Overview of Subsequent Entry Biologics for the Management of Inflammatory Bowel Disease and Canadian Association of Gastroenterology Position Statement on Subsequent Entry Biologics

Wook Hong S., Kim Y., Ye B.D.

The introduction of anti-TNFs, such as infliximab (IFX), has revolutionized the treatment of immune-mediated inflammatory diseases. Anti-TNF agents have shown outstanding efficacy and long-term improvement of clinical outcomes, but the cost has been relatively high. Out of this concern, several ‘biosimilar’ drugs of anti-TNF agents have been developed. CT-P13, the first biosimilar of reference IFX, was approved by the European Medicines Agency and licensed by the US FDA for use in all indications of IFX. This updated review summarizes all aspects of CT-P13, including pharmacology and pharmacokinetics, and evaluates its efficacy, safety and immunogenicity for all indications based on the results of the latest clinical trials as well as on real-world experiences.

Moayyedi P., Benchimol E.I., Armstrong D., Yuan C., Fernandes A., Leontiadis G.I.

The development of anti-tumour necrosis factor (TNF) therapies has transformed the care of patients with immune-mediated diseases such as inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, psoriasis and inflammatory arthropathies, including rheumatoid arthritis and ankylosing spondylitis. For IBD patients, these biologic therapies are effective at inducing and maintaining remission (1), reducing the need for surgery (2) and improving quality of life (3). Although anti-TNF therapies are effective in several different immune-mediated disorders, individual biologics are not, necessarily, equally effective in all disorders suggesting that their actions may differ between disorders. For example, the paradox that anti-TNF drugs used to treat rheumatoid arthritis (RA) and psoriasis may yet cause joint pains and skin reactions in IBD patients, emphasizes our imperfect understanding of the mechanism of action of these biologic therapies and the need to evaluate treatment outcomes separately for different disorders. The main factors that limit the use of anti-TNF drugs are adverse events and cost. Anti-TNF therapy is associated with joint pains, dermatological disorders and transfusion reactions (4). Transfusion reactions are associated with the development of antibodies to anti-TNF agents and this may also be associated with reduced treatment efficacy (5). Anti-TNF agents are also associated with an increased risk of infection (6) and risk of lymphoma although these risks may be exacerbated, to a greater or lesser extent, by the concomitant use of azathioprine or other immunosuppressive agents (7). Anti-TNF therapies are also expensive costing up to $20,000 per year for each patient in Canada. Canada spent more on biologic therapies for all indications than on any other class of drug in 2018 accounting for 8.2% of the $33.7 billion spent on prescription medications (8). While the cost of these therapies is significant, the cost of having IBD is also expensive to society. It is estimated that the indirect cost of IBD was $1.29 billion in Canada in 2018 (9,10). Anti-TNF therapies can improve quality of life and productivity and, accounting for these societal costs, biologics may offer value for money (11). In the Canadian setting, health care is mainly funded centrally by the tax payer and the government, understandably, focuses on how biologic therapy may reduce health care costs. This is less clear cut with research using health administrative data failing to demonstrate any significant decrease in hospitalizations or surgical resections in the anti-TNF era compared to what would be expected if these drugs had not been introduced (12). Given this perspective, it is understandable that approaches to reducing the cost of these drugs are being explored. The emergence of biosimilars, also known as subsequent entry biologics have provided an opportunity for third party payers to reduce anti-TNF therapy drug costs. A biosimilar is a biological medical product that is similar to the original but manufactured by a different company once the patent for that product has expired. They are typically less expensive than the original product and therefore an obvious target in attempts to reduce biologic drug costs. Biosimilars are distinct from usual generic drugs, which are simple small molecules that are relatively straightforward to reproduce and manufacture on a large scale, and identical to the original drug. Biologic therapies are more complex proteins and require replication in living cells. The product is dependent on the type of genetically modified cell being used, the production process and purification techniques (13). The manufacturing process is considerably more expensive than standard small molecules and therefore costs of biosimilars are higher than generically produced drugs. Furthermore, the variation from the originator is greater than would normally be seen with generics. However, it is important to emphasize that even with the original manufacturer there is potential for variability between each manufacturing run due to the complexity of living organisms. The Federal Drug Agency has released documents regarding the approval process for biosimilars (14) that other regulatory authorities have largely adopted (15). Essentially biosimilars must show a high degree of similarity to the original product and have no clinically meaningful differences in safety, purity and potency (14). This is a reasonable definition in principle but the definitions of ‘high degree of similarity’ as well as ‘clinically meaningful differences in safety and potency’ need further clarification in clinical practice. The Canadian Association of Gastroenterology has previously published a position statement on biosimilars (16) but this was 6 years ago, and more data are now available. Crohn’s and Colitis Canada has published a position statement more recently (17) but the two organizations felt it was of value to release a joint position statement after a full literature review. Several positions statements have been released by various organizations (Table 1) but none has provided an explicit literature search, nor have they assessed the quality of evidence of a defined clinical question according to GRADE criteria (18). Table 1. Position statements reached by other groups on the use of biosimilars

Gisbert J.P., Chaparro M.

To review the effectiveness and safety of switching from an originator anti-TNF (Remicade®) to a biosimilar (CT-P13) in patients with inflammatory bowel disease (IBD).Electronic and manual search up to September 2017.We identified 24 studies evaluating switching between Remicade® and CT-P13 in 1326 patients. Disease control (no worsening after switching) was confirmed in most of the patients (weighted mean, 88%; 95% CI=86-89%). No unexpected adverse effects were reported in any of the studies.The risks of switching from Remicade® to a biosimilar seem to be purely theoretical and are not supported by the (still limited) real-world clinical practice experience. On the contrary, a steadily increasing number of publications have shown that there seem to be no safety or efficacy concerns about switching. Therefore, switching from originator to biosimilar infliximab in patients with IBD may be considered acceptable.

Gisbert J.P., Chaparro M.

McKinnon R.A., Cook M., Liauw W., Marabani M., Marschner I.C., Packer N.H., Prins J.B.

The efficacy, safety and immunogenicity risk of switching between an originator biologic and a biosimilar or from one biosimilar to another are of potential concern. The aim was to conduct a systematic literature review of the outcomes of switching between biologics and their biosimilars and identify any evidence gaps. A systematic literature search was conducted in PubMed, EMBASE and Cochrane Library from inception to June 2017. Relevant societal meetings were also checked. Peer-reviewed studies reporting efficacy and/or safety data on switching between originator and biosimilar products or from one biosimilar to another were selected. Studies with fewer than 20 switched patients were excluded. Data were extracted on interventions, study population, reason for treatment switching, efficacy outcomes, safety and anti-drug antibodies. The systematic literature search identified 63 primary publications covering 57 switching studies. The reason for switching was reported as non-medical in 50 studies (23 clinical, 27 observational). Seven studies (all observational) did not report whether the reasons for switching were medical or non-medical. In 38 of the 57 studies, fewer than 100 patients were switched. Follow-up after switching went beyond 1 year in eight of the 57 studies. Of the 57 studies, 33 included statistical analysis of disease activity or patient outcomes; the majority of these studies found no statistically significant differences between groups for main efficacy parameters (based on P < 0.05 or predefined acceptance ranges), although some studies observed changes for some parameters. Most studies reported similar safety profiles between groups. There are important evidence gaps around the safety of switching between biologics and their biosimilars. Sufficiently powered and appropriately statistically analysed clinical trials and pharmacovigilance studies, with long-term follow-ups and multiple switches, are needed to support decision-making around biosimilar switching.

Heron V., Afif W.

In patients with Crohn's disease on biologic medications, the use of therapeutic drug monitoring leads to a personalized approach to optimize treatment. Using an algorithmic approach, measurement of drug concentrations and anti-drug antibodies can be used to improve treatment outcomes. Therapeutic drug concentrations and absence of antibodies are associated with improved clinical and endoscopic outcomes. In clinical practice, therapeutic drug monitoring has been shown to be clinically useful and cost-effective in patients experiencing a loss of response to treatment. This review highlights the available data on therapeutic drug monitoring in the treatment of patients with Crohn's disease on biologic medications.

Inotai A., Prins C.P., Csanádi M., Vitezic D., Codreanu C., Kaló Z.

Huang V.W., Fedorak R.N.

Inflammatory bowel disease (IBD) is often treated with biologic agents, such as infliximab, a monoclonal antibody against tumor necrosis factor (TNF)-α. Biosimilars are biologic agents developed to have similar biological properties in terms of safety and efficacy as the reference or innovator biologic. The development of biosimilars requires extensive preclinical testing, but entry of biosimilars into the clinical market does not require as extensive clinical testing as for innovator biologics. Since biologics such as infliximab are clinically indicated for rheumatologic conditions as well as for IBD, and biosimilar infliximab has been shown to be efficacious in the treatment of rheumatologic and other inflammatory conditions, there are concerns regarding the appropriateness of clinical extrapolation of the indication for biosimilar infliximab to the treatment of IBD. This chapter summarizes the issues surrounding the use of biosimilars in the treatment of IBD.

Danese S., Fiorino G., Raine T., Ferrante M., Kemp K., Kierkus J., Lakatos P.L., Mantzaris G., van der Woude J., Panes J., Peyrin-Biroulet L.

Ben-Horin S., Vande Casteele N., Schreiber S., Lakatos P.L.

Biologic drugs such as infliximab and other anti-tumor necrosis factor monoclonal antibodies have transformed the treatment of immune-mediated inflammatory conditions such as Crohn's disease and ulcerative colitis (collectively known as inflammatory bowel disease [IBD]). However, the complex manufacturing processes involved in producing these drugs mean their use in clinical practice is expensive. Recent or impending expiration of patents for several biologics has led to development of biosimilar versions of these drugs, with the aim of providing substantial cost savings and increased accessibility to treatment. Biosimilars undergo an expedited regulatory process. This involves proving structural, functional, and biological biosimilarity to the reference product (RP). It is also expected that clinical equivalency/comparability will be demonstrated in a clinical trial in one (or more) sensitive population. Once these requirements are fulfilled, extrapolation of biosimilar approval to other indications for which the RP is approved is permitted without the need for further clinical trials, as long as this is scientifically justifiable. However, such justification requires that the mechanism(s) of action of the RP in question should be similar across indications and also comparable between the RP and the biosimilar in the clinically tested population(s). Likewise, the pharmacokinetics, immunogenicity, and safety of the RP should be similar across indications and comparable between the RP and biosimilar in the clinically tested population(s). To date, most anti-tumor necrosis factor biosimilars have been tested in trials recruiting patients with rheumatoid arthritis. Concerns have been raised regarding extrapolation of clinical data obtained in rheumatologic populations to IBD indications. In this review, we discuss the issues surrounding indication extrapolation, with a focus on extrapolation to IBD.

Ha C.Y., Kornbluth A.

On February 9, 2016, the Food and Drug Administration Arthritis Advisory Committee recommended by a vote of 21 to 3, that the biosimilar to infliximab, CT-P13, be approved for rheumatoid arthritis and ankylosing spondylitis and, by extrapolation, for all the indications for which infliximab is currently approved, including adult and pediatric ulcerative colitis and Crohn's disease. On April 5, 2016, the Food and Drug Administration concurred with this recommendation and approved CT-P13 (Inflectra; Pfizer Inc.) for all diseases for which infliximab had previously been approved, including adult and pediatric moderate to severe ulcerative colitis and pediatric and adult moderate to severe and fistulizing Crohn's disease. This was despite the absence of any randomized controlled trials studying the infliximab biosimilar in any inflammatory bowel disease. This highly controversial approach has been criticized by various rheumatology and gastroenterology professional societies around the world. This review will cover the stepwise approach to biosimilar development, issues of extrapolation and interchangeability, and conclude with a discussion of the regulatory, intellectual property issues, and financial implications, which will all intersect in the decision and ability to prescribe a biosimilar or reference anti-tumor necrosis factor drug.

Włodarczyk M., Fichna J., Sobolewska-Włodarczyk A.

Braun J., Kudrin A.

CT-P13, the biosimilar of infliximab, has been recently approved in the EU, Australia, Canada, Japan and many other countries. Thus, it was the first biosimilar approved in the field of rheumatology, dermatology and gastroenterology. Since there has been debate about the issue of switching from RMP to the biosimilar and some national societies have expressed concerns, this review was written with the following objectives: The review concludes that whilst prudent switching practices should be employed, growing safety experience accumulated thus far with CT-P13 and other biosimilars is favorable and does not raise any specific concerns.

Wolf D.C.

Márquez Velásquez J.R.