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.

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).

Ultrasonographic non-radiographic erosions could predict the efficacy of belimumab in articular systemic lupus erythematosus.

The aim of this study is to characterise lupus-related arthritis and assess if the presence of ultrasound-detected erosions could be associated with belimumab in the treatment of systemic lupus erythematosus (SLE) articular manifestations. We performed a spontaneous, monocentric, retrospective, and observational study. We enrolled patients affected by SLE with articular involvement treated with belimumab. We excluded patients with positive rheumatoid factor (RF) or anti-citrullinated peptide antibody (ACPA), Jaccoud's arthropathy, and radiographic erosions. Patients were assessed at baseline, 3, and 6 months. We collected laboratory and clinical data from electronic records. Joint disease activity was assessed using disease activity score on 28 joints based on C-reactive protein (DAS28-CRP), swollen and tender joints count. All patients underwent an ultrasound examination of the wrist, metacarpophalangeal, proximal interphalangeal, and metatarsal-phalangeal joints before the initiation of treatment with belimumab. We performed Student's T-test and Mann-Whitney's U-test to assess the difference between means and Fisher's exact test to assess difference in proportions, and linear univariate regression to investigate predictors of disease activity. We enrolled 23 patients (female 82.6%, mean age of 50.65 ± 14.1 years). Seven patients (30.4%) presented bone erosions at baseline. Patients with bone erosions were generally older (61 ± 16.1 vs 46.13 ± 10.7 years, p = 0.016), more frequently male (42.8 vs 6.2%, p = 0.03), with higher baseline CRP levels (10.29 ± 11.6 vs 2.25 ± 3.1 mg/L, p = 0.015) and C4 levels (0.19 ± 0.17 vs 0.1 ± 0.04 g/L, p = 0.05). After 6 months of treatment with belimumab, patients without erosions improved their DAS28-CRP significantly (2.95 ± 0.89 vs 2.26 ± 0.48, p = 0.01), while patients with erosions did not (3.6 ± 0.79 vs 3.2 ± 0.95, p = 0.413). DAS28-CRP did not differ between the two groups at baseline, while it was significantly lower at the other two time points in patients without erosions. The majority of patients achieved remission at 6 months follow-up based on DAS28-CRP criteria (73.9%), with a significant difference between patients with and without erosions (42.8 vs 87.5%, p = 0.045). The presence of articular ultrasound-detected erosions could be predictive of a decreased efficacy of belimumab in the articular manifestations of SLE. A possible explanation is a rheumatoid-like articular phenotype, despite the lack of ACPA-positivity and radiologic erosions. However, due to the small sample population, larger cohorts are needed to assess the possible predictive role of this finding.

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.

Potential impact of the antirheumatic agent auranofin on proviral HIV-1 DNA in individuals under intensified antiretroviral therapy: Results from a randomised clinical trial.

Antiretroviral therapy (ART) is typically composed of a combination of three antiretroviral drugs and is the treatment of choice for people with human immunodeficiency virus type 1/acquired immune deficiency syndrome (HIV-1/AIDS). However, it is unable to impact on viral reservoirs, which harbour latent HIV-1 genomes that are able to reignite the infection upon treatment suspension. The aim of this study was to provide an estimate of the safety of the disease-modifying antirheumatic agent auranofin and its impact on the HIV-1 reservoir in humans under intensified ART. For this purpose, an interim analysis was conducted of three of the six arms of the NCT02961829 clinical trial (five patients each) with: no intervention, i.e. continuation of first-line ART; intensified ART (ART + dolutegravir and maraviroc); and intensified ART plus auranofin. Auranofin treatment was found to be well tolerated. No major adverse events were detected apart from a transient decrease in CD4+ T-cell counts at Weeks 8 and 12. Auranofin decreased total viral DNA in peripheral blood mononuclear cells compared with ART-only regimens at Week 20 (P = 0.036) and induced a decrease in integrated viral DNA as quantified by Alu PCR. Despite the limited number of patient-derived sequences available in this study, phylogenetic analyses of nef sequences support the idea that auranofin may impact on the viral reservoir. [ClinicalTrials.gov ID: NCT02961829].

Treatment patterns and economic outcomes in patients with juvenile idiopathic arthritis.

Purpose: To describe health care resource utilization (HCRU) and costs among patients with juvenile idiopathic arthritis (JIA) compared to patients without JIA and to describe treatment patterns among JIA patients who initiated biologic and non-biologic disease-modifying antirheumatic drugs (DMARDs). Patients and methods: The IBM MarketScan® Commercial Database was used to identify patients aged 2-17 years with a new JIA diagnosis (index date) and 12 months continuous enrollment pre- and post-diagnosis from 2008 to 2016. JIA patients were matched to non-JIA patients on age, gender, region, and health plan type. Patients with other rheumatic or autoimmune conditions were excluded. Receipt of a biologic and/or non-biologic was evaluated on or after the new JIA diagnosis. Results: A total of 3,815 JIA patients were matched to 11,535 non-JIA patients (mean age 10.0 [SD=4.5], 69% female). Average total costs were greater for JIA patients than non-JIA controls ($18,611 [SD=$42,104; median=$8,189] versus $2,203 [SD=$9,309; median=$649], p<0.001). Outpatient pharmacy costs were 33.6% of the total costs among JIA patients compared to 18.4% among non-JIA patients (p<0.001). The proportion of inpatient cost (11.4% versus 14.3%, p<0.001) and outpatient costs (55% versus 67.4%, p<0.001) of total costs was lower among JIA patients compared to non-JIA patients. Patients with 12 months of continuous enrollment post-treatment initiation (n=2,014) were classified as non-biologic only (n=734), biologic only (n=873), and both biologic and non-biologic (n=407) users. Among biologic and non-biologic users, 41.1% and 56.8% were persistent on their index medication for 12 months. Of patients treated with a biologic only, TNF inhibitors (TNFi) comprised 87.1% of the total treatment costs. Conclusion: JIA is associated with increased costs and utilization in every HCRU category compared to matched non-JIA patients. While JIA-related costs varied by treatment cohort, patients on biologic DMARDs had substantially higher costs than patients on non-biologic DMARDs and fewer than one-half were persistent at 12 months after biologic initiation.

Comparison of Serious Adverse Event Profiles Among Antirheumatic Agents Using Japanese Adverse Drug Event Report Database.

BACKGROUND: The association between drugs and adverse events (AEs) has been investigated using various AE databases. The aim of this study was to provide useful information for risk minimization of antirheumatic agents by investigating the safety profiles of antirheumatic agents using the Japanese Adverse Drug Event Report database (JADER), focusing on some important serious AEs (SAEs) and their relation to time. METHODS: Tumor necrosis factor-alpha inhibitors (TNF-Is), interleukin-6 inhibitors (IL-6-Is), and methotrexate (MTX) were selected as antirheumatic agents. Tuberculosis, malignant tumors, and bone marrow disorders were focused as typical SAEs. Disproportionate reporting of these SAEs was evaluated using the reporting odds ratio. Time to onset of each SAE was calculated using date information. RESULTS: Increased reporting odds ratios were observed in tuberculosis and malignant tumors associated with TNF-I, in tuberculosis and malignant tumors associated with IL-6-I, and in tuberculosis, malignant tumors, and bone marrow disorders associated with MTX. The median time to onset of the focused SAEs associated with TNF-I were 501, 681, and 254 days, respectively; those associated with IL-6-I were 387, 636, and 116 days; and those associated with MTX were 537, 1125, and 328 days. These results suggested different profiles for the focused SAEs. CONCLUSION: The time-to-onset profiles of the SAEs for TNF-I, IL-6-I, and MTX as antirheumatic agent were different among different SAEs, which suggests that they should be monitored carefully based on the profiles. The information from JADER is expected to contribute to the risk minimization of drugs in the actual clinical practice.

Use of a Cholestyramine Washout in a Patient With Septic Shock on Leflunomide Therapy: A Case Report and Review of the Literature.

Patients presenting with infections while receiving disease-modifying antirheumatic agents (DMARD) may be predisposed to a higher degree illness due to immunosuppression. This can be particularly problematic in patients who are receiving DMARDs with prolonged pharmacokinetic profiles. Leflunomide is a DMARD that has a prolonged half-life due to enterohepatic recirculation. We report a case of a patient with severe septic shock secondary to a prosthetic joint infection in which therapeutic levels of leflunomide were discovered, despite the patient ceasing therapy several weeks prior to admission. An orogastric cholestyramine washout was given to the patient to expedite the removal of the drug. Serum levels rapidly declined over the next several days, corresponding with resolution of her sepsis. A review of the literature relevant to the incidence of DMARD-related infections was conducted as well as discussion regarding the role of leflunomide drug monitoring and cholestyramine-facilitated removal of the drug in episodes of acute infectious syndromes.

Cost-effectiveness of TNF inhibitors vs synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a Markov model study based on two longitudinal observational studies.

OBJECTIVE: The objective of this study was to estimate the additional costs and health benefits of adding a TNF inhibitor (TNFi) (adalimumab, certolizumab, etanercept, golimumab, infliximab) to a synthetic DMARD (sDMARD), e.g. MTX, in patients with RA. METHODS: We developed the Norwegian RA model as a Markov model simulating 10 years of treatment with either TNFi plus sDMARDs (TNFi strategy) or sDMARDs alone (synthetic strategy). Patients in both strategies started in one of seven health states, based on the Short Form-6 Dimensions (SF-6D). The patients could move to better or worse health states according to transition probabilities. In the TNFi strategy, patients could stay on TNFi (including switch of TNFi), or switch to non-TNFi-biologics (abatacept, rituximab, tocilizumab), sDMARDs or no DMARD. In the synthetic strategy, patients remained on sDMARDs. Data from two observational studies were used for the assessment of resource use and utilities in the health states. Health benefits were evaluated using the EuroQol-5 Dimensions (EQ-5D) and SF-6D. RESULTS: The Norwegian RA model predicted that 10-year discounted health care costs totalled €124,942 (€475,266 including production losses) for the TNFi strategy and €65,584 (€436,517) for the synthetic strategy. The cost per additionally gained quality-adjusted life-year of adding a TNFi was €92,557 (€60,227 including production losses) using SF-6D and €61,285 (€39,841) using EQ-5D. Including health care costs only, the probability that TNFi treatment was cost-effective was 90% when using EQ-5D, assuming a Norwegian willingness-to-pay level of €67,300. CONCLUSION: TNFi treatment for RA is cost-effective when accounting for production losses. Excluding production losses, TNFi treatment is cost-effective using EQ-5D, but not SF-6D.