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Invited Commentaries

New Kids in the Neighborhood: Biosimilars

de Ridder, Lissy; Winter, Harland

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Journal of Pediatric Gastroenterology and Nutrition: September 2017 - Volume 65 - Issue 3 - p 265-266
doi: 10.1097/MPG.0000000000001670
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See “Induction Therapy With Biosimilar Infliximab in Children With Crohn Disease” by Sieczkowska-Golub et al on page 285.

In Europe, since 2015, biosimilar medications for infliximab treatment of Crohn disease are replacing the originator compound. The article by Joanna Sieczkowska-Golub et al (1) describes the experience at 3 academic medical centers in Poland using the biologic CT-P13, a biosimilar to replace infliximab. Although the number of patients reported in this study is small (n = 36), the safety and adverse event profiles were similar to that observed previously with infliximab. Without a reliable, prospective registry to monitor the efficacy and safety of biosimilar agents, clinicians and patients will need to rely on comparative data as required by regulatory agencies as reassurance that biosimilar medications are indeed bioequivalent and interchangeable with reference compounds that have gained approval by demonstrating efficacy and safety.

Generic drugs, when prescribed at the same molar dose, are identical to the reference medications with respect to rate and extent of absorption. This requirement for bioequivalence does not apply to biologic agents, which differ from the originator compound based on the cells lines used and differences in the manufacturing process (2). For approval, a biosimilar does not need to reach the same level of evaluation for efficacy as the reference drug, and studies with large numbers of patients in controlled trials are not required for approval. A difference that is essential to understand is that biosimilar development is not aimed at demonstrating clinical efficacy in a clinical condition, because this has already been done for the originator, but only needs to demonstrate similarity in specific conditions. This similarity may be demonstrated in many in vitro and ex vivo assays rather than in clinical trials. The FDA has published “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Guidance to Industry” in which the totality of evidence based on “structural and functional characterization, nonclinical evaluation, human PK and PD data, clinical immunogenicity data, and comparative clinical studies” is used for approval (3). The European Medicines Agency provides valuable information to the public about how they reached a decision to approve specific medications by citing the evidence for each specific area (4).

Next to efficacy, safety, and immunogenicity data from the Planetas and Planetra trials, crossreactivity between the infliximab (IFX) originator and CT-P13 has been shown by Ben-Horin et al (5–7). The NOR-SWITCH study, a large nationwide Norwegian trial, demonstrated noninferiority of CT-P13 to the IFX originator in adult patients with immune-mediated diseases (rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis). Switching from the originator to the biosimilar did not lead to any problems.

Based on the Planetas and Planetra trials extrapolation to other indications followed. This has enabled CT-P13 to be available for pediatric patients with IBD and avoids delays in availability and higher costs by requiring repetitive tests.

By now, multiple observational and prospective trials have been published comparing CT-P13 with its originator in CD. Recently, a systematic review and meta-analysis of adult patients with IBD was published. With data from 11 studies and 1007 IBD patients, there was no significant difference in terms of efficacy, safety, and immunogenicity of both products (8). So, the extrapolation to other populations and indications seems justified.

However, it still is a large step from adults to children. IBD pathogenesis, especially in young children may be different than in adults. Similarly, pharmacokinetics in children may not be the same as in adults (9,10).

Unfortunately, although data in adults are emerging, pediatric data are scarce. Although the study of Joanna Sieczkowska-Golub and colleagues is important, the number of subjects in this study are low and follow-up is short (14 weeks). Although larger numbers and long-term follow-up are needed, the horse has already left the barn. In many European countries both naïve pediatric patients with IBD and patients who have switched from the originator are treated with CT-P13.

On the one hand, these new comers are a blessing. Substantially lower costs will lead to wider availability for pediatric patients with IBD in need of effective and safe treatment. Anti-TNF has already proven effective in the treatment of pediatric IBD, and recently the Develop registry has shown that the use of IFX is not associated with an increased malignancy risk (11). Competition between pharmaceutical companies is an incentive to bring down costs and stimulate research on the appropriate use of biologics (12).

On the other hand, caution is still needed. Prospective registries and postmarketing surveillance to monitor the efficacy, immunogenicity, and safety of biosimilar in pediatric IBD are crucial.

In conclusion, IFX biosimilars already have become available in Europe to treat children with Crohn disease. Larger and longer-term studies on the use of CT-P13 (and in the future of SB2) in this field are, however, essential to test efficacy, durability, and sustained affordability of these new kids in the neighborhood.

REFERENCES

1. Sieczkowska-Golub J, Meglicka M, Plocek A, et al. Induction therapy with biosimilar infliximab in children with Crohn disease. J Pediatr Gastroenterol Nutr 2017; 65:285–288.
2. U.S. Food and Drug Administration. Guidance for industry: bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA. Draft guidance. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM377465.pdf. Accessed October 2, 2015.
3. U.S. Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed September 10, 2015.
4. European Medicines Agency. European public assessment reports. http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=WC0b01ac058001d124&searchTab=searchByAuthType&alreadyLoaded=true&isNewQuery=true&status=Authorised&keyword=Enter+keywords&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=biosimilars&genericsKeywordSearch=Submit. Accessed September 15, 2015.
5. Ben-Horin S, Yavzori M, Benhar I, et al. Cross-immunogenicity: antibodies to infliximab in Remicade-treated patients with IBD similarly recognise the biosimilar Remsima. Gut 2016; 65:1132–1138.
6. Park W, Yoo DH, Jaworski J, et al. Comparable long-term efficacy, as assessed by patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference infliximab in patients with ankylosing spondylitis: 54-week results from the randomized, parallel-group PLANETAS study. Arthritis Res Ther 2016; 18:25.
7. Yoo DH, Prodanovic N, Jaworski J, et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis 2017; 76:355–363.
8. Radin M, Sciascia S, Roccatello D, et al. Infliximab biosimilars in the treatment of inflammatory bowel diseases: a systematic review. BioDrugs 2017; 31:37–49.
9. Peloquin JM, Goel G, Villablanca EJ, et al. Mechanisms of pediatric inflammatory bowel disease. Annu Rev Immunol 2016; 34:31–64.
10. Hämäläinen A, Sipponen T, Kolho KL. Serum infliximab concentrations in pediatric inflammatory bowel disease. Scand J Gastroenterol 2013; 48:35–41.
11. Hyams JS, Dubinsky MC, Baldassano RN, et al. Infliximab is not associated with increased risk of malignancy or hemophagocytic lymphohistiocytosis in pediatric patients with inflammatory bowel disease. Gastroenterol 2017; 152:1901–1914.
12. Cozijnsen MA, Van Pieterson M, Samsom JN, et al. Top-down Infliximab Study in Kids with Crohn's disease (TISKids): an international multicentre randomised controlled trial. BMJ Open Gastroenterol 2016; 3:e000123.
Copyright © 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition