With the recent approvals of infliximab biosimilars, CT-P13 and SB2, and adalimumab biosimilar, ABP 501, by the U.S. FDA, the landscape of available anti-tumor necrosis factor (TNF) therapies for the treatment of inflammatory bowel disease (IBD) is changing right before our eyes. To understand the implications of this change, it is important to consider several factors. The World Health Organization defines a biosimilar monoclonal antibody as a monoclonal antibody “product that is similar in terms of quality, safety and efficacy to an already licensed reference product.”1 As biologic drugs are complex substances that are approximately 1,000 times larger than chemically synthesized drugs with tertiary and quaternary proteinfolding and post-translational modifications such as glycosylation, they are impossible to replicate and therefore the term, “generic,” does not apply. However, despite this complexity, biosimilars are required to have the same amino acid sequence as and perform similarly to the reference product in both nonclinical studies, including in vitro studies displaying similar mechanism of action and in vivo studies on pharmacokinetics, pharmacodynamics and safety. They must also perform similarly in clinical studies, including pharmacokinetic studies showing 90 percent confidence intervals of 0.80-1.25 for the ratio of biosimilar to reference product with respect to certain parameters (such as area under the curve and concentration maximum), pharmacodynamic studies and randomized controlled trials demonstrating non-inferiority for clinical outcomes as well as similar safety and rates of immunogenicity.2
The next factor to consider is extrapolation, meaning that the use of a biosimilar is extrapolated to indications other than what was tested in the randomized controlled trials. For example, the two infliximab biosimilars that have been approved by the FDA have been formally tested in rheumatoid arthritis and/or ankylosing spondylitis or psoriasis, but not IBD. The fact that they were approved for IBD implies that FDA is comfortable with the idea of their use to treat IBD in the absence of randomized data, but as an individual clinician treating an individual patient, taking that leap of faith can be a challenge. However, physicians can take comfort in two things. The first is just how similar these agents are to the originator products, as mentioned above.2 Along those lines, it was recently demonstrated that antibodies to infliximab cross-react with CT-P13 and vice versa, suggesting that these agents have similar immunogenicity and shared immunodominant epitopes.3 Second, there are some recently published data, including a metaanalysis of 11 observational studies4 and results from the prospective Italian cohort, PROSITBIO,5 documenting excellent real-world efficacy of CT-P13 in both Crohn’s disease and ulcerative colitis. Thus, even without randomized comparative efficacy data, the use of infliximab biosimilar in IBD seems reasonable.
Even without randomized comparative efficacy data, the use of infliximab biosimilar in IBD seems reasonable.
Another important factor is interchangeability. FDA defines interchangeability as substitution “for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product.”6 At the present time, anti-TNF biosimilars are not approved for interchangeability as there are no data for this. In contrast, there are some data regarding single transitions from originator to biosimilar. The recently published NORSWITCH randomized controlled trial found that switching from reference infliximab to CT-P13 was not inferior to continued treatment with infliximab in a mixed population of patients with autoimmune disease, although among the subgroup of patients with Crohn’s disease the confidence interval approached inferiority for CT-P13.7 Also worth considering are that U.S. Remicade has undergone multiple evolutions over the years and is no longer the same product as initially created, and that European and U.S. Remicade are not exactly the same product since they are manufactured in different facilities; hence, in some ways these products approach being biosimilars of each other. While the idea of a single transition from originator to biosimilar may be potentially reasonable in certain situations, interchangeability among multiple agents is theoretically more difficult to justify for at least two reasons aside from the lack of data: safety surveillance for individual drugs becomes challenging when making multiple switches, especially if relatively close in time; and even if multiple biosimilars are by definition similar to the reference product, it is not unequivocally apparent that they would necessarily also be biosimilars of each other.
Finally, while in some countries biosimilars may offer substantial cost savings and improve access to anti-TNF therapy, pricing in the U.S. may be neither so homogeneous nor straightforward, given the lack of a single-payor system. The relative cost of biosimilars in the U.S. will likely be determined by negotiations between manufacturers and payors regarding entire portfolios of products and potential discounts that can be provided. Nonetheless, having more competition in the anti-TNF space will likely have certain benefits, such as a drive for competitive pricing in the long term as well as the potential for fulfilling particular data gaps not provided by the reference products.
Dr. Osterman has consulted for AbbVie, Janssen, Lycera, Merck, Pfizer, Takeda and UCB. Dr. Osterman has received a research grant from UCB.
AGA Takes the Lead in Educating GIs about Interchangeable Biosimilars for IBD
AGA believes that gastroenterologists should have access to all treatments that can benefit patient care. Gastroenterologists and patients rely on biologics to manage IBD, including Crohn’s disease and ulcerative colitis. Biosimilar products, which are “highly similar” to the biologic, have begun to be approved by the FDA for indications, such as IBD. AGA works with the FDA, other regulatory agencies and Congress to ensure that the voice of gastroenterology is heard in relation to biosimilars and interchangeable products.
To prepare for the entry of biosimilars to the market, AGA is taking the lead in educating health care professionals and patients about biosimilars and how they can be used for IBD patient care.
Review our educational offerings and learn more at www.gastro.org/biosimilars.
1. World Health Organization.Guidelines on evaluation of monoclonal antibodies as biosimilar biotherapeutic products (SBPs), Annex 2. Technical Report Series No.. 1004, 2016.
2. Araújo, F., Cordeiro, I., Teixeira, F. et al, Pharmacology of biosimilar candidate drugs in rheumatology: a literature review. Acta Rheumatol Port. 2014;39:19-26.
3. Ben-Horin, S., Yavzori, M., Benhar, I. et al, Crossimmunogenicity: antibodies to infliximab in Remicadetreated patients with IBD similarly recognize the biosimilar Remsima. Gut. 2016;65:1132-8.7.
4. Komaki, Y., Yamada, A., Komaki, F. et al, Crossimmunogenicity: antibodies to infliximab in Remicadetreated patients with IBD similarly recognize the biosimilar Remsima. Gut. 2016;65:1132-8.7.
5. Fiorino, G., Manetti, N., Armuzzi, A. et al, The PROSITBIO cohort: a prospective observational study of patients with inflammatory bowel disease treated with infliximab biosimilar. Inflamm Bowel Dis. 2017;23:233-43.
6. U.S. Food and Drug Administration.Information on biosimilars.Available at: https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/default.htm. Accessed July 8, 2017.
7. Jørgensen, K.K., Olsen, I.C., Goll, G.L. et al, Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. 2017;389:2304-16.