Systematic review and meta-analysis for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis.

OBJECTIVES: To update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology (JCR) clinical practice guidelines (CPG) for the management of rheumatoid arthritis (RA). METHODS: We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, 2 independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses. RESULTS: Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to csDMARD. Rituximab with and without concomitant csDMARDs showed similar efficacy to other bDMARDs in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients. CONCLUSION: This systematic review provides latest evidence for the 2024 update of the JCR CPG for RA management.

Efficacy and safety of anti-TNF multivalent NANOBODY® compound 'ozoralizumab' without methotrexate co-administration in patients with active rheumatoid arthritis: A 52-week result of phase III, randomised, open-label trial (NATSUZORA trial).

OBJECTIVES: The aim is to assess the efficacy and safety of a 52-week subcutaneous ozoralizumab treatment at 30 and 80 mg without methotrexate (MTX) in active rheumatoid arthritis. METHODS: This randomised, open-label, multicentre phase III trial randomly allocated 140 patients in 2:1 ratio as subcutaneous ozoralizumab at 30 or 80 mg every 4 weeks for 52 weeks without MTX. RESULTS: Both groups administered ozoralizumab at 30 and 80 mg showed good clinical improvement. The American College of Rheumatology response rates were high at Week 24 and maintained through 52 weeks. The ozoralizumab groups also showed good improvement in other end points, and improvements observed from Week 1 were maintained through 52 weeks. Improvements in many efficacy assessments were similar between doses. No deaths were reported, and serious adverse events occurred in a total of 20 patients in the ozoralizumab groups. Increased antidrug antibodies were observed in approximately 40% of patients in the ozoralizumab groups, and 27.7% of the patients in the 30 mg group were neutralising antibody-positive. CONCLUSIONS: Ozoralizumab, at 30 and 80 mg, demonstrated significant therapeutic effects without MTX, and the efficacy was maintained for 52 weeks with active rheumatoid arthritis. Ozoralizumab showed an acceptable tolerability profile over 52 weeks.

Efficacy and safety of the anti-TNF multivalent NANOBODY® compound ozoralizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: A 52-week result of a Phase II/III study (OHZORA trial).

OBJECTIVE: To assess the efficacy and safety through a 52-week treatment with subcutaneous ozoralizumab at 30 or 80 mg in patients with active rheumatoid arthritis despite methotrexate therapy. METHODS: This multicentre, randomized, placebo-controlled, double-blind, parallel-group confirmatory trial included a 24-week double-blind treatment period followed by a 28-week open-label treatment period. The double-blind treatment period randomized 381 (2:2:1) patients to placebo and ozoralizumab at 30 or 80 mg, and patients receiving placebo were re-randomized (1:1) to ozoralizumab at 30 or 80 mg in the open-label period. RESULTS: The ozoralizumab groups showed good clinical improvement, with high American College of Rheumatology response rates at 52 weeks, as well as good improvements in other endpoints, which were observed from Day 3 and maintained through Week 52. Furthermore, the ozoralizumab groups showed a high remission rate in clinical and functional remission at Week 52. Serious adverse events occurred in a total of 23 patients in the ozoralizumab groups, without differences in incidence between doses. CONCLUSIONS: Ozoralizumab demonstrated significant therapeutic effects and efficacy, which was maintained for 52 weeks. The safety profile was consistent with the evaluated results in interim analysis at Week 24, and ozoralizumab was well-tolerated up to Week 52.

Structural, nonclinical, and clinical features of ozoralizumab: A novel tumour necrosis factor inhibitor.

Tumour necrosis factor (TNF) inhibitors are currently the most widely used biological agents to treat rheumatoid arthritis. Ozoralizumab (OZR), a novel TNF inhibitor, is an antibody using variable heavy-chain domains of heavy-chain antibody (VHHs) and became the first VHH drug approved for the treatment of rheumatoid arthritis in September 2022. VHHs isolated from camelid heavy-chain antibodies can bind antigens with a single molecule. OZR is a trivalent VHH that consists of two anti-human TNFα VHHs and one anti-human serum albumin (anti-HSA) VHH. This review summarizes OZR's unique structural characteristics and nonclinical and clinical data. The clinical data outline the pharmacokinetics, efficacy, relationship between efficacy and pharmacokinetics, and safety of OZR, focusing on a Phase II/III confirmatory study (OHZORA trial).

Effect of extended dosing interval of anti-TNF-alpha NANOBODY® compound ozoralizumab in patients with low disease activity rheumatoid arthritis.

OBJECTIVE: To evaluate the effect of extended dosing interval on the efficacy and safety of ozoralizumab in patients with rheumatoid arthritis (RA). METHODS: In a long-term extension study (HOSHIZORA trial) for patients who had completed a phase II/III study with methotrexate (MTX) or a phase III study without MTX, the dosing interval of ozoralizumab was allowed to extend from every 4 weeks (Q4W) to every 8 weeks (Q8W), at the physician's discretion, for patients who had maintained DAS28-ESR <3.2 at the last two time points. The continuation rate, efficacy and safety were examined in patients who had completed 24 weeks after the change in the dosing interval by the data cut-off point. RESULTS: Of the 32 patients who maintained DAS28-ESR <3.2 and changed the interval from Q4W to Q8W, 28 (87.5%) remained on Q8W for 24 weeks. At week 24, the percentages of patients who remained on Q8W and achieved DAS28-ESR <2.6 and <3.2 were 71.9% and 84.4%, respectively. No safety concerns were observed for 24 weeks in the Q8W group. CONCLUSIONS: In patients with RA and maintained DAS28-ESR <3.2 with ozoralizumab, efficacy was sustained and well tolerated after the dosing interval was extended from Q4W to Q8W.

Population Pharmacokinetics of Ozoralizumab in Patients with Rheumatoid Arthritis.

Ozoralizumab is a bispecific NANOBODY compound that binds tumor necrosis factor alpha (TNFα) and human serum albumin. Ozoralizumab inhibits the TNFα physiological activity while maintaining long-term plasma retention owing to its human serum albumin-binding ability. A population pharmacokinetic (PK) model was developed using data from 494 Japanese patients with rheumatoid arthritis in Phase II/III and Phase III trials to assess the effects of potential PK covariates. The ozoralizumab PK after subcutaneous administration was described using a 1-compartment model with first-order absorption and first-order elimination processes. A proportional error model was used for inter- and intra-individual variabilities, with covariance set between inter-individual variabilities of the apparent clearance and apparent distribution volume. Body weight, sex, antidrug antibody status, estimated glomerular filtration rate, and concomitant methotrexate use were identified as covariates for apparent clearance, while body weight and sex were covariates for apparent distribution volume in the final model. Body weight had the greatest effect on the PK of ozoralizumab, while the other covariates had minor effects. When administered at 30 mg every 4 weeks, the predicted steady-state plasma trough concentration in a patient weighing 83.2 kg exceeded the trough concentration required to maintain efficacy of ozoralizumab, and the estimated exposure in a patient weighing 42.5 kg did not exceed the mean exposure at 80 mg, a well-tolerated dose, throughout 52 weeks. We developed a population PK model that adequately described the ozoralizumab PK in Japanese patients with rheumatoid arthritis, and none of the evaluated covariates showed clinically relevant effects on the PK of ozoralizumab.

Ozoralizumab: first Nanobody® therapeutic for rheumatoid arthritis.

INTRODUCTION: Ozoralizumab (Nanozora), a novel TNF inhibitor, was first approved in Japan in September 2022 as a next-generation antibody for the treatment of rheumatoid arthritis (RA). Ozoralizumab potently inhibits TNF action through two human TNFα-binding domains, and a human serum albumin-binding domain that prolongs its plasma half-life enabling 4-week administration intervals. Its molecular weight is 38 kDa, which is one-fourth that of the conventional immunoglobulin G. AREAS COVERED: Structural characteristics of ozoralizumab, preclinical findings, clinical data, and its recommended positioning in current RA treatments have been summarized. EXPERT OPINION: Studies using mouse models have shown the rapid distribution of ozoralizumab in inflamed joint tissues, presumably because of its small molecular size and albumin-binding action. In clinical studies, remarkable improvements in clinical symptoms and patient-reported outcomes were observed 2 days after subcutaneous administration of 30 mg ozoralizumab with concurrent methotrexate therapy. Moreover, the efficacy and tolerability of the drug for up to 52 weeks, with or without methotrexate, were confirmed. Ozoralizumab is expected to be a highly practical option for patients with RA as a new type of TNF inhibitor with early symptom improvement despite subcutaneous administration.

Efficacy and pharmacokinetics of ozoralizumab, an anti-TNFα NANOBODY® compound, in patients with rheumatoid arthritis: 52-week results from the OHZORA and NATSUZORA trials.

INTRODUCTION: Ozoralizumab (OZR), a tumor necrosis factor alpha (TNFα) inhibitor, is a NANOBODY® compound that binds to TNFα 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 (Cmax) was reached in 6 days in both the 30 and 80 mg groups, with an elimination half-life of 18 days. The Cmax 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 TNFα 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 µg/mL at week 16 was obtained in both trials. The efficacy indicators in the subgroup with trough concentration ≥ 1 µg/mL were higher than those in the < 1 µg/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.