Y-ECCO Literature Review: Jalpa Devi

Methods

Two randomised, placebo-controlled, double-blind studies were conducted in patients with moderately to severely active CD or UC who had an inadequate response or intolerance to corticosteroids and immunomodulators. Patients received open-label CT-P13 IV 5 mg/kg at weeks 0, 2 and 6. At week 10, clinical responders were randomised (2:1) to receive CT-P13 SC 120 mg or placebo every 2 weeks until week 54. Co-primary endpoints were clinical remission and endoscopic response at week 54 for CD and clinical remission at week 54 for UC.

Key findings

1. Efficacy of CT-P13 SC:
• Crohn’s Disease (CD): In the study involving 396 patients with moderate to severe CD, clinical remission at week 54 was achieved in 62.3% of patients receiving CT-P13 SC compared to 32.1% in the placebo group (p<0.0001). Endoscopic response rates were 51.1% for CT-P13 SC versus 17.9% for placebo (p<0.0001). This significant difference underscores the potential of SC administration to maintain long-term disease control in CD patients.
• Ulcerative Colitis (UC): In the study involving 548 patients with moderate to severe UC, clinical remission at week 54 was seen in 43.2% of the CT-P13 SC group compared to 20.8% of the placebo group (p<0.0001). The endoscopic improvement mirrored these findings, highlighting the effectiveness of CT-P13 SC in reducing mucosal inflammation and promoting healing.

1. Safety profile of CT-P13
• Treatment-emergent adverse events (TEAEs): The incidence of TEAEs was higher in the CT-P13 SC groups (72.3% in CD and 67.6% in UC) compared to placebo (61.9% in CD and 59.3% in UC). However, most TEAEs were mild to moderate in intensity. This suggests that while the SC formulation increases the frequency of adverse events, these are generally manageable and do not outweigh the therapeutic benefits.
• Serious adverse events (SAEs): Serious adverse events were similar between CT-P13 SC and placebo groups, with no new safety signals identified. This indicates that the SC formulation does not introduce additional risks beyond those already associated with infliximab therapy.
• Infections: Infection rates were slightly higher in the CT-P13 SC groups (31.1% in CD and 28.0% in UC) compared to placebo (18.1% in CD and 25.7% in UC), but most infections were non-severe. This aligns with known risks of immunosuppressive therapies and underscores the need for vigilant infection monitoring.

1. Pharmacokinetics and immunogenicity of CT-P13
• Serum concentrations: Predose serum infliximab concentrations were consistent in the CT-P13 SC groups throughout the maintenance phase, maintaining therapeutic levels. This consistency is crucial for ensuring sustained disease control and minimising relapse risks.
• Anti-drug antibodies (ADAs): ADA positivity was observed in 65.1% of CD patients and 63.8% of UC patients in the CT-P13 SC groups, slightly lower values than in the placebo groups. The reduced immunogenicity profile suggests a potential advantage of SC administration in reducing the likelihood of antibody-mediated loss of response.

Discussion

The phase 3 LIBERTY trials of CT-P13 SC showed that this formulation is efficacious and generally safe for maintaining remission in patients with IBD. The ability for patients to self-administer the medication at home could lead to better adherence and an improved quality of life. However, the slightly higher infection rates compared to placebo highlight the importance of monitoring and managing potential infections. There are also several limitations to consider for this trial, including the absence of a direct comparison with intravenous (IV) infliximab. Future studies should explore this comparison to provide more comprehensive data. Furthermore, real-world studies are necessary to confirm these findings in diverse patient populations and to further investigate the long-term safety and efficacy of CT-P13 SC. In addition, the phase 3 LIBERTY trials do raise an important ethical dilemma. In the age of multiple effective therapies now being licensed for both CD and UC, it is increasingly likely that clinicians and patients will decline future involvement in placebo-controlled trials. Indeed, given the years of experience with IV infliximab and the multitude of observational studies already demonstrating effectiveness and safety of CT-P13 SC formulation in the real-world setting, it is certainly an important question to ask, Why was there a regulatory insistence for the LIBERTY trials to be conducted as placebo-controlled trials? Going forward and with future biosimilars due to enter the field, this will be an important aspect for patients, clinicians, trial sponsors and regulators to work together to resolve.

Conclusion

The LIBERTY trials demonstrate that CT-P13 SC is an efficacious and convenient maintenance therapy for IBD, offering significant clinical and endoscopic benefits over placebo. Its safety profile appears at least comparable to that of IV infliximab, with the added benefit of easier administration. Further research is needed to compare SC and IV formulations directly and to validate these findings in broader patient populations. Going forward, the ethical implications of performing placebo-controlled trials for biosimilar medication needs to be carefully considered by regulators with patients, clinicians and trial sponsors. Overall, data from the LIBERTY trials show that CT-P13 SC represents a promising additional treatment option for both UC and CD, and use of this treatment may potentially enhance patient adherence and help improve overall disease management.

References

1. Alten R, An Y, Kim DH, et al. Re-routing infliximab therapy: subcutaneous infliximab opens a path towards greater convenience and clinical benefit. Clin Drug Investig 2022;42:477–89.
2. Schreiber S, Ben-Horin S, Alten R, et al. Perspectives on subcutaneous infliximab for rheumatic diseases and inflammatory bowel disease: before, during, and after the COVID-19 era. Adv Ther 2022;39:2342–64.
3. Schreiber S, Ben-Horin S, Leszczyszyn J, et al. Randomized controlled trial: subcutaneous vs intravenous infliximab CT-P13 maintenance in inflammatory bowel disease. Gastroenterology 2021;160:2340–53.

Jalpa Devi - Short Biography

Jalpa Devi is an Advanced IBD Fellow at Washington University Barnes-Jewish Hospital, St. Louis, USA. She completed her MBBS with distinction and her Gastroenterology and Hepatology Fellowship at Liaquat University of Medical and Health Sciences, Pakistan. Her research focuses on IBD in low- and middle-income countries, particularly in improving diagnosis and management. She is involved in several ECCO Consensus projects and is a Social Media Ambassador for Evidence-Based GI by the American College of Gastroenterology. Currently, she is also pursuing advanced clinical research training through the Clinical Investigation Certificate Program at Washington University.