Inflammatory joint diseases, such as rheumatoid arthritis (RA), axial spondyloarthritis (SpA) and psoriatic arthritis (PsA), are characterised by chronic inflammation, joint destruction, and functional disability.1

Conventional synthetic disease-modifying drugs (csDMARD) are the mainstay of treatment for these patients. However, approximately one third of patients do not respond to them and require targeted synthetic (tsDMARD) or biological (bDMARD) disease modifying drugs.2 These drugs have been shown to control inflammatory activity and improve physical function and quality of life in these patients over the long term. A significant proportion of patients treated with a bDMARD do not respond to initial treatment or efficacy is lost over time,3 and treatment is discontinued in more than 10% due to side effects.4 Despite their advantages, the high cost of these treatments limits their use.5 Therefore, the biosimilar (BS) agents, because of their lower cost, are making biological therapies prompter and more accessible to a greater number of patients due to their greater efficiency.

According to the European Medicines Agency (EMA), a BS is a biological drug that contains a version of the active substance of an already authorised original biological product (the reference drug). It must demonstrate similarity to the reference drug in terms of quality characteristics, biological activity, safety, and efficacy, following a full comparability exercise. A BS is not like a generic drug that has a simpler structure and is identical to its reference drug.6

Enbrel® (etanercept) is an anti-TNF agent approved for use in adult patients with moderate to severe active and/or progressive RA, active and progressive, severe axial PsA, in young people with juvenile idiopathic arthritis, including polyarticular, extended oligoarticular, PsA and enthesitis-related arthritis, and severe plaque psoriasis.7 Several etanercept BS have been evaluated in clinical trials (CTs), as cheaper alternatives to the reference product. Reducing the cost of treatment is the main attraction for the BS that are entering the global market.8 Biogen's Benepali® (SB4) was the first etanercept BS approved for use in January 2016. Several studies have been published in the lead-up to its approval and marketing. A phase III parallel-group, randomised, double-blind, trial in 596 patients with moderate-severe RA previously treated with methotrexate showed equal efficacy to Enbrel, with a similar ACR20 response at week 24 in both groups (78.1% with Benepali vs. 80.3% with Enbrel) and with a comparable incidence of adverse events.9,10 In this regard, a phase I trial in a Korean population (n = 138) demonstrated an equivalent safety, pharmacokinetic and tolerability profile between Benepali and Enbrel. However, Benepali had a lower immunogenicity profile than Enbrel.11

However, other than these CTs, to date there have been no studies conducted under clinical practice conditions to confirm these results. Therefore, our aim was to evaluate the effectiveness, safety, and costs of the Benepali BS in patients with chronic inflammatory arthritis, and compare with the reference drug, under routine clinical practice conditions.

Between January 2015 and August 2018 (inclusive) 138 patients with different rheumatic diseases started treatment with etanercept: 85 (61.5%) patients with RA, 29 (21.0%) with axial SpA and 24 (17.3%) with PsA. Of these, 79 (57.2%) received the BS (43 [54.4%] RA, 20 [25.3%] AS and 16 [20.2%] PsA) and 59 (42.7%) the original drug (42 [71.2%] RA, 9 [15.2%] AS and 8 [13.5%] PsA).

The economic impact of the different rheumatic diseases is largely due to the costs of treatment. Therefore, the choice of each drug should not only depend on its efficacy, but also its efficiency and safety. We conducted a study to evaluate the efficacy, safety, and cost of the Benepali BS in a group of patients with different rheumatic diseases, based on our clinical practice. To date, no study had been conducted in clinical practice to compare efficacy between the BS and reference drugs. Nor has the survival of the BS in inflammatory rheumatic diseases been analysed. In our study, all patients showed significant improvement in disease activity and physical function parameters assessed at 52 weeks of treatment with Benepali or Enbrel. Furthermore, in both groups, half of the patients achieved a state of remission-low disease activity by DAS28 and BASDAI. In addition, we found no significant differences between the two treatment groups in the improvement observed in patients after 52 weeks. At 12 months we only observed differences between both groups in higher median CRP in patients treated with Benepali, but despite significant differences, the CRP value was lower than 5 mg/l in both groups. Neither could these results be explained by higher corticosteroid use in the Enbrel patients, as the mean dose used in both groups was similar. We observed a higher BASFI score in patients treated with Enbrel, which may be explained by the longer disease course of these patients.

The comparability in efficacy that we observed is similar to that described in other CTs. The study by Chadwick et al.20 shows the clinical efficacy of etanercept for RA evaluated in several randomised controlled trials (RCTs) and extension studies.20,21 It also evaluates the efficacy of different BS such as Benepali or Erelzi. In a phase III RCT conducted in 596 patients randomised to Benepali or Enbrel,22 a significant improvement in DAS28 at week 24 was observed in both groups of patients. About 50% of patients in this study achieved low disease activity or remission status at week 24 according to DAS28. Furthermore, no significant differences were observed between the two treatments in the improvement measured by DAS28 or in other activity variables such as ACR20, ACR50, or physical function by HAQ.22 Similarly, another phase III RCT23 compared the efficacy and safety of Benepali and Enbrel at week 52 in patients with RA. In this study they observed that 41% of patients with Enbrel achieved low disease activity-remission at 52 weeks versus 35% with Benepali, showing no significant differences either group. Furthermore, at 52 weeks, a significant improvement was also observed in all activity and physical function parameters measured in both groups of patients. However, we were not able to compare these data with other studies in routine clinical practice because so far, we only have the results from CTs on the effectiveness of these drugs and the different reference biologicals. Therefore, more data are needed in real clinical practice to corroborate this benefit.

There are many factors that influence a drug’s retention time, including the availability of treatment alternatives, effectiveness, drug toxicity, disease severity and adherence to treatment.24 Longer treatment retention time usually translates into greater effectiveness and safety of treatment. There are currently no survival studies in rheumatology with BS, but there are studies with its reference drug. Zink et al.25 conducted a survival study of different anti-TNFs in RA, in which they observed that after one year of treatment 70% of patients continued with Enbrel. In other studies, such as that by Khraishi et al.,26 this figure was 66%. In our study, these data are similar to the above, and after one year of follow-up 81% of patients were still on Enbrel and 72% were still on Benepali. In these data we can see that both treatment groups are similar in survival, with a slightly higher percentage with Enbrel.

As mentioned above, drug safety is a fundamental factor in influencing this survival. The use of BS has been the subject of debate in recent years and they have been used in clinical practice with caution, mainly due to a lack of knowledge of their possible adverse effects.27 In this regard, adverse effects were somewhat more frequent in the Enbrel group than in the Benepali group (46% vs. 36%), than mild-moderate adverse effects. However, drug discontinuation was higher with Benepali than with Enbrel (30.4% vs. 18.6%) due to inefficacy rather than adverse effects. This higher drug discontinuation rate may be the reason why the survival we observed with Benepali was somewhat lower than with Enbrel. In this regard, although both drugs showed efficacy, it is known that a significant proportion do not respond to initial treatment or efficacy is lost over time.3 In the phase III RCT by Emery et al.23 the percentage of adverse events in the Benepali group was 58% compared to 60% with Enbrel during the study up to week 52. Also, in the phase III CT28 the incidence of treatment emergent adverse events was comparable between the two groups (55.2% vs. 58.2%). In our data, the safety profile of Benepali was comparable to that of Enbrel and similar to those observed in these and other etanercept studies.22,29 They are also consistent in that most adverse effects are mild-moderate. The most frequently described adverse effects are always respiratory infections, liver profile disturbances and injection site reactions.30–32

In our study we show that, considering the cost-effectiveness of Benepali, the use of this BS is as effective as the reference drug, but more cost-effective, representing a great saving for the hospital.

One of the most important aspects of this study is the progress that is being made with the new incorporation of these treatments, with similar efficacy to their reference drugs, resulting in a reduction in hospital costs. According to our data, the savings from treatment in the Benepali group compared to Enbrel is €1,747.2/patient-year. A study by Kowalik et al.33 describes the introduction of BS as a measure to reduce direct and indirect costs in RA. Moreover, not only do they show savings in the prescription of the BS drug but also, after marketing, a reduction in the price of the original drug. In general, biological drugs are associated with high cost, which restricts their use and leads to inequality in different countries.34 Since BS are a lower-cost alternative to reference drugs, the current inequality in healthcare provision could be gradually diminishing.35 In fact, budget impact analyses following the introduction of BS, such as infliximab, in different European countries have shown that switching to BS therapy results in significant cost savings and increased access to these therapies.36

Our study has some limitations, primarily its retrospective design. Although the design is technically retrospective, it is in fact mostly prospective, as all variables analysed were collected prospectively and systematically, based on a previously designed protocol. This explains the absence of data loss and the very consistent results. A second limitation would be the small number of patients, which would influence the statistical power. However, all the patients are from routine clinical practice, and despite being a heterogeneous sample because we include different diseases in the study (unlike the RCTs mentioned, which only include RA), we found differences in the main variables in the use of the BS. Finally, there are limitations due to different follow-up times for each patient and disease course. The choice of treatment with Enbrel or Benepali, fell to each physician according to the characteristics of the patient and, obviously, taking cost into consideration. Therefore, since Benepali’s marketing, there has been increased prescription of Benepali compared to Enbrel, therefore more patients can be treated at the same price. The recent marketing of Benepali and increase in its prescription explain why, in our study, the percentage of patients who had previously received other biological drugs was higher with Enbrel than with Benepali (39% vs. 17%, P = .005), as well as the longer disease course in the patients with Enbrel.

In conclusion, these results demonstrate the effectiveness of Benepali in safely controlling the signs and symptoms of patients with inflammatory joint diseases, comparable to Enbrel in clinical practice. These results are comparable to those of the CTs. In addition, this disease control is maintained at a lower cost. Benepali represents a reduction in hospital costs that should be considered. These benefits are homogeneous, according to our study, in the different rheumatic diseases that we have included here; however, further studies with a larger number of patients and the inclusion in clinical practice of other already marketed BS are necessary to consolidate these results.

Research grants from the Spanish Rheumatology Foundation (FER). We received no other financial support or other benefits from commercial sources.

Marta Rojas-Giménez: talks for MSD.

Natalia Mena-Vázquez: talks for MSD, UCB and Roche.

Carmen María Romero-Barco: talks/presentations for AbbVie.

Sara Manrique-Arija: talks/presentations for AbbVie, Pfizer, and MSD.

Inmaculada Ureña-Garnica has no conflict of interest to declare.

Gisela Diaz-Cordovés: talks/presentations for AbbVie, Pfizer, and MSD.

Francisco Gabriel Jiménez-Núñez: talks/presentations for AbbVie, Pfizer, and MSD.