Development of a Subcutaneous Formulation of CT-P13 (Infliximab): Maintenance Subcutaneous Administration May Elicit Lower Immunogenicity Compared to Intravenous Treatment

Abstract

Background/Purpose: Intravenous (IV) use of CT-P13, an infliximab (INX) biosimilar, has resulted in comparable efficacy, safety and immunogenicity as innovator INX in various indications including rheumatoid arthritis (RA)1 and Crohn’s disease (CD)2. A subcutaneous (SC) formulation of CT-P13 is developed to provide patients with opportunities for self-injection, thereby enhancing convenience and flexibility in treatment. This work aimed to investigate immunogenicity by post-hoc analysis of two randomized controlled trials comparing pharmacokinetics of CT-P13 IV and CT-P13 SC.

Methods: Patients with RA (6 or more swollen and tender joints and serum C-reactive protein [CRP] concentration >0.6 mg/dL) and active CD (Crohn’s Disease Activity Index [CDAI] score of 220 – 450) were treated with CT-P13 IV at Weeks 0 and 2. At Week 6, patients were randomized for continuation with IV or SC administration. The IV cohorts received CT-P13 IV (3 mg/kg for RA and 5 mg/kg for CD) every 8 weeks and the SC cohorts were treated with CT-P13 SC (90, 120, 180 mg for RA and 120, 180 and 240 mg for CD) every 2 weeks up to Week 30. Trough serum concentrations (Ctrough) were assessed at Weeks 6, 14 and 22 for IV and Weeks 6, 8, 10, 14, 22, 24, 26 and 28 for SC. Target exposure level was considered as 1 µg/mL for RA3, 4 and 5 µg/mL for CD5, 6. Anti-drug antibody (ADA) was assessed before study drug administration at Weeks 0, 6, 14, 22 and 30 by a drug-sensitive, enzyme-linked immunosorbent assay.

Results: In total, 92 patients were randomized at Week 6 to IV (RA: n=13, CD: n=13) or SC (RA: n=35, CD: n=31). All RA patients used methotrexate as concomitant medication throughout the study. Among CD patients, immunomodulators were used at Week 6 by 9 (69.2%) and 15 (48.4%) patients in IV and SC cohorts, respectively. Efficacy results (EULAR [CRP] responder rate for RA and CDAI-70 responder rate for CD) were comparable between the IV and SC. Systemic safety profiles observed from CT-P13 SC after randomization were also comparable to those of IV. A sub-therapeutic Ctrough level below target exposure was detected at least once in 23 (92.0%) and 9 (14.1%) patients in IV and SC cohorts, respectively. ADA were detected at least once in 16 (64.0%) versus 11 (18.1%) of patients in the IV and SC cohorts (p<0.0001), respectively.

Conclusion: After initial loading two doses of CT-P13 IV, patients subsequently receiving biweekly maintenance treatment with CT-P13 SC achieve more stable steady state therapeutic blood levels of INX and have lower rate of ADA compared with patients receiving continued IV treatment. Further work to corroborate these findings is ongoing through a confirmatory efficacy trial.