Clinical Evaluation of Humira® Biosimilar ONS-3010 in Healthy Volunteers: Focus on Pharmacokinetics and Pharmacodynamics

Abstract

ONS-3010 is being developed by Oncobiologics Inc. (Cranbury, NJ, USA) as a biosimilar of Humira®. This randomized, double blind, single-center phase I study (EudraCT registration # 2013-003551-38) was performed to demonstrate pharmacokinetic (PK) biosimilarity between two reference products (Humira® EU and US) and ONS-3010 in healthy volunteers, and to compare the safety and immunogenicity profiles. In addition, the intended pharmacological activity was assessed and compared by application of a whole blood challenge. Hundred ninety-eight healthy volunteers received a single 40 mg subcutaneous dose of ONS-3010, Humira® EU, or US. The pharmacodynamic effects were assessed by lipopolysaccharide (LPS)/aluminum hydroxide whole blood challenges (n = 36; n = 12 per treatment arm; male:female, 1:1). Equivalence was demonstrated on the PK endpoints (AUC0–inf, Cmax, and AUC0–last) based on bounds of 80–125% for the ratio of the geometric means (ONS-3010/Humira®). The immunogenicity profiles were comparable between treatment groups, and there were no indications for differences in routine safety parameters. Administration of adalimumab resulted in the observation of dramatically reduced tumor necrosis factor-α (TNFα) levels upon stimulation with LPS/aluminum hydroxide (>99%), with no differences between the three treatment groups in terms of magnitude or duration. Adalimumab also resulted in a reduction of LPS/aluminum hydroxide-induced interleukin (IL)-8 release (maximally 30%), suggested to have a causal relationship with the anti-TNFα treatment. LPS/aluminum hydroxide-induced release of IL-1β and IL-6 was not inhibited by anti-TNFα treatment. Taken together, these data are promising for the further clinical development of ONS-3010, demonstrate the relevance of the LPS/aluminum challenge to monitor Humira® effects, and emphasize the value of whole blood challenges for monitoring of proximal drug effects in healthy volunteers, and potentially in the target population.

First‐in‐human, randomized dose‐escalation study of the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of PF‐06480605 in healthy subjects

“…However, it has also been shown that appropriate dose escalation can reduce the formation of ADA and therefore allow for sustained clinical response . ADA to adalimumab have been observed in up to 60% of healthy volunteers, higher than levels in patients with IBD which have been previously reported between 0.3% and 38.0% . This could be explained by the fact that patients with IBD are likely to have a background of immunosuppressant treatment, which has been shown to lead to reduced immunogenicity in patients treated with biologic therapies such as infliximab .…”

Comprehensive evaluation of microneedle‐based intradermal adalimumab delivery vs. subcutaneous administration: results of a randomized controlled clinical trial

“…for LPS/aluminium hydroxide-induced IFNγ production after adalimumab administration, 14 but this was not detected in this study (IFNγ P = .99; IL-6 P = .80; IL-8 P = .96; IL-1β P = .75; TNFα P = .08).…”

Favourable pharmacokinetics of intradermal adalimumab over subcutaneous administration: results of a randomized controlled trial

“…adalimumab administration was compared to s.c. adalimumab administration (IFNγ p=0.61; IL-6 p=0.31; IL-8 p=0.81; IL-1β p=0.61; TNFα p=0.80). For LPS/aluminium hydroxide induced IFNγ production after adalimumab administration, a gender effect has been reported (14). A gender effect was not detected in this study (IFNγ p=0.99, IL-6 p=0.80; IL-8 p=0.96; IL-1β p=0.75; TNFα p=0.08).…”