Yingjie Liu
Keying Wang
Wenjiang WuA Commentary on
Anti-TNFα in inflammatory bowel disease: from originators to biosimilars
by Zeng Z, Lin H, Jiang M, Yuan J, Li X, Jia Y, Yang L, and Zhang H (2024). Front. Pharmacol. 15:1424606. doi: 10.3389/fphar.2024.1424606
Introduction
The review by Zeng et al. (2024) provides a timely synthesis of clinical and economic implications of TNFα biosimilars in inflammatory bowel disease (IBD). While the article addresses critical aspects of biosimilar adoption, several methodological and contextual limitations warrant clarification to enhance its academic rigor and relevance. This commentary highlights key concerns, proposes actionable revisions, and underscores the importance of addressing these gaps to solidify the article’s utility for clinicians and policymakers.
Literature currency and scope
Outdated references
The review cites cost-saving data from 2017 U.S. biologics expenditures (Kappelman et al., 2008), which fails to reflect recent market dynamics. Furthermore, the review’s overall assessment of the evidence landscape appears inadequately updated. Consider the systematic review by Martelli and Peyrin-Biroulet (2019), which synthesized the state of knowledge up to 2016. Martelli et al. concluded that while infliximab biosimilars showed promise in IBD, significant knowledge gaps regarding long-term safety, interchangeability, and real-world effectiveness in complex populations persisted, necessitating large post-marketing studies. A 2024 review has the responsibility to critically evaluate how these gaps identified in 2019 have been addressed by subsequent evidence (e.g., Schreiber et al., 2021; Kennedy et al., 2019 on long-term safety; NOR-SWITCH extension on interchangeability; IQVIA 2023 on market penetration and cost savings). Failing to incorporate and discuss these key post-2019 developments - particularly immunogenicity monitoring strategies validated in prospective cohorts (Kennedy et al., 2019) - significantly diminishes the review’s currency and utility for understanding the current biosimilar landscape in IBD.
Evidence imbalance
The authors heavily rely on rheumatoid arthritis (RA) studies (e.g., VOLTAIRE-CD) to support biosimilar efficacy, while IBD-specific long-term safety data remain underrepresented. For instance, CT-P13’s safety profile in IBD cohorts beyond 2 years is scarcely discussed, despite robust evidence demonstrating the impact of immunogenicity on long-term outcomes (Schreiber et al., 2021; Kennedy et al., 2019). Prioritizing IBD-centric studies would align the review’s scope with its clinical focus.
Data consistency and methodological gaps
Contradictory claims
The manuscript states both “low biosimilar uptake in the U.S.” and “substantial cost savings,” creating ambiguity. Clarifying temporal trends—such as the 44% U.S. infliximab biosimilar market penetration by 2023 (IQVIA Institute, 2023)—would reconcile these statements. Additionally, regional disparities in biosimilar adoption (e.g., Europe’s 88% uptake vs the U.S.’s delayed growth) merit exploration to avoid oversimplification.
Small sample bias
Conclusions drawn from underpowered studies (e.g., PF-06438179/GP1111, n = 10) lack statistical robustness. This concern regarding methodological rigor and statistical power in IBD biosimilar research is not new. As acknowledged in the Martelli and Peyrin-Biroulet (2019) systematic review, much of the early real-world evidence supporting biosimilars in IBD, upon which subsequent understanding was built, stemmed from observational studies with inherent limitations in size and design. Martelli et al.'s call for ‘large prospective post-marketing studies’ underscores the recognized need for more robust data. Therefore, Zeng et al.’s inclusion and interpretation of conclusions from very small studies like PF-06438179/GP1111, without explicitly emphasizing their preliminary nature and placing them in the context of this established need for larger trials (such as the NOR-SWITCH extension study, n = 380; Goll et al., 2019), weakens the review’s evidence synthesis. Highlighting confidence intervals and the limitations of small samples is crucial to avoid overinterpreting findings.
Underdeveloped discussions
Immunogenicity oversight
While the review acknowledges biosimilar immunogenicity, its clinical implications—such as antibody-guided dosing (Strand et al., 2020) or the impact of multiple switches—are underexplored. Martelli and Peyrin-Biroulet (2019) specifically identified immunogenicity as a key area requiring deeper understanding, noting that while early data suggested a ‘similar immunogenicity profile’ for CT-P13 compared to the originator, the clinical consequences of immunogenicity in real-world settings and during switching scenarios were still being actively investigated (e.g., the then-ongoing NOR-SWITCH trial). Given that immunogenicity directly impacts treatment efficacy - increasing failure risk by 3.1-fold as shown in IBD cohorts (Kennedy et al., 2019) - a more nuanced discussion in Zeng et al.'s review was warranted. They could have built upon the foundation laid by Martelli et al. by incorporating subsequent findings on immunogenicity monitoring strategies (e.g., trough levels, antibody testing), the implications for switching decisions, and data exploring potential differences arising from multiple switches, which remain critical concerns for clinicians managing IBD.
Policy solutions
The manuscript omits actionable strategies to overcome patent barriers and reimbursement challenges. Lessons from the EU’s compulsory licensing framework or the FDA’s interchangeable designation for BI 695501 (adalimumab biosimilar) could provide policymakers with tangible pathways to enhance biosimilar accessibility.
Terminology and presentation issues
Semantic precision
The conflation of “biosimilar” and “generic” in Section Contradictory claims misrepresents distinct regulatory pathways. Biosimilars require comparative clinical trials, whereas generics rely solely on bioequivalence. Correcting this misclassification is essential to avoid confusion.
Figure incompleteness
The TNFα signaling pathway described by Zeng et al. (2024) (Figure 1), requires primary source attribution, reducing reproducibility. The biosimilar approval process should align with World Health Organization (2022), which would improve clarity, particularly in delineating the abbreviated approval pathway for biosimilars versus originators.
Additional recommendations
Structural flow
Transitions between Sections Underdeveloped discussions (benefits) and Terminology and presentation issues (challenges) are abrupt. Integrating cost-saving data with discussions on policy barriers (e.g., rebate traps in the U.S.) would enhance narrative cohesion.
Future directions
The review overlooks precision medicine advancements, such as biomarkers for biosimilar switching (e.g., trough drug levels, fecal calprotectin). Incorporating these aligns the manuscript with the “treat-to-target” paradigm and addresses personalized therapeutic monitoring.
Discussion
Zeng et al.’s review lays a foundational understanding of anti-TNFα biosimilars in IBD but requires revisions to achieve its potential as a pivotal resource. Updating literature, harmonizing data, and deepening critical analysis—particularly regarding immunogenicity, policy, and precision medicine—are imperative. Addressing these concerns will not only bolster academic rigor but also empower clinicians and policymakers to navigate the evolving biosimilar landscape confidently.
Future iterations should emphasize real-world evidence, regional adoption disparities, and innovative regulatory strategies to reflect the dynamic interplay between biosimilar accessibility and healthcare sustainability. By doing so, the review can serve as a comprehensive guide for optimizing IBD management in an era of biologic competition.
Author contributions
YL: Methodology, Conceptualization, Writing – original draft, Supervision, Formal Analysis, Funding acquisition, Writing – review and editing. KW: Supervision, Conceptualization, Writing – review and editing. WW: Writing – review and editing, Supervision.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Goll, G. L., Jørgensen, K. K., Sexton, J., Olsen, I. C., Bolstad, N., Haavardsholm, E. A., et al. (2019). Long-term efficacy and safety of biosimilar infliximab (CT-P13) after switching from originator infliximab: open-label extension of the NOR-SWITCH trial. J. Intern. Med. 285 (6), 653–669. doi:10.1111/joim.12880
IQVIA Institute (2023). Biosimilars in the United States 2023-2027: competition, savings, and sustainability. Available online at: https://www.iqvia.com/insights/the-iqvia-institute/reports-and-publications/reports/biosimilars-in-the-united-states-2023-2027.
Kappelman, M. D., Rifas-Shiman, S. L., Porter, C. Q., Ollendorf, D. A., Sandler, R. S., Galanko, J. A., et al. (2008). Direct health care costs of crohn's disease and ulcerative colitis in US children and adults. Gastroenterology 135 (6), 1907–1913. doi:10.1053/j.gastro.2008.09.012
Kennedy, N. A., Heap, G. A., Green, H. D., Hamilton, B., Bewshea, C., Walker, G. J., et al. (2019). Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal crohn's disease: a prospective, multicentre, cohort study. Lancet Gastroenterology and Hepatology 4 (5), 341–353. doi:10.1016/S2468-1253(19)30012-3
Martelli, L., and Peyrin-Biroulet, L. (2019). Efficacy, safety and immunogenicity of biosimilars in inflammatory bowel diseases: a systematic review. Curr. Med. Chem. 26 (2), 270–279. doi:10.2174/0929867323666161014153346
Schreiber, S., Ben-Horin, S., Leszczyszyn, J., Dudkowiak, R., Lahat, A., Gawdis-Wojnarska, B., et al. (2021). Randomized controlled trial: subcutaneous vs intravenous infliximab CT-P13 maintenance in inflammatory bowel disease. Gastroenterology 160 (7), 2340–2353. doi:10.1053/j.gastro.2021.02.068
Strand, V., Goncalves, J., Hickling, T. P., Jones, H. E., Marshall, L., and Isaacs, J. D. (2020). Immunogenicity of biosimilars for rheumatic diseases, plaque psoriasis, and inflammatory bowel disease: a review from clinical trials and regulatory documents. BioDrugs 34 (1), 27–37. doi:10.1007/s40259-019-00394-x
World Health Organization (2022). Guidelines on evaluation of biosimilars. Available online at: https://www.who.int/publications/m/item/guidelines-on-evaluation-of-biosimilars.
Keywords: IBS, inflammatory bowel disease, anti-TNFα, originators, biosimilars
Citation: Liu Y, Wang K and Wu W (2025) Commentary: Anti-TNFα in inflammatory bowel disease: from originators to biosimilars. Front. Pharmacol. 16:1625961. doi: 10.3389/fphar.2025.1625961
Received: 12 May 2025; Accepted: 16 June 2025;
Published: 07 July 2025.
Edited by:
Ralf Weiskirchen, RWTH Aachen University, GermanyReviewed by:
Manish Manrai, Armed Forces Medical College, Pune, IndiaGian Marco Leone, University of Catania, Italy
Aditya Pachisia, Command hospital, India
Copyright © 2025 Liu, Wang and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Wenjiang Wu, MTA1MzY2MDY0NUBxcS5jb20=