A Randomized, Phase I Pharmacokinetic Study Comparing SB2 and Infliximab Reference Product (Remicade®) in Healthy Subjects

BioDrugs (2015) 29:381–388 DOI 10.1007/s40259-015-0150-5 ORIGINAL RESEARCH ARTICLE A Randomized, Phase I Pharmacokinetic Study Comparing SB2 and Infliximab Reference Product (RemicadeÒ) in Healthy Subjects Donghoon Shin1 • Youngdoe Kim1 • Yoo Seok Kim1 • Thomas Körnicke2 • Rainard Fuhr2 Published online: 17 November 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Objective SB2, a biosimilar to infliximab reference product (INF), has an identical amino acid sequence and similar physicochemical functional properties to its reference product. The primary objective of this study is to demonstrate pharmacokinetic (PK) bioequivalence between SB2 and EU-sourced INF (EU-INF), between SB2 and US-sourced INF (US-INF), and between EU-INF and US-INF. Methods This study was a randomized, single-blind, three-arm, parallel group study in 159 healthy subjects. All subjects received a single 5 mg/kg intravenous infusion of study drug and then were observed for 10 weeks to study PK, safety and immunogenicity. The primary PK parameters were area under the concentration-time curve (AUC) from time zero to infinity (AUCinf), AUC from time zero to the last quantifiable concentration (AUClast) and maximum concentration (Cmax). Bioequivalence for the primary PK parameters was to be concluded using an analysis of variance (ANOVA) if the 90 % confidence intervals (CIs) for the ratio of geometric least squares means (LSMeans) of the treatments compared were completely contained within the pre-defined equivalence margin, 0.8–1.25. Results All of the 90 % CIs for the geometric LSMean ratios of primary PK parameters for each comparison were within the pre-defined equivalence margin. The proportion of subjects who experienced treatment-emergent adverse & Donghoon Shin 1 Samsung Bioepis Co., Ltd., 107 Chemdan-daero, Yeonsu-gu, Incheon, Republic of Korea 2 PAREXEL International Early Phase Clinical Unit, Berlin, Germany events was comparable between treatments. The incidences of anti-drug antibodies between the three treatments were comparable. Conclusion This study demonstrated biosimilarity of SB2 to its marketed reference products of infliximab in terms of PK equivalence in healthy subjects. SB2 was generally well tolerated and showed comparable safety and immunogenicity profiles to the reference products (ClinicalTrials.gov Identifier: NCT01922336). Key Points Single-dose pharmacokinetics of SB2 were shown to be bioequivalent to those of reference products (EUsourced RemicadeÒ and US-sourced RemicadeÒ) in healthy subjects, considered a sensitive population for PK comparison. Safety and immunogenicity of single-dose SB2 in healthy subjects are comparable to those of reference products. 1 Introduction Infliximab, which is a genetically engineered chimeric human/mouse glycosylated monoclonal antibody (mAb) directed against tumour necrosis factor alpha (TNFa), acts by neutralizing the proinflammatory action and regulatory role of TNFa [1–3]. Infliximab was approved as RemicadeÒ (Janssen Biotech Inc., Horsham, PA, USA) with the indications including rheumatoid arthritis, adult Crohn’s disease, paediatric Crohn’s disease, ankylosing spondylitis, 382 psoriatic arthritis, ulcerative colitis, paediatric ulcerative colitis and psoriasis [4]. Recently, RemsimaÒ (Celltrion Inc., Incheon, Korea), using RemicadeÒ as the reference product, was approved for use as an infliximab biosimilar in the EU by the European Medicines Agency (EMA) [5]. As per EU biosimilar requirements, the approval application included a detailed and thorough characterization of the mAb and non-clinical studies of the biosimilar with the reference product [6]. This was complemented by a clinical phase I study in ankylosing spondylitis patients and a clinical phase III study in rheumatoid arthritis patients to establish and confirm clinical biosimilarity [7, 8]. Samsung Bioepis Co., Ltd is developing SB2, a biosimilar to RemicadeÒ, that is produced by recombinant DNA technology and purified by various types of chromatography. In accordance with the regulatory agency biosimilar guidelines, the development of SB2 had involved biosimilarity studies starting with comparison of the structural characteristics, physicochemical properties and biological activities between SB2 and RemicadeÒ, followed by demonstration of similar in vivo behaviour between SB2 and its reference products [9, 10]. Based on the in vitro and in vivo non-clinical study results, clinical studies could be conducted to compare the clinical efficacy, safety, and pharmacokinetics (PK) of SB2 with those of infliximab reference products (INF). The aim of this study was to compare the PK of SB2 and its reference products after single administration of infliximab in healthy subjects. 2 Methods 2.1 Subjects Healthy female subjects of non-childbearing potential and healthy male subjects aged 18–55 years were eligible for participation in this study if bodyweight was between 60.0 and 94.9 kg and body mass index (BMI) was between 20.0 and 29.9 kg/m2. For inclusion, subjects had to be in good health without any infectious disease including active or latent tuberculosis as indicated by medical history, physical examination, vital signs, 12-lead electrocardiography (ECG), serology, clinical laboratory tests, QuantiFERONÒ-TB Gold test (QIAGEN, Venlo, The Netherlands) and urine drug screening. These screening tests were performed during a 3-week period prior to randomization. The nature and purpose of the study was fully explained to each subject and written informed consent was obtained from each subject before the subject was enroled in the study. D. Shin et al. 2.2 Study Design This study was a single-blind, parallel group, single-dose study with three treatment groups, which were SB2 and two infliximab reference products: EU-sourced RemicadeÒ (EU-INF) and US-sourced RemicadeÒ (US-INF). All subjects received a single dose of 5 mg/kg SB2, EU-INF or US-INF by intravenous (IV) infusion for 120 min on the first day of study and then were followed for 10 weeks during which the PK, safety and immunogenicity measurements were made. To avoid infusion-related reaction, premedication with IV hydrocortisone (100 mg), oral acetaminophen (1000 mg), and oral loratadine (10 mg) were administered 30 min to 1 h prior to the infusion of study drugs, which was adopted from a previous report [11]. In case of infusion-related reactions, the infusion could be temporarily discontinued or the infusion rate decreased based on assessment of the investigators. During the treatment period, subjects were hospitalized in the PAREXEL Early Phase Clinical Unit (Berlin, Germany) from 1 day before the study drug administration until 3 days after administration for serial PK sampling and close safety monitoring. After discharge, the subjects visited the site at 6, 8, 15, 22, 29, 43, 57, and 71 days after administration. Safety was assessed by vital signs, (...truncated)