Prospective Study Finds Multiple Switches Between Infliximab Reference Product and Biosimilars is Safe and Effective in IBD

Although a single non-medical switch from the infliximab originator to a biosimilar “is considered effective and safe for most patients with inflammatory bowel disease (IBD),very limited data are available on multiple successive switches,” according to authors of a new study on multiple switching between the reference product (Remicade) and biosimilars CT-P13 and SB2.

Infliximab and other tumor necrosis factor (TNF) alpha inhibitor biologics have been increasingly used to treat IBD in recent years. Remicade was first approved by the US FDA in 1998 and European Medicines Agency (EMA) in 1999. The first biosimilar infliximab, CT-P13 (Inflectra, Remsima), was approved in Europe in 2013 and in the United States 2016, followed by SB2 (Renflexis, Flixabi) in 2016 and 2017, respectively.

The study published in Inflammatory Bowel Diseases, which took place at multiple centers in The Netherlands, enrolled 176 adult patients with IBD, 71% with Crohn disease, 27.8% with ulcerative colitis, and 1.2% with IBD unclassified. The patients underwent 1 of 3 switching protocols: 2 switches from the originator infliximab to CT-P13 to SB2; 1 switch from CT-P13 to SB2; or 1 switch from the originator to CT-P13.

For most of the patients (88.6%), infliximab was the first biologic drug they had received. The authors noted differences in patient characteristics at the time of the most recent switch. The group switching from CT-P13 to SB2 had a lower rate of clinical remission compared to the other 2 groups; the patients undergoing 2 switches had longer disease duration than the other 2 groups. Since it was an observational study based on routine clinical care, the authors said, “inevitably, the characteristics of patients within each group were affected by the timing of switches, with patients undergoing multiple successive switches having a longer disease duration” than patients undergoing 1 switch.

Remission 12 months after most recent switch

The study outcomes were remission based on physician’s assessment, C-reactive protein (CRP), and fecal calprotectin (FC) at 4 and 12 months after each switch.

At 12 months after the most recent switch, 76.9% (n = 40/52) of patients in the multiple switch group were in clinical remission, compared to 65.7% (n = 46/70) of the patients in the CT-P13 to SB2 group, and 76.9% (n = 20/26) of those in the reference product to CT-P13 group. The researchers found no significant differences in the rate of remission as indicated by clinical assessment, CRP, FC, or treatment persistence at 12 months. The estimated treatment persistence was 85% in the multiple switch group, 87.0% for the CT-P13 to SB2 group, and 70.1% in the reference product to CT-P13 group at 12 months.

Regression analysis suggested that clinical remission at the most recent switch, but not for any other evaluated variables, such as disease duration, duration of exposure to infliximab before switching, immunomodulator at most recent switch, type of IBD (UC vs. CD), or switch group, was associated with clinical remission at 12 months.

Safety and immunogenicity

Three patients (3.8%) in the group that switched from CT-P13 to SB2 had infusion reactions, and 5 (6.3%) had an IBD disease flare-related hospitalization during the study period. All patients who had infusion reactions had anti-drug antibodies (ADAs). There were no infusion reactions or IBD-related hospitalizations in the other 2 groups.

Additional adverse events included worsening of eczema in 1 patient, worsening headache in 3 patients, and musculoskeletal pain in 1 patient. The researchers said that these side effects resolved following a switch back to the previously effective infliximab formulation. Also, treatment was interrupted in 1 patient in the CT-P13 to SB2 group by a malignant melanoma diagnosis.

At the time of the most recent switch, ADAs were detected in 5.8% of patients in the multiple switch group, 8.8% of the CT-P13 to SB2 group, and none of the patients in the originator to CT-P13 group. After the switch, new ADAs were detected in 3.8% of patients in the CT-P13 to SB2 switch group, and 3.7% of patients in the reference product to CT-P13 switch group. No new ADAs were detected in the multiple switch group. However, the authors noted, “studies on patients undergoing multiple successive switches, including ours, used drug-sensitive assays, which may have resulted in the underestimation of antibody development.”

Discontinuation of treatment

In the multiple switch group, 8.7% discontinued treatment due to active disease, 8.7% due to long-term sustained remission, and 2.9% due to adverse events. Of the patients who switched from CT-P13 to SB2, 8.8% discontinued treatment due to active disease, 3.8% due to adverse events, and 1.3% due to long-term sustained remission. Of the patients who switched from the reference product to CT-P13, 14.8% discontinued treatment due to active disease, 22.2% due to long-term sustained remission, and 14.8% due to adverse events.”

Largest real-world study of multiple switches between infliximab products

The investigators said theirs “is the largest study evaluating the efficacy and safety of multiple successive switches between [infliximab] originator and biosimilars in a real-world cohort of patients with IBD to date.” They concluded that multiple switching and switching between infliximab biosimilars appeared effective and safe.

Reference

Hanzel J, Jansen JM, Ter Steege RWF, Gecse KB, D'Haens GR. Multiple switches from the originator infliximab to biosimilars is effective and safe in inflammatory bowel disease: A prospective multicenter cohort study. Inflamm Bowel Dis. 2022;28(4):495-501. doi:10.1093/ibd/izab099