The PROSIT Cohort of Infliximab Biosimilar in IBD: A Prolonged Follow-up on the Effectiveness and Safety Across Italy
Abstract
Background
This comprehensive report details a prospective, nationwide cohort study specifically designed to evaluate the safety profile and therapeutic effectiveness of CT-P13, a biosimilar form of infliximab, in patients diagnosed with inflammatory bowel disease. The ongoing management of inflammatory bowel disease, encompassing conditions such as Crohn’s disease and ulcerative colitis, often relies on advanced biologic therapies, with anti-tumor necrosis factor alpha (anti-TNFα) agents like infliximab playing a pivotal role. As biosimilars enter the market, it becomes paramount to rigorously assess their real-world performance, moving beyond the controlled environment of initial clinical trials. This study aimed to gather extensive data on CT-P13 across a broad and diverse patient population, thereby providing crucial insights into its long-term safety and efficacy in routine clinical practice across the nation.
Methods
The methodology employed in this study involved the systematic collection of patient data using a meticulously structured database. This approach was vital for ensuring the consistency and integrity of the information gathered throughout the prospective follow-up period. Key parameters meticulously recorded included the occurrence of any serious adverse events, which are critical indicators of drug safety. Furthermore, the clinical response and attainment of remission were comprehensively evaluated, utilizing established criteria to gauge therapeutic effectiveness. To provide objective measures of disease activity and inflammation, specific inflammatory biomarkers, namely C-reactive protein (CRP) and fecal calprotectin, were regularly monitored and documented. Additionally, endoscopic findings were incorporated into the data collection, offering a direct visual assessment of mucosal healing and disease severity, which is considered a gold standard in inflammatory bowel disease management. This comprehensive data capture strategy allowed for a thorough and multifaceted evaluation of CT-P13′s performance.
Results
A substantial cohort of 810 patients suffering from inflammatory bowel disease was enrolled in this study, reflecting a significant representation of the patient population. Among these, 452 individuals had a diagnosis of Crohn’s disease, with the remaining patients diagnosed with ulcerative colitis. To gain a nuanced understanding of CT-P13′s efficacy and safety across various clinical scenarios, the cohort was strategically stratified into three distinct groups based on their prior exposure to anti-TNFα therapy. Group A comprised 459 patients who were entirely naive to anti-TNFα agents, receiving CT-P13 as their initial biologic treatment. Group B consisted of 196 patients who had previous exposure to an anti-TNFα therapy but were not actively switching from an originator biologic to CT-P13 at the time of enrollment. The final group, Group C, included 155 patients who were specifically switched from an originator infliximab product to CT-P13.
All enrolled patients were systematically included in the comprehensive safety evaluation, which spanned an impressive mean follow-up period of 345 days, with a standard deviation of 215 days, accumulating a remarkable total of 6501 individual infusions of the biosimilar. During this extensive monitoring period, 154 serious adverse events were reported, accounting for 19% of the patient cohort. These events necessitated the cessation of CT-P13 in 103 subjects, representing 12.7% of the total enrolled patients. Infusion reactions, a recognized potential side effect of biologic therapies, were observed in 71 patients. These reactions led to the discontinuation of the biosimilar in 53 individuals, equating to 6.5% of the total cohort. A noteworthy finding regarding infusion reactions was their statistically significant higher frequency in patients who had prior exposure to anti-TNFα agents (P = 0.017), suggesting a potential heightened sensitivity in this subgroup.
The efficacy of CT-P13 therapy was rigorously assessed in 754 of the inflammatory bowel disease patients, with a mean follow-up duration of 329 days, with a standard deviation of 202 days. Analysis revealed that 48 patients experienced primary failure, meaning they did not achieve an initial response to the treatment, representing 6.4% of the efficacy cohort. Furthermore, 188 patients, or 25.6%, experienced a loss of response during the follow-up period, indicating a secondary failure after an initial benefit. Patient retention for efficacy assessment remained substantial over time; 628 patients, including 364 with Crohn’s disease, completed their follow-up at the 6-month mark. By the 12-month endpoint, 360 inflammatory bowel disease patients, among whom 222 had Crohn’s disease, successfully completed the stipulated follow-up. At this 12-month juncture, the proportion of patients who maintained their response without experiencing a loss of efficacy varied across the groups: 71% in Group A (anti-TNFα naive), 64% in Group B (previously exposed), and a notable 82% in Group C (switched patients). The statistically significant difference observed among these groups (log rank P = 0.01) highlights the differential long-term effectiveness of CT-P13 based on prior anti-TNFα exposure and switching status. Beyond clinical response, objective measures of disease activity also showed significant improvements. Clinical and endoscopic scores demonstrated a marked reduction in both Crohn’s disease and ulcerative colitis patients when compared to baseline measurements (P = 0.01). Similarly, inflammatory biomarkers, including CRP and calprotectin, exhibited highly significant decreases from baseline levels (P < 0.0001) in both patient populations, underscoring the profound anti-inflammatory effect of the biosimilar.
Conclusions
The findings from this extensive prospective nationwide cohort study provide robust evidence regarding the performance of CT-P13 in the real-world management of inflammatory bowel disease. Crucially, the data did not reveal any novel or concerning signals regarding differences in either the safety profile or the overall effectiveness of CT-P13 compared to what is already known for infliximab. This reinforces the existing body of evidence supporting the use of CT-P13. The large patient numbers, the prospective design, and the long follow-up period lend significant credibility to these conclusions, offering further reassurance to clinicians and patients about its use across various patient populations, including those new to biologic therapy, those with prior anti-TNFα exposure, and those successfully switched from the originator biologic.
Keywords: CT-P13; Crohn’s disease; Inflectra; Infliximab; Remsima; biosimilar; inflammatory bowel disease; ulcerative colitis.
Introduction
The therapeutic landscape for inflammatory bowel disease, which encompasses the chronic and debilitating conditions of Crohn's disease and ulcerative colitis, underwent a profound transformation with the advent of biologic therapies. This class of medication represented a significant breakthrough, offering new hope and improved outcomes for patients who previously had limited effective treatment options. Infliximab, marketed under the brand name Remicade by Janssen, received its initial approval in 1998, marking the beginning of a new era in managing these complex autoimmune disorders. As an anti-tumor necrosis factor alpha (anti-TNFα) monoclonal antibody, infliximab, along with subsequent agents in this class, has consistently demonstrated remarkable potency. These therapies have been instrumental in inducing deep mucosal healing, a critical goal in IBD management, which translates into prolonged periods of disease remission. Beyond symptom control, their use has also been associated with a significant reduction in the incidence of hospitalizations and the necessity for surgical interventions, thereby greatly enhancing the quality of life for countless individuals.
Despite their undeniable clinical benefits, anti-TNFα agents are inherently complex and costly to manufacture, leading to high prices that have, in turn, placed a substantial financial burden on healthcare systems and national pharmacy budgets in many countries. This economic strain has unfortunately led to situations where access to these life-changing treatments may be restricted for a considerable number of patients, particularly in regions with limited healthcare resources. However, the impending or actual expiration of patents for originator biologic products, including infliximab, in major markets such as the European Union and the United States, has paved the way for a transformative development: the emergence of biosimilar therapies. Biosimilars are highly similar versions of already approved biological medicines, designed to provide comparable efficacy, safety, and quality at a potentially lower cost, thereby fostering increased access and competition within the pharmaceutical market.
Among the pioneering biosimilars, CT-P13, developed by Celltrion, Inc., based in Incheon, Republic of Korea, stands out as the first monoclonal antibody biosimilar of infliximab to undergo rigorous evaluation and subsequently receive approval from both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). The comprehensive program designed to demonstrate its biosimilarity was multifaceted and meticulously structured. It initially involved a phase 1 pharmacokinetic study conducted in patients with ankylosing spondylitis, which focused on establishing equivalent drug exposure and disposition in the body. Concurrently, a pivotal phase 3 study was undertaken to evaluate the clinical efficacy of CT-P13 in patients suffering from rheumatoid arthritis. Both of these foundational studies were characterized by their robust design, being randomized, double-blinded, and multinational trials, providing valuable data from up to 30 weeks of treatment. Building upon these initial successes, subsequent investigations extended the follow-up period to 54 weeks, and an additional open-label 48-week extension phase was conducted, during which patients initially receiving the reference infliximab were systematically switched to CT-P13. Cumulatively, these studies definitively demonstrated both pharmacokinetic equivalence and comparable clinical efficacy of CT-P13 to its originator in patients with ankylosing spondylitis and rheumatoid arthritis for periods extending up to 102 weeks, as well as in those who underwent a switch from reference infliximab. Importantly, the development of antidrug antibodies, a critical aspect of immunogenicity that can impact treatment effectiveness, was found to be similar between CT-P13 and the originator infliximab across both trials, providing further reassurance regarding its immunological profile.
The approval of CT-P13 by the EMA in 2013 represented a significant milestone. This decision was based not only on the compelling clinical trial data but also on extensive *in vitro* product characterization and a thorough comparability exercise. Notably, CT-P13 was approved not just for rheumatoid arthritis and ankylosing spondylitis but broadly across all indications for which the originator infliximab was licensed. This included adult and pediatric Crohn's disease and ulcerative colitis, psoriatic arthritis, and psoriasis, underscoring the regulatory authorities' confidence in its interchangeable use across a wide range of immune-mediated inflammatory conditions. Following this pivotal EMA approval, CT-P13 subsequently obtained licenses for all these indications in other major global markets, including South Korea, Japan, the United States, and Canada, further solidifying its global presence and availability.
The widespread introduction of biosimilars has undoubtedly yielded positive repercussions for healthcare systems, most notably by reducing the financial strain associated with costly biologic therapies and stimulating healthy competition within the pharmaceutical sector. This competition has a direct beneficial impact by enabling more patients to gain access to essential treatments that might have been otherwise cost-prohibitive. However, despite the rigorous regulatory scrutiny and positive clinical data in rheumatologic indications, there was an understandable initial period of apprehension and a lack of extensive real-world experience and confidence among clinicians regarding the use of biosimilar infliximab specifically in inflammatory bowel disease. This caution stemmed from several factors. Primarily, there was a perceived paucity of dedicated clinical studies specifically conducted in IBD patient cohorts, which led to questions about the direct applicability of data from rheumatologic diseases. Furthermore, concerns were raised about potential subtle differences in the downstream effects of the mechanism of action or variations in immunogenicity of infliximab in IBD patients compared with those with rheumatologic conditions. For instance, it is understood that while infliximab in rheumatoid arthritis is thought to act predominantly through the direct neutralization of both soluble and transmembrane forms of TNFα, its mechanism in Crohn's disease is believed to involve a more prominent role for signaling through membrane-associated forms of TNFα and the Fcγ receptor, implying potentially distinct immunological interactions in the gut.
Prior to the current study, most of the available information regarding the efficacy and safety of CT-P13 in IBD patients—whether they were naive to anti-TNFα therapy or had transitioned from originator infliximab—was largely confined to studies characterized by relatively small sample sizes and limited follow-up durations. This limitation was critically highlighted in a comprehensive review by Komaki Y et al in 2017. A significant development addressing some of these gaps was the publication of a single randomized controlled non-inferiority, double-blinded, phase 4 trial, registered as NCT02148640, with a substantial 52-week follow-up period. This trial enrolled adult patients who were on stable treatment with originator infliximab for at least six months for various immune-mediated diseases and were managed in a hospital setting. A total of 482 patients were enrolled and randomized equally, with 241 assigned to continue on infliximab originator and 241 to switch to CT-P13. Importantly for the IBD community, this cohort included a notable number of patients with Crohn's disease (155) and ulcerative colitis (93). The findings from this pivotal trial provided crucial real-world evidence, demonstrating that following a switch to the biosimilar, the frequency of serious adverse events (10% in the originator group versus 9% in the CT-P13 group) and the rate of disease worsening (26% versus 30%, respectively) were strikingly similar between the two groups, further bolstering confidence in the biosimilar.
In February 2015, the patent for infliximab officially expired in Italy, leading to the market availability of two distinct CT-P13 formulations: REMSIMA, distributed by Celltrion Healthcare Hungary Kft., and INFLECTRA, marketed by Hospira, UK Limited. Capitalizing on this significant regulatory and market shift, a prospective, nationwide, observational study was meticulously planned in Italy. The overarching objective of this extensive investigation was to comprehensively evaluate the real-world effectiveness, safety profile, and immunogenicity of CT-P13 in patients diagnosed with inflammatory bowel disease. The study was designed to assess the biosimilar’s performance in both the induction and maintenance phases of remission, and critically, to do so across a diverse patient population, encompassing individuals who were entirely naive to anti-TNFα therapy, those who had previous exposure to anti-TNFα agents, and those who had been successfully switched from originator infliximab. Preliminary data from an earlier phase of this cohort, involving 547 patients with a mean follow-up of 4.3 months, had been published previously. The current report represents a substantial expansion of that original cohort, now including a considerably larger number of patients (n = 810), with an extended mean follow-up duration of one year. More importantly, this updated analysis integrates crucial data pertaining to modifications in endoscopic activity and inflammatory biomarkers, providing a more objective and in-depth assessment of the therapeutic impact of CT-P13.
Methods
Study Population and Data Collection
The study design focused on the prospective enrollment of consecutive patients diagnosed with inflammatory bowel disease who initiated treatment with CT-P13. Recruitment for this large-scale observational study took place across 30 specialized centers throughout Italy, comprising 12 academic institutions and 18 tertiary referral centers, from April 2015 to August 2017. Eligibility criteria mandated that all patients had received a definitive diagnosis of either ulcerative colitis or Crohn's disease, established through a rigorous combination of clinical assessment, radiological imaging, endoscopic evaluation, and histological confirmation, adhering to widely accepted international diagnostic guidelines. To ensure patient privacy and data integrity, all collected clinical information was meticulously anonymized before being organized and stored within a highly structured database, which facilitated comprehensive tracking throughout the entire follow-up period. The study protocol underwent thorough review and received ethical approval from the institutional review board of each participating center, further demonstrating adherence to ethical research standards, and was officially registered under the EUDRACT identifier 2015-005254-35.
For each individual patient enrolled in the study, a comprehensive array of clinical characteristics was systematically collected. This included fundamental demographic information such as gender and age at the time of diagnosis, as well as the specific type of inflammatory bowel disease diagnosed. Detailed treatment-specific data were also gathered, including the patient’s age at the initiation of CT-P13 therapy, the commercial name and specific batch number of the CT-P13 administered, and whether the biosimilar was used as part of a combination therapy regimen with other immunosuppressants. The primary indication for initiating CT-P13 therapy was recorded, along with a thorough history of any previous anti-TNFα therapies, including the name of the prior drug, its duration of use, and the observed clinical outcomes. The duration of follow-up while on CT-P13 and the total number of infusions received were also documented to provide a measure of treatment exposure. Furthermore, detailed evaluations of therapeutic efficacy were performed, noting the reason for any eventual withdrawal from the biosimilar. Information on any co-occurring immune-mediated associated diseases was collected, as these can influence treatment response and safety. Crucially, the number and specific details of any serious adverse events that occurred during the follow-up period were meticulously recorded, along with the date of the last follow-up and any instances of surgical procedures undergone by the patient.
To objectively assess disease activity and response to treatment, standardized clinical and endoscopic scoring systems were employed. For patients with ulcerative colitis, the Mayo score, specifically the partial Mayo score, was utilized for both clinical and endoscopic evaluation. In individuals with Crohn's disease, the Harvey-Bradshaw Index (HBI) was used for clinical assessment, while the Simple Endoscopic Score for Crohn's Disease (SES-CD) and the Rutgeerts score were applied for endoscopic evaluation, providing a visual and quantifiable measure of mucosal inflammation and postoperative recurrence, respectively. Beyond these scoring systems, specific treatment outcomes such as the rate of primary failure, the incidence of loss of response, and the necessity for dose escalation were also systematically recorded according to predefined criteria. In line with each participating site's routine clinical practice, biological samples were periodically collected to measure C-reactive protein (CRP) and fecal calprotectin (FC), both well-established inflammatory biomarkers. Additionally, where feasible, drug trough levels and the presence of antidrug antibodies were assessed to gain insights into drug pharmacokinetics and potential immunogenicity.
Outcome Measures
The overarching aim of this study was clearly defined through its primary and secondary endpoints. The primary endpoint focused intently on the rigorous evaluation of safety, specifically quantifying the rate of serious adverse events (SAEs) observed throughout the entire follow-up period. This emphasis reflects the paramount importance of patient safety in the context of new therapeutic agents.
Secondary endpoints were designed to provide a comprehensive assessment of CT-P13's performance beyond just safety. These included: a) the detailed evaluation of effectiveness, which encompassed both the achievement of clinical remission and clinical response, as well as the crucial metric of treatment persistency over time; b) the quantification of changes in objective disease activity parameters, specifically the alteration of clinical scores such as the Harvey-Bradshaw Index and Mayo Score, endoscopic scores like SES-CD and Rutgeert’s score, and key inflammatory biomarkers including C-reactive protein and fecal calprotectin from baseline values; c) a thorough assessment of immunogenicity, which involved recording the occurrence of infusion reactions and identifying instances of loss of response, both of which can be influenced by the body's immune reaction to the drug; and d) the identification of any predictive factors that might influence either the safety profile or the therapeutic efficacy of CT-P13 in the studied population.
To ensure consistent and accurate reporting, precise definitions were established for key outcome measures. Serious adverse events were broadly defined to encompass a range of severe clinical occurrences, including death, any life-threatening adverse event, the necessity for inpatient hospitalization, the prolongation of an existing hospitalization, the development of a persistent or significant incapacity or a substantial disruption to the patient's ability to conduct normal life functions. Additionally, any medical condition that, in appropriate medical judgment, might jeopardize the patient or necessitate medical or surgical intervention, including the pivotal decision to withdraw the ongoing CT-P13 therapy, was classified as a serious adverse event.
Clinical remission was specifically defined for each disease. For ulcerative colitis, it was characterized by a partial Mayo score of less than 2, with no individual partial score exceeding 1, and crucially, the absence of rectal bleeding, signifying quiescent disease activity. For Crohn's disease, clinical remission was defined as a Harvey-Bradshaw Index score of 4 or less, indicating minimal or no symptoms. Clinical response, denoting a significant improvement without necessarily achieving full remission, was defined as a 30% reduction and a decrease of at least 3 points in the partial Mayo score for ulcerative colitis, and a reduction of at least 3 points in the Harvey-Bradshaw Index for Crohn's disease. Endoscopic remission, a more objective and stringent measure of disease control, was defined as an endoscopic Mayo score of 0 for ulcerative colitis, an SES-CD score of less than 4 for Crohn's disease, and a Rutgeerts score of ir2 or less for postoperative Crohn's disease, all indicative of mucosal healing or very mild recurrence.
Primary failure of CT-P13 was explicitly defined as the absence of any clinical response, or only a minor and insufficient clinical response, observed within 8 weeks following the completion of the induction regimen. This also included any deterioration in the patient's clinical condition that directly led to surgical intervention, an early change in therapy, or the withdrawal of CT-P13. In contrast, loss of response was defined as a clinical situation where a patient initially demonstrated a positive response to CT-P13 therapy but subsequently experienced a diminished or less durable therapeutic effect over time. This decline in effectiveness ultimately led to a decision, based on the investigator's clinical judgment, to either discontinue the drug or implement a dose escalation strategy to regain disease control. Dose escalation, when deemed necessary, was performed either by increasing the dosage of CT-P13 to 10 mg/Kg or by reducing the interval between infusions to every 4–6 weeks, depending on the investigator's clinical preference and the patient's specific needs.
Statistical Analysis
The statistical approach for analyzing the extensive dataset collected in this study commenced with descriptive statistics, presenting baseline patient characteristics as means accompanied by their standard deviations, medians with interquartile ranges, or as percentages, as appropriate for the nature of the data. Given that most of the variables collected were found not to follow a normal distribution, non-parametric statistical tests were chosen for data analysis. Specifically, the chi-squared test was employed for categorical variables to assess associations, while the Kruskal-Wallis rank test was utilized for comparing equality of populations across more than two independent groups with non-normally distributed continuous data.
The assessment of primary failure to CT-P13 was conducted specifically among patients who had completed a minimum treatment and follow-up duration of 8 weeks, ensuring a standardized initial observation period. Subsequently, the phenomenon of loss of response was meticulously investigated among those patients who were deemed responders at week 8. This analysis utilized time-to-event methods, which are particularly well-suited for handling censored observations. Patients who were withdrawn from the study due to the occurrence of adverse events, or those who had not yet experienced a loss of response by the final data collection date, were carefully considered as "censored" observations in the time-to-event analysis, meaning their full event time was not observed. Conversely, for the purpose of this specific analysis, patients for whom the treatment dose was optimized through escalation were also considered to have experienced a loss of response, as this intervention indicates a diminished prior efficacy. The time to an event (either loss of response or censoring) was precisely defined as the duration from week 8 until the date of the event or the date of censoring. Kaplan-Meier estimates were generated to construct cumulative incidence curves, providing a visual representation of the proportion of patients remaining free from loss of response over time. These curves were then compared statistically using the log-rank test, and Hazard Ratios (HR) were derived from Cox proportional hazards analysis to quantify the relative risk of loss of response across different patient groups or strata, while adjusting for potential confounding factors. In an alternative and complementary analytical approach, the study also meticulously analyzed overall treatment persistency. This alternative metric took into account those patients for whom the treatment dose had been optimized, yet they successfully remained on CT-P13 treatment, providing a broader perspective on long-term drug retention in real-world clinical practice. For all statistical tests performed, a P-value of less than 0.05 was predetermined as the threshold for statistical significance, indicating a low probability that the observed results occurred by chance. All statistical tests conducted were two-sided, reflecting the absence of a preconceived direction for the observed effects. The entirety of the statistical analyses was performed using Stata software, produced by Stata Corp., College Station, TX, USA, a robust and widely recognized statistical package.
Results
The comprehensive clinical characteristics of the study cohort are presented in detail. The total study population comprised 810 patients, with a distribution of 452 individuals diagnosed with Crohn's disease and 358 with ulcerative colitis. To facilitate a nuanced analysis of CT-P13's performance across varied patient histories, the cohort was systematically divided into three distinct groups. Group A consisted of 459 patients who were entirely naive to any anti-TNFα therapy. Group B included 196 patients who had a history of prior exposure to one or more anti-TNFα agents. Specifically, within this group, 36 patients had previously received infliximab, 124 had been treated with adalimumab, 27 with golimumab, and 9 patients had received two different anti-TNFα drugs. It is important to note that anti-TNFα agents in Group B were discontinued for reasons other than intolerance, ranging from 4 to 24 months before the initiation of CT-P13. The remaining 155 patients formed Group C, which comprised individuals who were specifically switched from originator infliximab to CT-P13, having previously received a mean of 17 infusions of infliximab, with a range spanning from 2 to 72 infusions.
Statistical comparisons between these three groups revealed several significant differences. The groups exhibited variations in the prevalence of Crohn's disease versus ulcerative colitis, average age at diagnosis, frequency of concomitant therapy (typically with thiopurines), and the use of steroids at baseline. Additionally, the average duration of follow-up differed across the groups. However, there were no statistically significant differences observed regarding the overall duration of the disease, gender distribution, or smoking status among the three cohorts, ensuring comparability on these fundamental patient attributes. Notably, the study also included a pediatric sub-cohort of 51 patients, 31 of whom had Crohn's disease. Among these pediatric patients, 27 were naive to anti-TNFα therapy, while the remainder were switched from originator infliximab, adding an important dimension to the study's findings on a younger population.
Safety
Regarding drug administration, 290 patients received Inflectra, while the remaining 520 patients were administered Remsima. Cumulatively, this amounted to a substantial 6,501 infusions of CT-P13 across the entire cohort. The mean follow-up duration for safety evaluation was 344.7 days, with a standard deviation of 215.6 days, translating to a median follow-up of 327 days and an interquartile range of 161 to 530 days. This extensive observation period totaled 764 patient-years of exposure to the biosimilar, providing robust data for safety assessment.
Any Serious Adverse Events
Serious adverse events, encompassing all types of severe clinical occurrences including infusion reactions, were reported in a total of 154 patients across the entire cohort, representing an overall incidence of 19%. When stratified by group, these events occurred in 79 of 459 patients (17%) in Group A (naive patients), 57 of 196 patients (29%) in Group B (previously exposed patients), and 18 of 155 patients (11.6%) in Group C (switched patients). A detailed breakdown of the types of serious adverse events is provided. Specifically, the most frequently reported serious infections included pneumonitis, observed in 4 cases, and herpes zoster, reported in 3 cases. When considering the incidence rates adjusted for exposure time, the rates were 74, 48.5, and 18.5 per 100 person-years for Groups A, B, and C, respectively. Further analysis, expressed as relative risk, indicated that serious adverse events in patients with prior anti-TNFα exposure (Group B) were twice as frequent as in naive patients (Group A) and 2.5 times more frequent than in patients who switched from infliximab (Group C). Both of these comparisons yielded statistically significant differences, highlighting a notably higher risk of serious adverse events in the previously exposed cohort.
Any Serious Adverse Events (Excluding Infusion Reactions)
When serious adverse events were analyzed separately, excluding infusion reactions, they were observed in 45 of 459 patients (9.8%) in Group A, 31 of 196 patients (15.8%) in Group B, and 18 of 155 patients (11.6%) in Group C. The corresponding incidence rates were 42, 26.4, and 19 per 100 person-years for Groups A, B, and C, respectively. The relative risk of experiencing these non-infusion-related serious adverse events was significantly higher in Group B compared to Group A (P = 0.03) and Group C (P = 0.0019), further underscoring the increased safety risk in the previously exposed cohort. The most frequently reported non-infusion related serious adverse events were diverse skin reactions. Crucially, no deaths, new cancer diagnoses, or other unexpected serious adverse events were reported during the study period, providing reassurance regarding the safety profile.
Infusion Reactions
Infusion reactions, specifically, occurred in 34 of 459 patients (7.4%) in Group A, 26 of 196 patients (13.2%) in Group B, and 11 of 155 patients (7.1%) in Group C. The corresponding incidence rates per 100 person-years were 31.8 for Group A, 22.5 for Group B, and 11.8 for Group C. A more in-depth analysis revealed that infusion reactions were twice as frequent in patients with previous anti-TNFα exposure (Group B) compared to both naive patients (Group A) and patients who switched (Group C). However, only the comparison between Group B and Group A demonstrated statistical significance (P = 0.017). A detailed examination within Group B further elucidated this finding: among the 45 patients previously exposed to infliximab, 11 (24.4%) experienced infusion reactions. In contrast, among the 151 patients previously exposed to other anti-TNFα agents, 15 (9.9%) reported infusion reactions. This yielded a significant relative risk of 2.24 (95% CI, 1.21–4.97, P = 0.012) for infusion reactions in those previously exposed to infliximab compared to other anti-TNFα agents, suggesting a specific predisposition for reactions in this subgroup.
Serious Adverse Events Leading to Discontinuation (Excluding Infusion Reactions)
Serious adverse events, exclusive of infusion reactions, that led to the discontinuation of CT-P13 were observed in 30 of 459 patients (6.5%) in Group A, 14 of 196 patients (7.1%) in Group B, and 6 of 155 patients (3.9%) in Group C. No statistically significant differences were found among the three groups concerning these discontinuation rates. The most common reasons for discontinuation due to non-infusion related serious adverse events included skin lesions (16 cases), serious infections (11 cases), immunological problems (7 cases), severe arthralgia (6 cases), surgery for perianal fistula (4 cases), transient ischemic attack (2 cases), headache (1 case), alterations in liver function tests (2 cases), and lack of adequate venous access (1 case).
Infusion Reactions Leading to Discontinuation
Infusion reactions specifically leading to the discontinuation of CT-P13 occurred in 28 of 459 patients (6.1%) in Group A, 21 of 196 patients (10.7%) in Group B, and 4 of 155 patients (2.6%) in Group C. The relative risk ratios for discontinuation due to infusion reactions were significantly higher in patients with prior anti-TNFα exposure (Group B) compared to naive patients (Group A) and switched patients (Group C). Specifically, these discontinuations were twice as frequent as in naive patients (P = 0.04) and four times as frequent as in patients who switched (P = 0.0078), with both comparisons being statistically significant. Within Group B, the rate of discontinuation due to infusion reactions was significantly higher in patients previously exposed to infliximab (20%) compared to those exposed to other anti-TNFα agents (8%), yielding a relative risk of 2.5 (95% CI, 1.13–5.58, P = 0.023).
It is also noteworthy that by the end of the follow-up period (August 2017), surgical intervention, specifically colectomy for 34 ulcerative colitis patients or intestinal resection for 44 Crohn's disease patients, was either performed or planned in a total of 78 patients. Of these, 49 patients were naive to anti-TNFα (Group A), 18 had prior anti-TNF exposure (Group B), and the remaining 11 patients, predominantly those with Crohn's disease (10 patients), were from Group C, having been switched to CT-P13 after a mean of 36 months of originator infliximab therapy (ranging from 8 to 66 months) and 13.8 months of biosimilar therapy (ranging from 5 to 24 months). The overall rates of surgery were 10.6% for Group A, 9.3% for Group B, and 7.1% for Group C, with no statistically significant difference observed among the three groups.
Effectiveness
For the evaluation of effectiveness, 754 patients had either completed the minimum treatment and follow-up time of 8 weeks or had experienced failure prior to that point. This cohort included 433 patients from Group A, 170 from Group B, and 151 from Group C. Among these patients, primary failure, defined as no or minor clinical response at 8 weeks, was observed in 48 individuals, representing an overall rate of 6.4% (95% CI, 5.7–11.0). When examined by group, the primary failure rate was 7.4% in Group A (95% CI: 5.2%–10.2%), 7.6% in Group B (95% CI: 4.5%–12.6%), and a remarkably lower 2% in Group C (95% CI: 0.7%–5.7%). A statistically significant difference was found in primary failure rates among the groups (P = 0.047), with Group C demonstrating superior initial response.
Following the assessment of primary failure, the study investigated the rate of loss of response among the 722 patients who had achieved initial response at week 8. During the subsequent follow-up period, 188 patients, or 25.6% of this responder cohort, experienced a loss of response. The total time at risk for loss of response, from week 8 onwards, was approximately 609 patient-years, averaging 315 days per patient. Kaplan-Meier estimates illustrating the probability of maintaining response throughout the follow-up period revealed a significant difference among the three groups (log-rank test, P = 0.01). Specifically, patients in Group C demonstrated significantly better long-term response persistence compared to both Group A (P = 0.006) and Group B (P = 0.004). However, it is important to contextualize this finding by acknowledging that most patients in Group C were already in remission at the time of switching to the biosimilar and were more frequently on combination therapy compared to the naive group (31% vs 21%, P < 0.001), factors that could influence their sustained response. Detailed Kaplan-Meier estimates, including 95% confidence intervals, for the probability of response at various predetermined time-points are provided.
In an alternative analytical approach, the study also evaluated treatment persistency among the 722 week-8 responders, taking into account instances of dose intensification that allowed patients to remain on CT-P13. During the follow-up, treatment was ultimately withdrawn in 78 patients (10.5%), while dose intensification was implemented in 203 additional patients (27.5%) to maintain efficacy. Kaplan-Meier estimates for the probability of treatment persistency were also calculated. In this broader evaluation of persistency, which includes dose optimization, the difference among the subgroups was not found to be statistically significant (log-rank test, P = 0.25), suggesting that while some patients required dose adjustments, many were able to continue CT-P13 therapy successfully.
Clinical Scores
Clinical scores were rigorously tracked at baseline, 6 months, and 12 months, providing a longitudinal assessment of disease activity. For ulcerative colitis patients, 358 individuals were assessed at baseline, 264 at 6 months, and 138 at 12 months. Further, 70 and 8 patients remained available for evaluation up to 18 and 24 months, respectively, extending the long-term data. For Crohn's disease patients, 452 were evaluated at baseline, 364 at 6 months, and 222 at 12 months. Additionally, 124 and 18 patients reached follow-up at 18 and 24 months, respectively.
Across the entire cohort, both the Mayo score for ulcerative colitis and the Harvey-Bradshaw Index for Crohn's disease demonstrated a statistically significant decrease by month 6 (P < 0.0001), and these improvements were consistently maintained at month 12. This significant reduction in disease activity was observed not only in the anti-TNFα naive Group A and previously exposed Group B (P < 0.0001 for both) but also in Group C (P = 0.01 for Mayo score, P < 0.001 for HBI), despite patients in Group C often having lower baseline values due to being in remission at the start of biosimilar infusion.
Endoscopic Scores
Objective endoscopic evaluations were performed at baseline and at 12 months to assess mucosal healing. For ulcerative colitis, endoscopic data were available for 333 of 358 patients (93%) at baseline and 131 of 138 patients (95%) at 12 months. For Crohn's disease, endoscopic data were available for 343 of 452 patients (76%) at baseline and 135 of 222 patients (61%) at 12 months. Notably, in 43 Crohn's disease patients, CT-P13 therapy was specifically initiated for the management of post-surgical recurrence, with endoscopic activity evaluated using the Rutgeerts score. Both the Mayo endoscopic score for ulcerative colitis and the SES-CD for Crohn's disease demonstrated highly significant improvements at the 12-month evaluation (P < 0.0001), indicating substantial mucosal healing. When stratified by groups, a significant improvement was observed for Groups A and B (P = 0.002 for Mayo, P < 0.0001 for SES-CD). Furthermore, a discernible improvement was also calculated for Group C (Mayo: P = 0.01; SES-CD: P = 0.06), suggesting continued endoscopic benefit even in patients who were already in remission prior to the switch. The Rutgeerts score, which assesses post-surgical recurrence in Crohn's disease, also demonstrated a significant overall improvement in the entire cohort (P = 0.01), with a noticeable trend toward improvement across all subgroups.
Inflammatory Biomarkers
The measurement of inflammatory biomarkers provided additional objective evidence of treatment efficacy. C-reactive protein (CRP) evaluation was available for 805 patients at baseline, 620 patients at 6 months, and 355 patients at 12 months. Fecal calprotectin (FC) data, while crucial, were available for approximately 25% of the cases. Across the entire cohort, both CRP and fecal calprotectin levels were significantly reduced from baseline to both 6 and 12 months (ranging from P < 0.01 to P < 0.0001), demonstrating a robust anti-inflammatory effect of CT-P13.
Upon stratification by groups, in ulcerative colitis patients, a significant reduction in CRP was observed in Group A and Group B, indicating a robust response in these naive and previously exposed cohorts. However, in Group C (switched patients), there was no significant change in CRP compared to baseline, likely due to their already normalized or near-normal CRP levels at the time of switching. Similarly, in Crohn's disease patients, a significant reduction for CRP was found in Groups A and B, but not in Group C. Fecal calprotectin levels were also significantly reduced in both ulcerative colitis and Crohn's disease patients in Groups A and B, further confirming the anti-inflammatory effect. In Group C, while a numerical reduction in calprotectin was observed, it did not reach statistical significance, again likely attributable to lower baseline values in these patients already on stable treatment.
Deep Remission
Achieving deep remission, defined as a composite endpoint encompassing clinical remission, mucosal healing (as indicated by endoscopic scores), and normalization of inflammatory biomarkers, was a key outcome. At the conclusion of the follow-up, deep remission was achieved in 48 of 117 Crohn's disease patients (41%) and 35 of 141 ulcerative colitis patients (25%) for whom all necessary information was available. These figures highlight the significant proportion of patients achieving comprehensive disease control with CT-P13.
Steroid-Free Remission
At the commencement of biosimilar therapy, a notable proportion of patients were receiving concomitant steroid therapy: 167 of 358 ulcerative colitis patients (46.6%) and 112 of 452 Crohn's disease patients (24.8%). The use of steroids was particularly prevalent in Group A (190 patients) and Group B (68 patients), indicating the higher disease activity or the need for bridge therapy in these cohorts at baseline. By the last follow-up, the number of patients still on steroids had significantly decreased to 61 (17%) for ulcerative colitis patients and 45 (10%) for Crohn's disease patients. More importantly, when focusing solely on patients who had achieved clinical remission, a very low percentage remained on steroid therapy: only 5 of 231 (2.2%) Crohn's disease patients and 6 of 150 (4%) ulcerative colitis patients in clinical remission were still receiving steroids, demonstrating the steroid-sparing effect of CT-P13.
Multivariate Analysis
Multivariate analyses using Cox proportional hazards models were performed to identify significant prognostic factors for two key outcomes: loss of response to CT-P13 and the occurrence of serious adverse events. Regarding the risk of losing response, the analysis identified that patients in Group A (naive to anti-TNFα) and Group B (previously exposed to anti-TNFα) exhibited a significantly greater hazard ratio (P = 0.033 and P = 0.024, respectively) to lose response compared to Group C (switched patients). Similarly, ulcerative colitis patients were found to have a significantly higher hazard ratio for losing response (P = 0.028) compared to Crohn's disease patients. Conversely, patients who were no longer on steroid therapy at the last follow-up demonstrated a significantly lower hazard ratio for loss of response (P < 0.0001), indicating that achieving steroid-free remission is a strong positive prognostic indicator.
When evaluating risk factors for serious adverse events, patients in Group B (previously exposed to anti-TNFα) had a significantly higher hazard ratio for experiencing an SAE (P = 0.003). A similar trend, though not reaching full statistical significance, was also observed in Group A (P = 0.057). In contrast, the hazard ratio for SAEs was significantly lower in male patients compared to female patients (P = 0.001), and also significantly lower in patients who were off steroids at the last follow-up (P = 0.010), suggesting that gender and steroid-free status are important modulating factors for safety.
Cost Savings
A significant economic benefit of using CT-P13 was quantified by estimating the cost savings realized within this cohort. Based on an approximate average dosage of 350 mg of CT-P13 per infusion and considering a mean price reduction of 35% compared to the cost of the originator Remicade, the estimated annual cost savings for the entire study cohort exceeded 3.8 million Euros. This substantial financial advantage underscores the potential for biosimilars to alleviate healthcare budgetary pressures while maintaining high standards of patient care.
Discussion
This study represents a significant contribution to the growing body of knowledge surrounding the use of CT-P13, the first monoclonal antibody biosimilar approved for inflammatory bowel disease, specifically in a real-world clinical setting. We meticulously followed a substantial cohort of patients, capturing data under conditions reflective of daily practice. Our key findings underscore several critical aspects of CT-P13's performance. Firstly, the observed rate of serious adverse events, at 19%, and their overall characteristics are entirely consistent with what has been previously documented with the originator infliximab, suggesting a comparable safety profile. Secondly, the occurrence of infusion reactions and the rate of drug withdrawal specifically due to serious adverse events were 8.7% and 12.7%, respectively. Thirdly, a notable observation was that drug withdrawal attributed to infusion reactions occurred significantly more frequently in patients who had a history of prior exposure to anti-TNFα agents, especially those who had previously received infliximab. Fourthly, the overall effectiveness of CT-P13, whether for inducing or maintaining remission and response, was found to be high, with an estimated effectiveness at 12 months approximating 71% in patients naive to anti-TNFα and a robust 82% in patients who were switched from infliximab. Fifthly, the rates of primary failure (6.4%) and loss of response (25.6%) align well with historical data reported for the originator infliximab, indicating consistent therapeutic performance. Finally, a particularly reassuring finding for clinical practice is that patients who were switched to CT-P13 experienced either a lower or comparable incidence of serious adverse events and, importantly, a significantly lower rate of loss of response when compared to patients who were anti-TNFα naive or had previous exposure to other anti-TNFα agents.
The market introduction of monoclonal antibody biosimilars like CT-P13 signifies a pivotal moment, primarily driven by their profound pharmacoeconomic implications for healthcare systems globally. In the United States, the escalating prescription volumes of biologics have led to them accounting for a substantial 28% of all drug spending, with projections estimating global biologic sales to reach approximately $180 billion USD in 2017. A significant portion of these sales, nearly half, is expected to transition to biosimilar products as patents for 11 key biologics expire within the next five years. Biosimilars offer a crucial economic advantage due to their inherently lower development costs, as they do not necessitate the intensive and expensive clinical development process required for novel originator drugs. Additionally, their marketing costs are typically reduced. IMS Health, in its 2016 estimation, projected that the widespread adoption of biosimilars could generate remarkable savings for healthcare systems, potentially exceeding $56 billion USD in Europe and up to $112 billion USD in the United States over a five-year period. The impact is already evident in Europe, where anti-TNFα biosimilars now command a significant 72% market share, contributing to an overall increase in the volume of infliximab prescriptions (inclusive of both originator and biosimilar products) by approximately 20%. By substantially reducing the financial outlay associated with inflammatory bowel disease treatment, the availability and increased utilization of biosimilars hold immense potential to improve patient access to vital medication, a benefit that has already been demonstrated across several European nations.
A critical point of ongoing discussion and clinical consideration, however, revolves around the practice of extrapolating indications for biosimilars to all approved uses of the originator product, particularly in the absence of dedicated, extensive clinical trial data specifically within each of those extrapolated indications. This creates a dilemma for clinicians who are faced with adopting new biotechnological agents when comprehensive clinical information pertaining to their specific area of interest, such as inflammatory bowel disease, may appear limited. This situation is currently pertinent for CT-P13 and Flixabi in Italy for IBD, and it will undoubtedly become a recurring theme in the near future as more biosimilars of other infliximab and adalimumab products gain market approval.
Despite CT-P13's initial introduction in Korea in 2013, the clinical data on its safety and efficacy specifically within the inflammatory bowel disease population have remained relatively sparse. A recent systematic review and meta-analysis compiled data from only 11 observational series, encompassing a modest total of 829 patients. This review reported adverse event rates in naive patients to be 0.08 (95% CI, 0.02–0.26) for Crohn's disease and 0.08 (95% CI, 0.03–0.17) for ulcerative colitis. A slight numerical increase in adverse events was noted after switching (CD = 0.10 [95% CI, 0.02–0.31]; UC 0.22 [95% CI, 0.04–0.63]). The pooled rates for clinical response at 24–30 weeks were 0.77 (95% CI 0.62–0.86) for Crohn's disease and 0.77 (95% CI 0.67–0.85) for ulcerative colitis. For switched patients, the sustained clinical response rates at 48–63 weeks were 0.75 (95% CI, 0.44–0.92) and 0.83 (95% CI, 0.19–0.99). It is important to highlight that even the largest cohort included in that review comprised only 210 patients followed for 54 weeks. Since the publication of that review, several other substantial series, including our own, have emerged, significantly bolstering the available evidence base for CT-P13 in IBD.
The occurrence of serious adverse events in our study, at 19%, aligns consistently with previous experiences with both originator infliximab and CT-P13. Crucially, no unexpected safety signals were identified within the evaluated timeframe, although it is important to acknowledge that the median duration of treatment for any single patient in our cohort was approximately 11 months. A specific finding of note was that skin reactions constituted the most frequent type of serious adverse event, excluding infusion reactions, observed in 34 of 810 patients (4.2%), leading to drug withdrawal in 16 of these patients. More significantly, infusion reactions themselves were observed to be statistically more frequent in patients with prior anti-TNFα exposure (13.2%), representing a doubled relative risk when compared to anti-TNFα naive patients (P = 0.017) or those who had switched from infliximab (P = 0.06). Delving deeper into Group B, it was found that infusion reactions were more than twice as frequent in patients who had previously received infliximab specifically, compared to those exposed to other anti-TNFα agents. Correspondingly, infusion reactions leading to drug discontinuation were twice as frequent in naive patients and four times as frequent in switched patients, with a statistically significant higher rate in patients previously exposed to infliximab (Relative Risk = 2.5, P = 0.023). These findings strongly suggest the need for heightened caution when administering CT-P13 to patients with a history of prior infliximab exposure.
The clinical effectiveness of CT-P13 was evaluated over a median follow-up period of 11 months, although the follow-up was significantly longer, at 11.9 months, for patients who had switched from infliximab. To account for these varying follow-up durations and censored observations, the estimated efficacy was rigorously calculated using time-to-event methods, projecting outcomes up to 24 months from the initiation of therapy. Out of 754 patients who had a minimum of 8 weeks of follow-up or experienced earlier failure, 48 (6.4%) were categorized as primary failures. Among the remaining 722 patients who responded at 8 weeks, an estimated 72% maintained efficacy at 12 months, and 58% at 24 months, highlighting sustained long-term benefits. When considering overall treatment persistency, which includes patients who required dose optimization but remained on CT-P13, the rates were even higher: 90% at 12 months and 84% at 24 months. Interestingly, when evaluating potential differences in loss of response and treatment persistency among the groups, no statistically significant difference was found between patients who were anti-TNFα naive and those with prior anti-TNFα exposure.
A significant strength of this study lies in its comprehensive data collection beyond just clinical evaluations. We incorporated crucial information on inflammatory biomarkers and endoscopic activity at baseline, 6 months, and 12 months, providing objective measures of disease status. As presented in detail, both for the overall cohort and within the individual subgroups, there was a statistically significant improvement in clinical scores (Harvey-Bradshaw Index for Crohn's disease and Mayo score for ulcerative colitis) at both 6 and 12 months (P < 0.0001). Similarly, endoscopic scores (Mayo Endoscopic score, SES-CD, and Rutgeerts score) also showed significant improvement at 12 months (Mayo, SES-CD, P < 0.0001; Rutgeerts, P = 0.01). Furthermore, objective inflammatory biomarkers corroborated these clinical and endoscopic improvements. C-reactive protein levels significantly improved at 6 and 12 months in both ulcerative colitis (P < 0.0001) and Crohn's disease patients (P = 0.04 at 6 months, P < 0.01 at 12 months). Fecal calprotectin levels similarly demonstrated significant improvement at 6 and 12 months in both ulcerative colitis (P = 0.01 at 6 months, P < 0.0001 at 12 months) and Crohn's disease patients (P = 0.006 at 6 months, P = 0.001 at 12 months).
A persistent debate in the field of inflammatory bowel disease management concerns the appropriateness of switching patients from an originator biologic to a biosimilar, particularly when the patient is already clinically stable and well-controlled, and the switch is driven by economic rather than medical considerations. The NOR-SWITCH study is often cited as the only available controlled trial addressing this issue. However, this study has been subject to several methodological criticisms. For instance, it did not include detailed information on mucosal healing, a critical endpoint in IBD. Its duration of 52 weeks was considered by some as insufficient for long-term assessment, and it evaluated diverse endpoints across different disease states, employing an arbitrary cutoff for clinical insignificance of a 15% difference. Moreover, given its non-inferiority design, a much larger sample size would have ideally been required to definitively detect subtle yet meaningful differences, whereas only fewer than 250 IBD patients were enrolled. Furthermore, the study only assessed a single switch from the originator to the biosimilar, limiting its applicability to real-world scenarios that might involve multiple transitions. Another ongoing study, sponsored by Celltrion, is designed to assess the non-inferiority in efficacy and overall safety of CT-P13 compared with infliximab in patients with active Crohn's disease, with a follow-up extending up to week 54. This trial also aims to provide data on switching from infliximab to CT-P13 and even from CT-P13 back to infliximab. While enrollment for this study is complete with 220 patients, no data have been released yet.
Our study, which to date reports the largest cohort of inflammatory bowel disease patients (n = 155) who were switched from originator infliximab to a biosimilar, surpassing the numbers in the NOR-SWITCH trial, offers highly reassuring data. Not only was the rate of serious adverse events numerically lower in the switched group compared to both naive and previously exposed patients, despite a significantly longer follow-up duration for the switched group, but the rate of loss of response was also significantly lower (P = 0.004), accompanied by a trend toward higher treatment persistency (P = 0.09). This favorable outcome in the switched group is likely partially attributable to selection bias, as these patients were already established responders to and tolerant of infliximab therapy at the time of switching. Additionally, this group had a significantly higher utilization of combination therapy compared to the naive group, a factor known to enhance therapeutic durability. Interestingly, even within this subgroup of already stable patients, our study demonstrated that at 12 months, there was a significant further improvement in total Mayo score and endoscopic Mayo score in ulcerative colitis patients, and in the Harvey-Bradshaw Index, SES-CD, and Rutgeerts scores in Crohn's disease patients, respectively. This improvement occurred despite the fact that most patients in this group were already in remission at the point of switching, suggesting a continued, perhaps subtle, benefit or stabilization of disease activity. While C-reactive protein and calprotectin levels generally declined in this group, they did not always reach statistical significance, likely owing to their already low baseline values. Similar encouraging data on switching have been reported in various other non-controlled cohorts.
Through a robust multivariate analysis, we identified several significant prognostic factors for both loss of efficacy and the occurrence of serious adverse events. Regarding the risk of losing response, the hazard ratios were significantly increased in ulcerative colitis patients compared to Crohn's disease patients, and also in patients belonging to the anti-TNFα naive (Group A) and previously exposed (Group B) subgroups compared to the switched group (Group C). Conversely, the hazard ratio for loss of response was significantly decreased in patients who were not receiving steroids at their last follow-up, highlighting the importance of achieving steroid-free remission. For serious adverse events, the hazard ratio was significantly higher in Group B compared to Group C, and notably lower in male patients compared to female patients, as well as in patients who were off steroids at their last follow-up. These findings collectively reinforce the need for careful consideration and potentially closer monitoring of patients with previous anti-TNFα exposure and those who are still undergoing steroid therapy, as these factors appear to be associated with increased risks of both treatment failure and adverse events.
While our study represents the largest available cohort to date providing real-world data on CT-P13 in inflammatory bowel disease, it is important to acknowledge certain limitations. Due to economic constraints, comprehensive data on drug trough levels of CT-P13 or the presence of antidrug antibodies were not available for the entire cohort, although some data exist for a subgroup published elsewhere. The mean duration of follow-up, while substantial for a real-world study at one year, could still be extended for a more complete understanding of very long-term outcomes. Furthermore, while clinical remission and response were evaluated by different clinicians across multiple centers, the findings were strongly corroborated by objective endoscopic and inflammatory biomarker evaluations, enhancing their reliability. Crucially, this study did not include a direct head-to-head comparison with the originator infliximab. Despite these limitations, the study possesses significant strengths. It accurately reflects daily clinical practice across a large majority of Italian centers prescribing biologic therapy for inflammatory bowel disease. It encompasses a considerable number of patients with detailed endoscopic and inflammatory biomarker data, including a valuable cohort of pediatric patients who successfully switched from infliximab to CT-P13. The cumulative length of follow-up time provides a robust basis for investigating serious adverse events. Importantly, this study was investigator-driven, conducted without any financial or logistical support from pharmaceutical companies, thus reinforcing its independence and impartiality.
Conclusions
In conclusion, this comprehensive study demonstrates within the evaluated timeframe that the safety profile and therapeutic effectiveness of the CT-P13 biosimilar are entirely consistent with the existing literature concerning the originator infliximab. Importantly, no alarming signals indicative of unexpected immunization or increased adverse events were detected in patients who were switched from originator infliximab to CT-P13. However, a significant finding was that infusion reactions and subsequent drug discontinuation due to these reactions were notably more frequent—two and three times higher, respectively—in patients who had a history of prior exposure to infliximab. This underscores a specific area where heightened clinical vigilance may be warranted. Conversely, and perhaps most reassuringly, this study provides strong evidence that patients who underwent a switch from originator infliximab to CT-P13 experienced a comparable rate of serious adverse events and, crucially, a significantly lower rate of loss of response when compared to both anti-TNFα naive patients and those with previous anti-TNFα exposure. The economic impact of CT-P13 is also substantial; an estimated saving of approximately 4 million Euros for the National Health Service in Italy was realized within just one year of the biosimilar's utilization, highlighting its considerable pharmacoeconomic benefits.
The biosimilar infliximab CT-P13 is now widely available in nearly all parts of the world, leading to its increasing adoption in clinical practice. Given this escalating use of biosimilars, it becomes increasingly imperative to acquire a comprehensive understanding of their long-term efficacy and safety in real-world clinical settings. Furthermore, A-196 with the advent of multiple biosimilars for the same originator product already available and more expected in the future, it is conceivable that patients might undergo multiple switches between different biosimilar products or even back to the originator. The long-term consequences of such multi-directional switching on patient safety and therapeutic outcomes remain largely unknown. Therefore, continued vigilance through well-designed clinical trials, robust patient registries, and proactive, long-term pharmacovigilance studies will be absolutely essential. These ongoing efforts will provide the necessary evidence to continually inform clinical decision-making, address existing knowledge gaps, and ultimately ensure optimal patient care in the evolving landscape of biologic and biosimilar therapies.