Efficacy and pharmacokinetics of ozoralizumab, an anti-TNF[alpha] NANOBODY[R] compound, in patients with rheumatoid arthritis: 52-week results from the OHZORA and NATSUZORA trials

Introduction Ozoralizumab (OZR), a tumor necrosis factor alpha (TNF[alpha]) inhibitor, is a NANOBODY.sup.[R] compound that binds to TNF[alpha] and human serum albumin. The main objective of this study was to analyze the pharmacokinetics (PK) of the drug and its correlation with clinical efficacy in patients with rheumatoid arthritis (RA). Methods Efficacy data were analyzed from the OHZORA trial, in which OZR 30 or 80 mg was administered to Japanese patients with RA at 4-week intervals for 52 weeks in combination with methotrexate (MTX; n = 381), and the NATSUZORA trial, in which OZR 30 or 80 mg was administered without concomitant MTX (n = 140). Effects of patient baseline characteristics and anti-drug antibodies (ADAs) on the PK and efficacy of OZR were investigated, and a post hoc analysis of PK effects on drug efficacy was performed. Results The maximum plasma concentration (C.sub.max) was reached in 6 days in both the 30 and 80 mg groups, with an elimination half-life of 18 days. The C.sub.max and area under the plasma concentration-time curve increased in a dose-dependent manner, and the trough concentration reached steady state by week 16. The exposure of OZR correlated negatively with patient body weight and was not affected by other patient baseline characteristics. Effects of ADAs on the exposure and efficacy of OZR were limited in both trials. However, antibodies that neutralize the binding to TNF[alpha] had some effect on the exposure and efficacy of OZR in the NATSUZORA trial. The receiver operating characteristic analysis of the effect of trough concentration on the American College of Rheumatology 20% and 50% improvement rates was retrospectively performed, and a cutoff trough concentration of approximately 1 [mu]g/mL at week 16 was obtained in both trials. The efficacy indicators in the subgroup with trough concentration [greater than or equal to] 1 [mu]g/mL were higher than those in the < 1 [mu]g/mL subgroup at week 16, while no clear cutoff was obtained at week 52 in both trials. Conclusions OZR showed a long half-life and favorable PK properties. A post hoc analysis suggested sustained efficacy independent of trough concentration by subcutaneous administration of OZR 30 mg at 4-week intervals for 52 weeks. Trial registration JapicCTI, OHZORA trial: JapicCTI-184029, registration date July 9, 2018; NATSUZORA trial: JapicCTI-184031, registration date July 9, 2018. Keywords: Pharmacokinetics, Pharmacodynamics, Arthritis rheumatoid, Tumor nec