A randomized phase l pharmacokinetic study comparing SB4 and etanercept reference product (Enbrel®) in healthy subjects

Abstract

AimsSB4 has been developed as a biosimilar of etanercept. The primary objective of the present study was to demonstrate the pharmacokinetic (PK) equivalence between SB4 and European Union ‐sourced etanercept (EU‐ETN), SB4 and United States‐sourced etanercept (US‐ETN), and EU‐ETN and US‐ETN. The safety and immunogenicity were also compared between the treatments.MethodsThis was a single‐blind, three‐part, crossover study in 138 healthy male subjects. In each part, 46 subjects were randomized at a 1:1 ratio to receive a single 50 mg subcutaneous dose of the treatments (part A: SB4 or EU‐ETN; part B: SB4 or US‐ETN; and part C: EU‐ETN or US‐ETN) in period 1, followed by the crossover treatment in period 2 according to their assigned sequences. PK equivalence between the treatments was determined using the standard equivalence margin of 80–125%.ResultsThe geometric least squares means ratios of AUCinf, AUClast and Cmax were 99.04%, 98.62% and 103.71% (part A: SB4 vs. EU‐ETN); 101.09%, 100.96% and 104.36% (part B: SB4 vs. US‐ETN); and 100.51%, 101.27% and 103.29% (part C: EU‐ETN vs. US‐ETN), respectively, and the corresponding 90% confidence intervals were completely contained within the limits of 80–125 %. The incidence of treatment‐emergent adverse events was comparable, and the incidence of the antidrug antibodies was lower in SB4 compared with the reference products.ConclusionsThe present study demonstrated PK equivalence between SB4 and EU‐ETN, SB4 and US‐ETN, and EU‐ETN and US‐ETN in healthy male subjects. SB4 was well tolerated, with a lower immunogenicity profile and similar safety profile compared with those of the reference products.

Response to: ‘Lower anti-drug antibodies with etanercept biosimilar: Can Ctrough explain the differences’ by Shah

“…Additional data from the PK population on immunogenicity with a more sensitive assay with regard to drug tolerance have been reported in the response to Marshall et al 6: 2.4% in SB4 and 21.1% in ETN (results to be published). Together with the SB4 phase I immunogenicity results,7 which showed that ADA incidence was significantly lower in SB4 (0.0%) compared with European-sourced ETN (15.6%, p=0.006 compared with SB4) or US-sourced ETN (22.7%, p<0.001 compared with SB4) without the concern of drug interference,6 we hope the data of our study can provide insight into the impact of C trough on ADA.…”

Patient Perceptions and Preferences of Two Etanercept Autoinjectors for Rheumatoid Arthritis: Findings from a Patient Survey in Europe

“…Benepali, which underwent robust preclinical and clinical (phase I and phase III) testing in both healthy volunteers and patients with RA [14, 15], is approved for all the adult indications for which Enbrel is approved—namely, moderate-to-severe RA, psoriatic arthritis, axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis), and plaque psoriasis [16]. Both Benepali and Enbrel are available as autoinjector devices.…”

Clinical trials of biosimilars should become more similar

“…Perhaps critically, assays of ADAs were performed more frequently and at earlier time points than in previous studies—it was at those earlier time points that differences in ADA incidence were detected. Notably, a lower incidence of ADAs was also demonstrated in a phase I pharmacokinetic study of SB4 compared with bio-originator etanercept in healthy subjects 25. The EMA presented its overall findings in an EPAR and, regarding immunogenicity, concluded: “Possible explanations for the differences in ADA incidence between Benepali [SB4] and Enbrel [bio-originator etanercept] could be the slightly different drug concentrations in samples or differences in the sensitivities of the corresponding analytical methods … Therefore as the observed differences with respect to ADA formation … appeared to be transient, with almost no differences after 8 weeks of treatment, their clinical significance was considered minimal” 19…”