Phase 3 Trials Find Subcutaneous Infliximab CT-P13 Superior to Placebo in IBD

Two phase 3 trials, 1 in Crohn disease (CD), and 1 in ulcerative colitis (UC), found higher clinical remission rates in patients treated with the subcutaneous formulation of infliximab biosimilar CT-P13 (Remsima, Inflectra; Celltrion) compared with placebo as maintenance therapy following an induction phase of intravenous CT-P13.

Subcutaneous CT-P13 “was well tolerated, with no new safety signals, and provided consistent serum infliximab concentrations,” according to the authors.

CD and UC, collectively known as inflammatory bowel disease (IBD), are chronic inflammatory conditions of the gastrointestinal tract that are frequently treated with tumor necrosis factor (TNF)-α inhibitors, including infliximab. The intravenous formulation of CT-P13 was the first infliximab biosimilar approved by the European Medicines Agency in 2013 and US FDA in 2016.

For a more convenient mode of delivery, a subcutaneous formulation of CT-P13 has been developed. The authors noted that the subcutaneous formulation “resulted in exposure of patients to infliximab qualitatively and quantitatively different from infliximab [intravenous].” Whereas intravenous infliximab delivers high peak levels that then fall to low trough levels before the next infusion, the subcutaneous formulation results in consistent drug levels with small variation. Because of this difference in exposure profile, “potentially leading to substantial differences in efficacy and safety,” they said, the FDA classified subcutaneous CT-P13 as a new drug which requires phase 3 confirmatory efficacy trials.

The subcutaneous version of CT-P13 is known as Remsima SC in Europe and Zymfentra in the US.

Patients with moderate to severe CD (n = 396) or UC (n. =548) and either an inadequate response or intolerance to corticosteroids and immunomodulators received 3 biweekly infusions of intravenous CT-P13. Clinical responders were then randomized to receive subcutaneous CT-P13 or placebo biweekly from week 10 to week 54. Approximately 80% of patients remained in the study until week 54.

Both Studies Met Co-Primary Endpoints

Baseline characteristics “were generally well balanced between groups in both studies,” the authors said. The co-primary end points of the studies were clinical remission based on Crohn’s Disease Activity Index (CDAI) and endoscopic response based on Simplified Endoscopic Activity Score for Crohn’s Disease (SES-CD) for CD and clinical remission based on modified Mayo score for UC. The differences were significant between groups in both studies.

In CD, 144 patients (62%) receiving CT-P13 and 32% receiving placebo achieved clinical remission, and 51% and 18% of patients achieved endoscopic response. In UC, 43% of patients treated with CT-P13 and 21% of patients receiving placebo achieved clinical remission.

Key secondary efficacy end points were also significantly higher in the subcutaneous CT-P13 group compared with placebo at week 54 in both studies, such as clinical remission by abdominal pain and stool frequency in CD, endoscopic-histologic mucosal improvement in UC; and corticosteroid-free remission in both studies.

The authors added that subgroup analyses “showed generally consistent findings by sex, age, race, disease severity, disease duration, and previous exposure to biologic agents and/or Janus kinase inhibitors.” They also noted greater efficacy of CT-P13 compared to placebo in the subgroup of patients with severe disease activity. Furthermore, C-reactive protein and fecal calprotectin concentrations decreased during the induction phase, “were generally maintained or further decreased” in the subcutaneous CT-P13 groups during the maintenance phase and were “consistently lower compared with the placebo groups.”

No New Safety Signals

During the maintenance phase of the study, 72% and 62% of patients with CD and 68% and 69% of patients with UC in the subcutaneous CT-P13 and placebo groups experienced a treatment-emergent adverse event (TEAE). Serious TEAEs were experienced by 7% and 8% of patients in the CD study and 6% and 3% of patients in the UC study receiving CT-P13 and placebo. The authors reported that most serious adverse events were considered unrelated to the study drug, and similar proportions of patients in each group experienced TEAEs leading to discontinuation of the study drug. No TEAEs of special interest (infections and local injection-site reactions) were severe or serious, and there were no new safety findings.

Immunogenicity

Antidrug antibodies (ADAs) were detected in 65% and 76% of patients with CD and 64% and 92% of patients with UC in CT-P13 and placebo groups. Within the CT-P13 groups, predose infliximab concentrations “tended to be lower” in patients positive for ADAs, the authors wrote. Clinical remission and endoscopic response rates in the CD study “trended slightly lower” in ADA-positive patients compared to ADA-negative patients. However, in the UC study, clinical remission rates were “comparable” between ADA-positive and ADA-negative patients. ADA status was not associated with safety outcomes.

The authors concluded subcutaneous CT-P13 was superior to placebo as maintenance therapy in patients with IBD who responded to intravenous CT-P13 induction and was well-tolerated. Although subcutaneous CT-P13 was not directly compared to intravenous CT-P13 in their study, they said, “this comparison has been assessed previously in studies in patients with inflammatory bowel disease and rheumatoid arthritis.” They noted that theirs are the first randomized, placebo-controlled phase 3 trials to demonstrate efficacy of subcutaneous CT-P13 in CD and UC, and that their study measured efficacy with up-to-date endpoints such as histoendoscopic assessments for UC and Simplified Endoscopic Activity Score for Crohn’s Disease (SES-CD). They added that their study “provides a greater understanding of the efficacy and safety of a novel exposure profile” of subcutaneous infliximab CT-P13 in IBD.

Reference

Hanauer SB, Sands BE, Schreiber S, et al. Subcutaneous Infliximab (CT-P13 SC) as maintenance therapy for inflammatory bowel disease: Two randomized phase 3 trials. Gastroenterology. 2024:S0016-5085(24)04918-7. doi:10.1053/j.gastro.2024.05.006