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Optimising anti-TNF treatment using biosimilars

Practical Advice

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Practical advice and considerations for the use of Biosimilars

Biosimilars offer health care practices large potential cost savings and the opportunity to widen patient access to treatment, but what are the different factors that are important to consider when prescribing biosimilars in gastroenterology, rheumatology and dermatology?1

One of the main factors for consideration when optimising a biologic and/or biosimilar dose regimen is potential loss of response over time, which is often attributed to increased drug clearance linked to anti-drug antibodies.2 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 range.3 For patients with Crohn’s disease (CD) and 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 mg/kg every 8 weeks).4 However, there is substantial variability regarding drug exposure and treatment responses between patients who receive standard infliximab biosimilar doses. 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 treatment.3 There are, however, limitations to adjusting serum levels of infliximab due to approved dosing. Additionally, immunogenicity may not make dose adjustments beneficial.3

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.5–7 One study of a cohort of 121 patients with rheumatic arthritis (RA) found that anti-drug antibodies were present in 17% of patients treated for 28 weeks with adalimumab and concomitant immunosuppressive agent (methotrexate) use was lower in the group with anti-drug antibodies (52% vs. 84%, P = 0.003).8 At 28 weeks, patients with RA that were responding to treatment were less likely to have anti-drug antibodies than those not responding (5% vs. 34%).8 With episodic infliximab therapy, immunosuppressive agents should be considered to decrease immunogenicity and secondary loss of response.9

If, following dose optimisation, the efficacy of an anti-TNF fades in a patient with initial response, a degree of flexibility is required in order to counteract the loss of response. Possible strategies include increasing drug exposure by decreasing the dosing interval or increasing the dose or switching to another product.9 Current guidelines advise a number of alternative systemic biologic therapies for moderate-to-severe psoriasis, as well as more conventional systemic therapies and ultraviolet treatment.10 When selecting the systemic treatment for patients with psoriasis, HCPs should consider the clinical criteria as well as the patient and product characteristics.10

Table 1, factors associated with loss of response to anti-TNF therapy.11 ANA, antinuclear antibodies; ATI, antibodies to infliximab; BMI, body mass index; CRP, c-reactive protein; WBC, white blood cell. 


Therapeutic drug monitoring (TDM) of anti-TNF products

Recent data highlights that TDM may more effectively optimise anti-TNF therapy efficacy, safety and cost compared with other treatment strategies. So, what is the evidence that TDM results in patients with gastroenterology, rheumatology or dermatology diseases remaining on anti-TNF therapy for longer?12

One study showed that the majority of patients with IBD that initiated an anti-TNF product, such as infliximab or adalimumab, had loss of response (58%), while 37% had a second loss of response.12 Data from the ACCENT1 trial showed that a large percentage (approximately 40%) of patients with CD treated with infliximab will lose response over time.13 A systematic review on loss of response in adult and pediatric patients with CD reported the mean percentage of patients who lost response over the course of a year to adalimumab was 18.2% among a total of 955 primary responders.14,15

For patients at risk of loss of response, TDM can play a preventative role. Through the monitoring of serum levels of anti-TNF products, using TDM, treatment can be intensified to ensure adequate drug exposure.16 Combination therapy with an immunosuppressive agent may also be considered to prevent anti-drug antibody formation.3 Treatment strategies should be tailored to the individual patient and desired therapeutic outcome. In a multicenter, retrospective study of 264 consecutive patients with 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 patient 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 hospitalization, and less immunogenicity.17 For many patients who are monitored reactively, the monitoring has occurred too late to receive any kind of treatment optimization.17


Figure 1, loss of response management algorithms for patients taking anti-TNF products.18 ATI, antibodies to infliximab; IFX, infliximab. 

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Cycling versus swapping of anti-TNF products

When patients experience failure with anti-TNF therapy the clinical guidelines recommend either cycling to a new therapeutic drug or switching to a new drug with a different mechanism of action, but which option is the most optimal?

Whilst a percentage of patients with CD or UC do not respond to induction therapy with anti-TNF therapy28,29 and some patients may experience a loss of response over time, or develop intolerance,30 anti-TNF product cycling can be an important and cost-effective treatment strategy with substantial benefit. For example, in a retrospective study of 5543 patients with UC and 7561 patients with CD a substantial proportion of patients required only one product of anti-TNF therapy throughout the 24-month follow-up, as the disease was effectively controlled by cycling of anti-TNF products and so did not require additional products.31 For the majority of cases, cycling to another anti-TNF product is associated with a response.

Other studies have shown that, overall, between one third and one half of patients do not respond to anti-TNF products, with a second product often prescribed when the first fails.31,32 Patients may benefit from being switched to another biosimilar with a different mechanism of action.31,33 For example, 40% of patients with UC who previously received infliximab responded well when switched to adalimumab and 21% of patients with CD who experienced intolerance or a loss of response to infliximab were able to achieve remission with adalimumab.31,33 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 safety.34 It has also been argued that, at lower prices, cycling from infliximab to adalimumab may be more cost-effective. One study simulating the most cost effective position of vedolizumab among the available biologic drugs for the treatment of UC showed that when infliximab and adalimumab were offered at a 50% discounted price the incremental cost-effectiveness ratio of vedolizumab use in UC rose by $600,258.35

Amongst patients with rheumatology disease, anti-TNF product cycling is often first considered as a treatment strategy because it represents a lower cost option compared to switching mechanism of action and can provide successful therapeutic outcomes.36 For the majority of patients (92%) with anti-drug antibodies cycling to another anti-TNF product is associated with a response.36 A systematic review evaluating the effectiveness of anti-TNF product cycling versus switching in 4394 patients with RA concluded that both strategies are equally effective in terms of patient reported outcomes.37 Through TDM, patients with low serum product levels, due to the formation of anti-drug antibodies,36 may be identified that will most benefit from anti-TNF cycling – in particular, patients who have yet to receive a second anti-TNF product.

In some cases, largely dependent on the prices of products used in the analyses (list vs discounted prices), switching has been associated with higher treatment persistence and lower healthcare costs compared with anti-TNF product cycling.38 In one such study, a patient population of 581 (38.3%) mechanism of action switchers and 935 (61.7%) anti-TNF product cyclers were investigated with regards treatment persistence and cost per patient. Treatment persistence was significantly higher for switchers versus cyclers (47.7% versus 40.2%, P = 0.004) and when costs were divided by treatment persistence, costs per persistent patient were lower among switchers versus cyclers ($25,436 lower total RA-related cost and $25,999 lower medication costs).38 When assuming a discounted price (as is the case for biosimilars) the cost of cycling is likely to be much improved. Whilst there is debate about the benefits to switching out of class, given the lowered costs of anti-TNFs due to the arrival of biosimilars, cycling from one anti-TNF to another may be preferred.

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