Abstract: Monoclonal antibody biologic therapies, introduced nearly 20 years ago, revolutionized the treatment of inflammatory bowel disease (IBD) and are now well established as the most effective agents available. As the first of these biologic agents starts to come off patent, biosimilar agents have emerged as alternatives to originator drugs. The unique drug development and manufacturing processes involved in the creation of biologic agents pose distinct regulatory challenges compared to generic formulations of conventional medications. Reductions in medication costs have been proposed to be a major benefit of biosimilar therapies; however, there are concerns regarding the adequacy of the existing regulatory process and data requirements for biosimilar therapy approval, as well as the true bioequivalence of these agents. Infliximab biosimilars for the treatment of IBD have been available in Europe and Asia for a few years and are expected to become available in the United States within the next 1 to 2 years. This article reviews biosimilar therapies and the current data with respect to IBD.
Since infliximab (Remicade, Janssen) was approved for the treatment of Crohn’s disease in 1998,1 monoclonal antibody biologic therapies have proven to be the most potent therapeutic agents available to treat inflammatory bowel disease (IBD). The first biologic agents targeted the tumor necrosis factor-alpha (TNFα) pathway (infliximab, adalimumab [Humira, AbbVie], and certolizumab pegol [Cimzia, UCB]).2-9 More recently, biologic agents targeting different pathways have either been approved (eg, anti-integrins, such as natalizumab [Tysabri, Biogen] and vedolizumab [Entyvio, Takeda], and the anti–interleukin-12/-23 agent ustekinumab [Stelara, Janssen])10-13 or are pending imminent approval for IBD. Biologic agents were initially reserved for the most advanced and aggressive disease as a treatment of last resort. However, increasing data and comfort regarding their safety profile have led to a shift in practice toward early implementation of biologic agents in at-risk patients to arrest progression early in the disease course before irreversible tissue damage has occurred.14 Biologic agents are currently considered chronic, long-term therapy and are often continued indefinitely upon commencement unless there is either loss of response or side effects, with data showing an increased likelihood of relapse upon cessation even in patients with long-term remission.15 Biologic agents are also expensive, and given the increasing prevalence of IBD,16 the lower threshold to institute biologic agents, and their subsequent long-term use, they are now the major source of total IBD expenditure.17,18
As the biologic era approaches 20 years, the first biologic agents have either come off patent or are approaching patent expiration, resulting in the expected emergence of biosimilars (Table 1). Janssen’s patent relating to its infliximab formulation has already expired in Europe, and its US patent expires in September 2018. AbbVie’s adalimumab formulation is expected to expire on December 31, 2016 in the United States and in April 2018 in Europe.19-22
Biosimilars: What They Are and Are Not
A biologic agent is a medicinal product that is derived from a natural source and includes large, protein-based therapeutic agents that are typically obtained from living cell lines using recombinant DNA technology such as hormones and monoclonal antibodies (Table 2). Biologic agents differ from conventional medications and have a much greater degree of structural complexity, not only being larger in size but also subject to posttranslational modifications. A biosimilar is a biologic product that is highly similar to a reference product (originator biologic agent) with respect to quality characteristics, biologic activity, immunogenicity, efficacy, and safety, notwithstanding minor differences in clinically inactive components.
A biosimilar is not considered a generic medication (Table 3). A generic drug is identical or bioequivalent to a brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use.23 It is also important to distinguish biosimilars from next-generation biologic agents (eg, adalimumab, certolizumab pegol), which, while directed toward the same molecular target as first-generation agents (eg, infliximab), are chemically distinct, independently developed, and do not depend upon demonstration of biosimilarity with an originator product for abbreviated approval.24,25
To be designated as interchangeable (Table 2) requires a higher standard than simply being biosimilar, and implies that free exchange with the originator biologic agent can occur with no greater risk of adverse effects or diminished efficacy. An interchangeable product must produce the same clinical result as the originator product in a specific patient. In addition, in order to receive the designation of being interchangeable, the biosimilar must have similar effectiveness and safety when switched -multiple times with the originator product, and such switches must not cause more risk than remaining on the originator product for the same amount of time.26
Regulatory and Developmental Processes
The manufacture of biologic agents is distinct from that of other pharmacologic agents in that biologic agents are derived from a natural source, often a unique cell line, and are sensitive to manufacturing conditions with the potential for posttranslational modifications.
The regulatory process for biosimilars is substantially more rigorous than for traditional generic medications, although it is abbreviated relative to originator biologic agents.27,29-32 For originator biologic agents, approval by the US Food and Drug Administration (FDA) is dependent upon multiple preclinical and clinical phases of trials demonstrating the safety and effectiveness of the product.26
The European Medicines Agency first outlined its biosimilar regulatory pathway in 2005 and the FDA developed a framework in 2012.27,33 FDA approval of biosimilars is based on evidence that the product is highly similar and has no clinically meaningful differences from the originator product in the parameters of safety, purity, and effectiveness.26
The developmental process for biosimilars is inverted compared with originator biologic agents, with an emphasis on proving biosimilarity with the originator product, or lack of clinically meaningful difference, rather than independently re-establishing efficacy and safety. Biosimilars are reverse-engineered based on the originator product, and, thus, the main developmental stage is the comprehensive analytical characterization of structure and function relative to the originator biologic product.27,29-32 Clinical trials are permitted after demonstration of structural and functional biosimilarity to the originator product; thus, no clinically meaningful difference in outcomes would be expected to exist.34
Clinical Testing and Extrapolation
After passing regulations based on analytical characterization and pharmacodynamics and pharmacokinetic studies of the biosimilarity, proposed biosimilars are then required to complete adequately powered, comparative, randomized, controlled trials (RCTs) in a select sensitive patient population. The purpose of these clinical trials is to establish equivalence and detect clinically meaningful differences in efficacy, safety, and immunogenicity between the biosimilar and the originator product.
A controversial area within the biosimilar regulatory and approval processes is the concept of extrapolation. Extrapolation is the philosophy that clinical studies of biosimilars can be performed in one disease state or sensitive population group and then inferred to work in other disease settings or indications for which the reference biologic is approved and licensed (Table 2). Extrapolation is dependent on sufficient scientific justification, including (but not limited to) mechanism of action.27 As such, there is no requirement to independently perform trials in each of the originator biologic indications in order to obtain approval of the biosimilar across all of the same indications. Rather, such approval can be granted based on the principle of clinical experience with the originator biologic and presumed identical mechanism of action due to the totality of evidence of biosimilarity.27
Approval is of particular importance for IBD, as the anti-TNFα biosimilars currently utilized for IBD across the world were approved without independent trials in IBD patients and were instead accepted as effective for these patients based on trials in rheumatologic conditions. Some IBD clinicians and researchers have argued that differences between IBD and other conditions in terms of immunogenicity and other factors mean that equivalence studies may not translate across conditions35 and that comparative, noninferiority RCTs should be conducted specifically in IBD patients. Conversely, others, including biosimilar manufacturers, argue that the principle of extrapolation is already in place for changes in manufacturing protocols for originator biologic agents and that the requirements for biosimilars are more stringent in that they require clinical trials.
Due to the abbreviated phase 3 clinical testing and extrapolation, structured, prospective, phase 4, postmarketing surveillance takes on greater significance, and in essence becomes mandatory, as often this is the first time that disease-specific data for a biosimilar become available.
Proposed Advantages and Disadvantages
The main proposed advantage of biosimilars is that increased competition will lead to decreased costs and increased availability and accessibility of biologic therapies. It is partly upon this premise that regulatory authorities permit extrapolation to minimize drug development and regulatory approval costs. Five-year savings from adoption of CT-P13 (an anti-TNFα antibody biosimilar to infliximab marketed as Remsima [Celltrion Healthcare] in Europe and as Inflectra [Celltrion Healthcare] in the United States) for Crohn’s disease in the United Kingdom, Italy, and France have been predicted at 76 to 336 million euros.36 However, it has been argued that the cost savings will not be impressive relative to conventional and generic medications, as the regulatory process for biosimilars is rigorous. It is estimated that introducing a novel biologic therapy to market may cost as much as $800 million and that the cost for biosimilars may be less but still substantial, despite an abbreviated pathway for biosimilars.37 Although biosimilars are predicted to be less expensive and to drive down costs, it is unclear to what degree these savings will affect patients in terms of decreased insurance costs or improved biologic accessibility.38
Disadvantages of biosimilars include the possibility of inferior clinical outcomes in the absence of a sufficient clinical evidence base prior to approval and concerns regarding nonmedical switching by insurance providers or governmental funding sources for health economic reasons. In turn, there is a theoretical concern that switching may result in the potential for increased immunogenicity and development of antidrug antibodies. It is also important to acknowledge that biosimilars should not be considered an additional or new therapeutic strategy and are unlikely to be effective in circumstances in which the originator biologic product failed or antidrug antibodies have developed. The clinical settings in which biosimilars will likely be of greatest value is in the de novo commencement of biologic therapy and potentially in the stabilized responder once interchangeability has been established.
Perceptions of Patients and Gastroenterologists and Position Statements of Inflammatory Bowel Disease Associations
IBD patient perspectives of biosimilars were assessed in an online survey completed by 1181 patients.39 Thirty-eight percent of patients had previously heard of biosimilars. Respondents’ primary concerns were regarding safety (47%), efficacy (40%), and molecular basis (35%), with 25% of respondents expressing no concerns. The majority felt that the lower cost of biosimilars should not come at the expense of safety and efficacy, and only 12.5% of respondents felt that extrapolation was rational. Twenty-one percent of respondents were against the idea of interchangeability if not informed of the change. Overall, most patients were not familiar with biosimilars, had concerns, and wished to be involved in therapeutic decisions. A Canadian study suggested that patients were better informed but found similar reservations.40
Studies have been performed assessing the perceptions of gastroenterologists toward biosimilar therapy. The results reveal a degree of skepticism, particularly in regard to the abbreviated regulatory process, concept of extrapolation, and consequences of switching in terms of immunogenicity in the context of a limited evidence base. A survey of 307 European Crohn’s and Colitis Organisation (ECCO) members in 2014 showed that IBD specialists were reasonably informed on biologic agents, regarded cost sparing (89%) as the main advantage, and listed immunogenicity (67%) as their main concern.41 Most respondents felt that postmarketing surveillance and well-designed RCTs should be required. Interestingly, 64% disagreed with automatic replacement of originator biologic agents with a biosimilar by a pharmacist, although 18% supported substitution for new prescriptions, and only 6% felt that biosimilars were interchangeable. The majority of respondents were not confident about the use of biosimilars in clinical practice.41
These findings are reflected in the position statements of professional IBD associations, including the Crohn’s and Colitis Foundation of America (CCFA) and ECCO.42-47 The ECCO expressed concern regarding extrapolation and specified direct testing in IBD populations with a request that evidence specific to IBD patients be required to confirm efficacy and safety in this patient group, as prior experience with originator biologic agents suggests differences in effectiveness across different indications or disease states.43 Key points of the CCFA statement include the need for (1) thorough human testing of the highest safety standards; (2) product information clearly defining and stating the risk of immunogenicity; (3) proof stating that switching (ie, interchangeability) would not lead to immunogenicity; (4) prescriber notification of substitution, with the ability to prevent substitution if deemed necessary; and (5) a unique name or identification number to minimize confusion.42 Interestingly, a follow-up survey on biosimilars in 2016 suggested that IBD specialists have remained well informed and had fewer concerns and more confidence about their clinical use; 44% of IBD specialists now consider biosimilars and originator products interchangeable and only one-third were against extrapolation across indications.48
Currently Available Anti–Tumor Necrosis Factor-Alpha Biosimilars
Biosimilar growth factors have been utilized in Europe since 2006. CT-P13, the first biosimilar for IBD, was approved by the European Medicines Agency in mid-2013 across all originator infliximab (Remicade) indications based on a pharmacokinetics biosimilarity study in ankylosing spondylitis49 and a single phase 3 clinical trial in rheumatoid arthritis.50 CT-P13 has been utilized in several countries throughout Europe and Asia for the last 2 years and is now approved in over 60 countries. Although CT-P13 was approved in the United States in April 2016, it is not yet available for clinical use due to ongoing patent and legal issues. The infliximab biosimilar is indicated for treatment-naive patients or for a one-time switch or single transition from the originator infliximab and, importantly, is not considered interchangeable with the originator infliximab.51 In July 2016, the FDA recommended licensure of the adalimumab biosimilar ABP 501 (Amgen) based on a pharmacokinetics study and 2 RCTs in rheumatoid arthritis and psoriasis.52 The policy of extrapolation has meant that there have not been any RCTs of the new anti-TNFα biosimilar agents in IBD to date, as they are not a requirement for regulatory approval.
A recent systematic review of anti-TNFα biosimilar agents identified 19 studies, of which only five were phase 3 RCTs in rheumatoid arthritis (0 in IBD), with eight phase 1 studies (7 in healthy individuals) and 6 observational studies.53 The researchers found that the pharmacokinetics, clinical efficacy, and adverse event data supported the comparability of biosimilar and originator products. Only 4 small cohort studies were identified that switched from originator biologic agent to biosimilar, although these studies suggested similar remission maintenance rates.54-57
At the 2016 ECCO and Digestive Disease Week conferences, a number of abstracts reporting the preliminary clinical experiences of IBD specialty centers with infliximab biosimilars were presented.58,59 The observational data to date appear to be encouraging overall, although they are only short term (Tables 4-6). In general, infliximab biosimilars appeared to have equivalent efficacy and safety to the originator infliximab in the de novo induction setting for anti-TNFα–naive IBD patients. As expected, some studies suggested lower remission and response rates and higher infusion reaction rates in patients with prior anti-TNFα exposure. While the data appear to justify the policy of extrapolation, there is still insufficient evidence regarding interchangeability and the immunogenic consequences of switching, especially in otherwise stable patients who switch for financial rather than medical reasons. Available data for switching involve limited follow-up duration and almost exclusively involve a single switch. The largest cohort to date by Fiorino and colleagues60 suggested that although biosimilar therapy is safe and effective, there was a 5-fold increase in loss of response (12.2% vs 2.3%; P=.001) in patients who were switched. Subtle posttranslational modifications unique to the biosimilars relative to the originator biologic product may be sufficient to lead to antidrug antibody formation with associated loss of response and drug reactions upon switching, especially if multiple switches back and forth between agents occur.61 Longer-term observational and investigator-initiated biosimilar trial data specific to IBD are still required, with a particular emphasis on the immunogenic sequelae of switching to establish the validity of interchangeability, such as the recently completed NOR-SWITCH study.62 NOR-SWITCH was a phase 4, multi-indication (Crohn’s disease, ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis), multicenter, prospective, double-blind, noninferiority, RCT of nonmedical biosimilar-switching conducted by the Norwegian government, presented in abstract form at the United European Gastroenterology Week 2016 meeting.63 A total of 481 patients were recruited across 40 centers; all patients had been on stable treatment with the originator infliximab for at least 6 months. The primary outcome was disease worsening at 12 months, which was noted in 53 of 202 (26.2%) originator infliximab–treated patients compared with 61 of 206 (29.6%) of the CT-P13–switched patients, with no significant difference between the 2 arms. When looking specifically at IBD patients, disease worsening was noted in 21.2% of originator infliximab–treated patients and 36.5% of CT-P13–treated Crohn’s disease patients (n=155), while the respective values for ulcerative colitis were 9.1% and 11.9% (n=93), with the adjusted treatment differences within the prespecified noninferiority margin. No difference was identified in the detection of antidrug antibodies (originator infliximab, 7.1% vs CT-P13, 7.9%), trough drug levels, and frequency of adverse events, including infusion reactions.
With regard to therapeutic monitoring, good correlation of CT-P13 serum levels with various commercially available infliximab assays has been reported.64 Furthermore, a recent study assessed sera of IBD patients both with and without measurable anti–originator infliximab antibodies to infliximab for cross-reactivity with CT-P13.65 Results of the study showed that anti–originator infliximab antibodies similarly recognized and inhibited CT-P13, suggesting similar immunogenicity and shared epitopes. This study did not identify cross-reactivity with anti-adalimumab antibodies.
Conclusion
The emergence of biosimilar agents poses unique challenges and opportunities in the care of IBD patients, for whom biologic agents are often the most effective therapies available. There is concern regarding the abbreviated regulatory process and extrapolation of biosimilar formulations and risks involved with nonmedical switching. However, the data currently available are positive in regard to the bioequivalence of these agents in the de novo setting, although interchangeability has not been adequately established. An important new risk for clinicians to understand is the cross-reactivity of biosimilar and originator antidrug antibodies. Ongoing postmarketing studies are essential to clearly define the safety, efficacy, and immunogenicity profiles of biosimilar agents in IBD and inform future regulatory processes.
Dr Rubin is a consultant for and has received grant support from AbbVie, Janssen, Takeda Pharmaceuticals, Pfizer, Amgen, and Samsung Bioepis, and is chair of the Government and Industry Affairs Committee with the Crohn’s & Colitis Foundation of America. The other authors have no relevant conflicts of interest to disclose.
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