single switch from an originator product to a biosimilar is associated with any significant risk or reduction in patient safety³⁰.

Among patients with rheumatological disease, anti-TNF cycling is often considered first as a treatment strategy because it represents a lower cost option, compared with switching to a drug with a different mechanism of action (MoA), and can provide successful therapeutic outcomes, given the availability of anti-TNF biosimilars^23,31. A study evaluating the utility of measuring infliximab and anti-infliximab antibodies found that cycling to a different anti-TNF was associated with a partial or complete response in 92% of patients who were positive for infliximab antibodies^32,33. 

A systematic review evaluating the effectiveness of anti-TNF cycling versus switching to an agent with a different MoA in 4394 patients with RA concluded that both strategies are equally effective in terms of patient-reported outcomes³⁴. Similarly, the CERTAIN study, a prospective, protocol-driven 12 month study, compared the effectiveness of cycling versus swapping in adults with moderate-to-severe RA who had been treated with one or more anti-TNF³⁵. The study found no significant difference between cycling and swapping in the likelihood of achieving low disease activity³⁵.

In some cases, largely dependent on the prices of agents used in the analyses (list vs discounted prices), swapping has been associated with higher treatment persistence and lower healthcare costs, compared with anti-TNF cycling³⁶. Treatment persistence and cost per patient were investigated in a study of 581 (38.3%) patients who swapped from an anti-TNF to an agent with a different MoA and 935 (61.7%) patients who cycled to a different anti-TNF ³⁶.  Treatment persistence was significantly higher for those who swapped than for those who cycled (47.7% versus 40.2%, P=0.004; Figure 2). When were divided by treatment persistence, estimated costs were lower among those who swapped than among those who cycled ($25,436 lower total RA-related cost and $25,999 lower medication costs)³⁸.

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