CME Author: Zeena Nackerdien
Study Authors: Akos Ilias, Kata Szanto, et al.
Target Audience and Goal Statement:
Gastroenterologists and internists
The goal was to examine the effects of a reverse switch from maintenance therapy with a biosimilar to the reference biologic infliximab (Remicade) in a real-life cohort of patients with inflammatory bowel diseases (IBD).
Background and Questions Addressed:
IBD biosimilars have been registered in the European Union since 2013, and two infliximab biosimilars are currently available in that region. Key areas of interest for clinicians are switching data (from the biosimilar to the original biologic or vice versa) and safety issues surrounding the switch period. Therefore the investigators addressed the following questions:
- What was the short-term sustainability and efficacy of switching from the biosimilar to the originator, infliximab, in consecutive IBD patients in a multi-center, real-life IBD cohort?
- Could any changes in clinical remission rates during a 24-week follow-up period be correlated to drug trough levels, drug-antibody interactions, or enhanced safety signals after switching from the biosimilar to the originator infliximab?
Synopsis and Perspective:
Biologics are described as “any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the the prevention, treatment, or cure of disease or injuries of man.” These complex agents include the anti-tumor-necrosis-factor (TNF) monoclonal antibody, infliximab, which is indicated for several chronic conditions, including Crohn’s disease (CD). But not all patients who need biologics receive them. A pathway for the development of biosimilars was constructed to increase access to these agents. Cost concerns and patent expiration have also driven the development of infliximab biosimilars, such as CT-P13 and SB2.
SB2 was recently approved by the FDA and the European Medicines Agency (EMA) for all indications of the originator product. CT-P13 — the world’s first monoclonal antibody biosimilar approved by the EMA — is indicated for eight autoimmune conditions including rheumatoid arthritis and IBD.
Previous analysis of real-world data showed that CT-P13 was equivalent to infliximab in infliximab-naive patients with CD. Comparable results were reported for a number of studies of switched patients. This led to the conclusion that there was no clinically meaningful difference between the biosimilar, CT-P13, and the originator infliximab in terms of efficacy and safety, so it was acceptable to switch from an originator to an approved biosimilar.
But as the biosimilar agent market expands, there is a need to obtain more data on reverse and/or multiple switches to guide decision making, and to shed light on the interchangeability of the biologics.
Peter L. Lakatos, MD, DSc, of Semmelweis University in Budapest and McGill University in Montreal, and colleagues prospectively studied 174 Hungarian unselected and consecutive patients with IBD, 136 with CD (proportion of males/females were 49.3%/50.7%) and 38 with ulcerative colitis (UC: proportion of males/females were 44.7%/55.3%).
Median ages at onset and disease durations were 27.5 years and 8 years for the CD group, and 25 years and 7 years for the UC group. All had been on maintenance therapy with the biosimilar CT-P13 (14 patients had previously received the originator infliximab), but they were switched to the originator product in 2017 as a result of a change in reimbursement policies in the Hungarian national healthcare system. Patients were on a drug holiday for 12 months prior to initiation of their current infliximab treatment regimen.
Clinical remission was defined as a CD activity index <150 points or no fistula drainage, or a partial Mayo score <3 points for patients with UC.
Clinical remission rates for the CD and UC subgroups were monitored 8 weeks prior to switching from the infliximab biosimilar maintenance therapy to the originator, at baseline (time of the switch), at week 16, and at week 24 following the switch. Pre-switch clinical remission rates in the CD and UC subgroups were 82.5% and 82.9%, respectively. The rates were 80.6% and 81.6% for CD and UC, respectively, at baseline and were not significantly changed at week 16 (77.5% with CD and 83.7% with UC) and at week 24 (76.3% with CD and 84.9% with UC).
Mean serum trough levels of infliximab were 5.33 μg/mL at baseline and 5.69 μg/mL at week 16 (P=0.71). No significant differences were noted in the prevalence of anti-drug antibody levels at baseline (16.2%) compared with week 16 (16.9%). Overall, there were no differences in outcomes or trough or antidrug antibody levels between patients with or without previous exposure to the originator.
Adverse events (AEs) were few, with four infusion reactions at week 24 in patients who had detectable antidrug antibodies at baseline but no previous exposure to the originator drug. No anaphylaxis occurred.
Source Reference: Clinical Gastroenterology and Hepatology, Jan. 7, 2019; DOI:10.1016/j.cgh.2018.12.036
Study Highlights: Explanation of Findings
To the best of the investigators’ knowledge, this was the first analysis of a mandatory reverse switch from a biosimilar to the originator, infliximab, in a real-life cohort of IBD patients. During a 24-week follow-up period, the authors saw no significant changes with respect to clinical remission rates, drug trough levels or antidrug antibody status after the reverse switch. Other parallel findings included good short-term drug susceptibility and no new safety signals.
The authors cited a robust unselected, consecutive patient cohort with harmonized follow-up and monitoring practices across all the centers as study strengths. Additionally, the cohort resembled real life in terms of multiple switches (i.e., a substantial number of patients had prior exposure to the originator infliximab before being treated with the biosimilar).
Results from this study are in keeping with the extrapolation concept — biosimilars function similar to the originators including in indications that were licensed based on extrapolation. Compelling supportive literature evidence came from one phase III trial in which patients were randomized to maintenance (CT-P13 vs originator infliximab) or switched (CT-P13 to originator infliximab vs originator infliximab to CT-P13) groups. Select clinical responses, remissions, AEs, serious AEs, and anti-drug antibodies at prespecified follow-up periods were similar between groups.
Switching from the originator infliximab to CT-P13 was not inferior to continued treatment with the reference agent in patients with various inflammatory disorders, including CD, who were enrolled in the randomized, double-blind, parallel-group phase IV NOR-SWITCH trial. Clinical outcomes and immunogenicity analysis of another study following a switch from the originator infliximab to the SB2 biosimilar yielded analogous findings. No statistically significant difference in median serum drug trough levels and anti-drug antibody levels were observed after a switch from the originator infliximab to the biosimilar SB2.
Taken together with other observational studies, the European Crohn’s and Colitis Organisation (ECCO) statement on biosimilars concluded that “switching from the originator infliximab to an approved biosimilar product in patients with IBD can be regarded as safe and acceptable after discussing with the patients individually.”
In addition to the need for a robust pharmacovigilance program for each biosimilar, the authors noted that “physicians may need to prepare for different scenarios including not only one-way switching from the originator to its biosimilar, but also reverse, multiple or cross-switching among biosimilars.”
Benjamin H. Click, MD, of the Cleveland Clinic, told MedPage Today that the study was a timely and important contribution to the area of biosimilars in IBD, as many U.S. healthcare systems implement biosimilars in clinical practice.
“The authors should be commended for recognizing and diligently evaluating a unique clinical opportunity,” said Click, who was not involved with the research. “While several studies have addressed switching from originator to a biosimilar product, this novel study examines the unique situations of reverse biosimilar to originator switching and multiple switching in an IBD population.”
This study provides reassuring real-world data that reverse and multiple switching may be safe and clinically well tolerated, Click added. “Patients may be faced with different formularies or coverage plans, and switching to and from biosimilars will likely become a practical reality in the near future. Understanding the implications of switching is critical to providing high-quality care for IBD patients while reducing healthcare costs in America.”
However, Click cautioned that the study was limited by a small sample size, relatively short 24-week follow-up, and lack of a control population. “Larger, prospective, controlled studies with reverse, multiple, and cross-switches with long-term follow-up are needed to confirm these findings and further inform this important topic in IBD,” he noted.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco