Inflammation-mediated drug interactions of olokizumab and cytochrome P450 activities in patients with rheumatoid arthritis.

AIMS: In patients with rheumatoid arthritis (RA), interleukin (IL)-6 affects the activity of cytochrome P450 (CYP) enzymes. Treatment with anti-IL-6 therapy can reverse the IL-6-mediated downregulation of CYP enzymes, resulting in changes in plasma levels of CYP substrates. The primary objective of this study was to evaluate the impact of the IL-6 inhibitor olokizumab on the pharmacokinetics of CYP probe substrates in subjects with active RA. METHODS: Seventeen patients with active RA were orally administered a phenotyping cocktail of midazolam (CYP3A4 substrate), omeprazole (CYP2C19 substrate), warfarin (CYP2C9 substrate) and caffeine (CYP1A2 substrate) alone and 2 weeks after a single subcutaneous injection of 128 mg olokizumab. The pharmacokinetic parameters of each substrate were calculated using noncompartmental analysis. RESULTS: Sixteen of 17 enrolled patients received the complete doses of the cocktail drugs and olokizumab and were eligible for the pharmacokinetic evaluations. After single-dose administration of olokizumab, the exposure of midazolam and omeprazole decreased by 30-33% and 26-32%, respectively, compared to when the substrates were administered along via cocktail. In the presence of olokizumab, caffeine exposure increased by 19-23% compared to caffeine administration alone. There were no significant changes in S-warfarin exposure. CONCLUSION: In patients with active RA, olokizumab potentially reverses the IL-6-mediated suppression of CYP3A4 and CYP2C19. According to FDA guidance, olokizumab is considered a weak inducer of CYP3A4 and CYP2C19.

Comparison of the efficacy and safety of tocilizumab, sarilumab, and olokizumab in patients with active rheumatoid arthritis: a network meta-analysis of randomized controlled trials.

OBJECTIVE: This study compared the relative efficacy and safety of olokizumab, tocilizumab, and sarilumab in rheumatoid arthritis (RA) patients who were intolerant or responding inadequately to methotrexate (MTX). METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of olokizumab, tocilizumab, and sarilumab in RA patients who were intolerant or responding inadequately to MTX. RESULTS: Six RCTs comprising 4439 patients met the inclusion criteria. Tocilizumab, sarilumab, olokizumab, and adalimumab treatments achieved a significant American College of Rheumatology 20% (ACR20) response rate compared with placebo. However, tocilizumab was associated with the most favorable surface area using the cumulative ranking curve (SUCRA) for the ACR20 response rate. The ranking probability based on the SUCRA indicated that tocilizumab treatment had the highest probability of providing the best ACR20 response rate, followed by sarilumab, olokizumab every 2 weeks (Q2W), olokizumab Q4W, adalimumab 40 mg, and placebo. The ACR50 and 70 response rates showed a distribution pattern similar to that of the ACR20 response rate. However, olokizumab Q4W had a higher ranking probability than olokizumab Q2W. The SUCRA rating showed that the placebo was the best intervention with the least adverse events (AEs) and withdrawal due to AEs, followed by interleukin­6 inhibitors. CONCLUSION: Tocilizumab, sarilumab, and olokizumab are more effective than adalimumab and have similar efficacy and safety in RA patients with inadequate responses to MTX.

Comparison of the efficacy and safety of olokizumab at different dosages in patients with active rheumatoid arthritis: a network meta-analysis of randomized controlled trials.

OBJECTIVE: This study aimed to assess the relative efficacy and safety of olokizumab at different dosages in patients with active rheumatoid arthritis (RA). METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of olokizumab administered intravenously to RA patients at 64 mg/kg every 2 or 4 weeks (Q2 or Q4W). RESULTS: Five RCTs comprising 2609 patients met the inclusion criteria. Both olokizumab Q2 and Q4W treatments achieved a significant American College of Rheumatology 20% response (ACR20) compared with the placebo (odds ratio [OR] 3.21, 95% credible interval [CrI] 2.53-4.09; OR 3.05, 95% CrI 2.43-3.86). However, olokizumab Q2W was associated with the most favorable surface using the cumulative ranking curve (SUCRA) for the ACR20 response rate. The ranking probability based on the SUCRA indicated that olokizumab Q2W had the highest probability of being considered the best treatment option for achieving the ACR20 response rate, followed by olokizumab Q4W, adalimumab, and placebo. The ACR50 and 70 response rates showed a similar distribution pattern to the ACR20 response rate, except that olokizumab Q4W had a higher-ranking probability than olokizumab Q2W for ACR50. The SUCRA rating likelihood of adverse events (AEs) and withdrawal due to AEs showed that a placebo was likely to be the best intervention. CONCLUSION: Both olokizumab Q2 and Q4W were efficacious and well-tolerated treatments for active RA.

Results of a 12-Week Open-Label, Non-Interventional Study of the Efficacy and Safety of Olokizumab Therapy in Patients with Rheumatoid Arthritis after Switching from Anti-B-Cell Therapy during the SARS-CoV-2 Pandemic.

ABSTTACT: -The COVID-19 pandemic has significantly changed the understanding of the safety profile of therapies for immunoinflammatory rheumatic diseases (IRDs). This is primarily due to the negative impact of a number of basic disease-modifying antirheumatic drugs (DMARDs) and genetically engineered biological drugs (biological DMARDs, or biologics) on the course and outcomes of a new coronavirus infection. A number of studies have shown that anti-B-cell therapy (rituximab) gave a statistically significant increase in the risk of severe COVID-19 and an increase in mortality. At the same time, the analysis of real clinical practice data dictated the need to establish a number of restrictions on the use of certain classes of biologics and to search for alternative therapy programs to maintain control over disease activity. PURPOSE OF THE STUDY: The purpose of the study was to evaluate the efficacy and safety of the drug Artlegia® (olokizumab), solution for subcutaneous injection, 160 mg/ml-0.4 ml, manufactured by R-Pharm JSC, Russia) for the treatment of patients with rheumatoid arthritis in real clinical practice after switching with rituximab during the COVID-19 pandemic. MATERIALS AND METHODS: The study included 14 patients with a confirmed diagnosis of rheumatoid arthritis (RA), who were previously on rituximab therapy at a dose of 1000-500 mg twice with an interval of 2 weeks, who received at least one course of therapy with this drug. As RA worsened, patients were switched to olokizumab against the background of standard DMARDs. On weeks 0, 4, 8, and 12 after the switch, the severity of pain was assessed on the VAS scale, the number of tender and swollen joints (TJC28 and SJC28), the level of acute-phase inflammation markers, the DAS28 (disease activity score), ESR, CRP, CDAI (clinical activity index), and the functional state index HAQ (Health Assessment Questionnaire) were determined, as well as the safety profile of therapy was assessed. RESULTS: Data analysis was performed using median values (Me) were used for data analysis. A significant decrease in TJC28 was detected after 8 and 12 weeks of treatment with olokizumab (Artlegia®) (Me baseline = 10, Me 8 weeks = 4, Me 12 weeks = 4, p < 0.05) and a decrease in TSC28 was detected after 4, 8, and 12 weeks of treatment (Me baseline = 9, Me 4 weeks = 3.5, Me 8 weeks = 2.5, Me 12 weeks = 2.0, p < 0.05). Laboratory markers of inflammation showed a decrease in CRP and ESR levels after 4 weeks of treatment (CRP: Me4 weeks = 21, Me4 weeks = 1, p < 0.05, ESR: Mesno = 31, Me4 weeks = 7, p < 0.05). Positive dynamics persisted on 8 and 12 weeks (CRP: Me 8 weeks = 1, Me 12 weeks = 0; ESR: Me 8 weeks = 4, Me 12 weeks = 5). The level of CRP by week 4 became within the normal range, regardless of the initial values. All activity indices improved from week 4 in each evaluation period compared to baseline: DAS28-ESR: Me baseline = 5.52, Me 4 weeks = 3.59, Me 8 weeks = 3.33, Me 12 weeks = 3.22, p < 0.05; DAS28CRP: Me baseline = 5.39, Me 4 weeks = 3.71, Me 8 weeks = 3.35, Me 12 weeks = 3.45, p < 0.05; CDAI: Me baseline = 28.5, Me 4 weeks = 18.0, Me 8 weeks = 16.5, Me 12 weeks = 16.0, p < 0.05. All patients showed a reduction in pain (VAS scale) by week 8. The functional status of patients, according to the HAQ index, showed a significant decrease only by week 12 of the study: Me baseline = 1.62, Me 12 weeks = 1.31, p < 0.05. CONCLUSIONS: The study found that switching from rituximab to olokizumab was effective and safe during the COVID-19 pandemic.

Efficacy of Olokizumab against Comorbid Depressive Disorder in Patients with Rheumatoid Arthritis: Preliminary Results of the Study.

Interleukin (IL) 6 plays an important role in the pathogenesis of depression comorbid with rheumatoid arthritis (RA), and IL-6 inhibitors used to treat patients with RA may have an antidepressant effect. The objective of the study was to evaluate the effectiveness of Russian iIL-6 olokizumab (OKZ) in reducing symptoms of depression in patients with moderate/high RA activity. To date, 49 RA patients have been included, of which 43 (87.7%) are women, with an average age of 47.8 ± 12.8 years; with a predominant high activity of RA according to DAS28 (CRP) indices (89.8%), SDAI (79.6%) and CDAI (75.5%) and inefficacy of stable 12-week therapy with сDMARDs. In all patients, a psychiatrist, in accordance with ICD-10, diagnosed depression (chronic or recurrent) of varying severity during a semi-structured interview. At week 0, all patients were randomized by the method of sequential numbers in a ratio of 1 : 1 : 1 to one of the three study groups: group 1-cDMARDs + OKZ 64 mg subcutaneously once every 4 weeks (n = 18); group 2-cDMARDs + OKZ 64 mg subcutaneously once every 4 weeks + psychopharmacotherapy (PPT) (n = 26); group 3-cDMARDs + PPT (n = 5). The duration of the study is 24 weeks. The dynamics of depression severity was assessed on the PHQ-9, MADRS scales; anxiety, on HAM-A; experimental psychological projective techniques were also used. After 12 and 24 weeks of therapy, there was a significant decrease in the severity of depression and anxiety in all groups of patients. However, the difference between the final and initial values of all scales was statistically significantly greater (p <0.05) in the groups of patients receiving PPT: cDMARDs + OKZ + PPT (ΔPHQ-9 24-0 = -6.75 ± 3.91; ΔMADRS 24-0 = -22.5 ± 4.83; ΔHAM-A 24-0 = -14.6 ± 5.37) and cDMARDs + PPT (ΔPHQ-9 24-0 = -15.5 ± 3.53; ΔMADRS 24-0 = -25.0 ± 1.41; ΔHAM-A 24-0 = -18.5 ± 3.53), compared with the cDMARDs + OKZ group (ΔPHQ-9 24-0 = -4.00 ± 3.89; ΔMADRS 24-0 = -5.75 ± 8.29; ΔHAM-A 24-0 = -8.50 ± 8.21). According to a semi-structured interview with a psychiatrist and design experimental psychological techniques, the proportion of patients without depression after 24 weeks of therapy was significantly higher in the groups of patients receiving PPT: 90% in the group of cDMARDs + OKZ + PPT and 100%-cDMARDs + PPT, as opposed to 25% in the group of cDMARDs + OKZ. OKZ therapy contributed to the normalization of night sleep but did not lead to a decrease in the frequency and severity of cognitive disorders (CDs). OKZ has an antidepressant effect, leads to a decrease in the frequency of sleep disorders. However, a complete regression of depression symptoms when OKZ is prescribed without PPT is possible only in 25% of RA patients, mainly in the patients with mild depression. A combination of OKZ and PPT is optimal for the complete regression of depression and anxiety and a decrease in the frequency and severity of CDs.

Olokizumab's Effectiveness and Safety in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: In the development of rheumatoid arthritis, the cytokine interleukin-6 plays a role. An interleukin-6 cytokine-specific monoclonal antibody called olokizumab directly targets this cytokine. OKZ effectiveness and safety are being evaluated through this meta-analysis. METHOD: I looked up every published randomized controlled study on Clinicaltrials.gov, Scopus, Web of Science, Cochrane, and PubMed. I conducted the study using both the Mantel-Haenszel and inverse variance approaches. I evaluated bias in the included studies using the risk of bias tool 2. RESULTS: In this meta-analysis, five trials totalling 2227 participants, were examined. In contrast to the placebo group, the olokizumab group had a significantly higher incidence of American College of Rheumatology 20; RR = 1.83, 95% CI [1.69, 1.99], P < 0.00001. Regarding Health Assessment Questionnaire-Disability Index improvement, olokizumab significantly outperformed the placebo group; MD = -0.28, 95% CI [-0.32, -0.24], P < 0.00001. The incidence of treatment-emergent adverse events was significantly higher in the olokizumab group than in the placebo group; RR = 1.10, 95% CI [1.04, 1.17], P = 0.0006. Furthermore, the incidence of treatment-emergent serious adverse events did not differ significantly between the olokizumab group and the placebo group; RR = 0.85, 95% CI [0.60, 1.20], P = 0.35. CONCLUSION: In patients with rheumatoid arthritis, olokizumab combined methotrexate is well tolerated and more effective than placebo plus methotrexate.

[Experience of olokizumab use in COVID-19 patients].

Most subjects with the COVID-19 experience mild to moderate symptoms, but approximately 10% of cases suffer from severe course of disease. IL-6 inhibitors are actively used to neutralize and prevent the cytokine storm. Olokizumab is a humanized monoclonal antibody belonging to the G4/Kappa immunoglobulin isotype that selectively binds to human IL-6 and effectively neutralizes it. AIM: To evaluate the efficacy and safety of Artlegia (olokizumab) for the treatment of subjects with a disease caused by the SARS-COV-2 virus in a real-world clinical setting. MATERIALS AND METHODS: The analysis included data of 610 subjects aged 55.0812.68 years who received olokizumab at a single dose of 160 mg/mL 0.4 mL subcutaneously as a preemptive anti-inflammatory therapy. The comparison group included 511 subjects aged 55.2311.23 years who received standard therapy without IL-6 inhibitors. Control Endpoints: 1. Positive clinical changes on Day 7. 2. Changes in the CRP levels on Days 1, 2, and 7. 3. Duration of oxygen therapy. 4. Number of days in hospital. 5. Number of adverse events. 6. Disease outcome. RESULTS: If a cytokine storm occurs, immune regulatory events will trigger the development of either a protective immune response or an exacerbated inflammatory response. The use of preemptive anti-inflammatory therapy has both a short-term and, most importantly, a long-term effect on the T and B parts of the immune process. These aspects definitely require further research and observation. CONCLUSION: The use of olokizumab to treat the new COVID-19 coronavirus disease has demonstrated a positive effect on clinical and laboratory parameters. Primarily, it affects the severity of clinical parameters by improving the general condition already on the first day of observation, and decreasing body temperature to normal values. The changes in the C-reactive protein levels show a significant effect of the IL-6 inhibitor on the systemic inflammatory response.

Probing binding mechanism of interleukin-6 and olokizumab: in silico design of potential lead antibodies for autoimmune and inflammatory diseases.

Computer-aided antibody engineering has been successful in the design of new biologics for disease diagnosis and therapeutic interventions. Interleukin-6 (IL-6), a well-recognized drug target for various autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis, was investigated in silico to design potential lead antibodies. Here, crystal structure of IL-6 along with monoclonal antibody olokizumab was explored to predict antigen-antibody (Ag - Ab)-interacting residues using DiscoTope, Paratome, and PyMOL. Tyr56, Tyr103 in heavy chain and Gly30, Ile31 in light chain of olokizumab were mutated with residues Ser, Thr, Tyr, Trp, and Phe. A set of 899 mutant macromolecules were designed, and binding affinity of these macromolecules to IL-6 was evaluated through Ag - Ab docking (ZDOCK, ClusPro, and Rosetta server), binding free-energy calculations using Molecular Mechanics/Poisson Boltzman Surface Area (MM/PBSA) method, and interaction energy estimation. In comparison to olokizumab, eight newly designed theoretical antibodies demonstrated better result in all assessments. Therefore, these newly designed macromolecules were proposed as potential lead antibodies to serve as a therapeutics option for IL-6-mediated diseases.

Efficacy and safety of olokizumab in Asian patients with moderate-to-severe rheumatoid arthritis, previously exposed to anti-TNF therapy: Results from a randomized phase II trial.

OBJECTIVES: This phase II, dose-ranging, double-blind, placebo-controlled, randomized study (NCT01463059) evaluated efficacy and safety of olokizumab (OKZ), a humanized anti-interleukin 6 monoclonal antibody, in Asian patients with moderately-to-severely active rheumatoid arthritis (RA) who had previously failed anti-TNF therapy. METHODS: Patients were randomized to one of six treatment arms: placebo or OKZ (60 mg/120 mg/240 mg every four weeks [Q4W]; or 60 mg/120 mg every two weeks [Q2W]); stratified by country and number of prior anti-TNFs. Primary efficacy variable was Week 12 change from baseline (CFB) in DAS28 CRP for 4-week cumulative dose groups of OKZ and placebo; secondary efficacy variables were Week 12 ACR20/ACR50/ACR70 response rates. Patients continued MTX treatment from baseline, without additional csDMARDs. RESULTS: Of 119 randomized patients, 88.2% completed the study. Greater improvements in DAS28(CRP) mean CFB at Week 12 were observed in all OKZ 4-week cumulative dose groups (60 mg/120 mg/240 mg) versus placebo (p < 0.0001). Week 12 ACR20/ACR50 response rates were higher in all OKZ cumulative dose groups versus PBO (p < 0.05). Incidences of adverse events were similar across OKZ 4-week cumulative dose groups (76.9-84.4%) and placebo (82.8%) with no deaths. CONCLUSIONS: OKZ demonstrated improvements in efficacy variables versus placebo in Asian patients with moderately-to-severely active RA who had previously failed anti-TNF therapy. The safety profile was as expected for this class of drug.

The efficacy and safety of olokizumab for rheumatoid arthritis: a systematic review, pairwise, and network meta-analysis.

Olokizumab (OKZ) is a novel IL-6 inhibitor that directly targets IL-6 rather than its receptor. We aim to evaluate the efficacy and safety of OKZ for patients with rheumatoid arthritis (RA) and to investigate the optimal treatment regimen. A systematic review, pairwise, and network meta-analysis synthesizing randomized controlled trials (RCTs) from WOS, CENTRAL, SCOPUS, EMBASE, and PubMed until August 31, 2022. We used the risk ratio (RR) and mean difference (MD) for dichotomous and continuous outcomes, respectively, presented with the corresponding 95% confidence interval (CI). We registered our protocol in PROSPERO with ID: CRD42022358082. Five RCTs with 2277 patients were included. OKZ significantly improved the American College of Rheumatology criteria (ACR) 20 (RR: 1.97 with 95% CI [1.49, 2.58], P = 0.00001), ACR50 (RR: 3.83 with 95% CI [2.13, 6.87], P = 0.00001), ACR70 (RR: 3.83 with 95% CI [2.13, 6.87], P = 0.00001), disease activity score 28 based on C-reactive protein (DAS28-CRP) (RR: 3.91 with 95% CI [2.65, 5.79], P = 0.00001), clinical disease activity index (CDAI) (RR: 2.80 with 95% CI [1.43, 5.48], P = 0.003), and health assessment questionnaire disability index (HAQ-DI) (MD: - 0.28 with 95% CI [- 0.38, - 0.18], P = 0.00001) after 12 weeks, compared to placebo. However, OKZ was also associated with a higher incidence of any adverse events (AEs) (RR: 1.15 with 95% CI [1.06, 1.25], P = 0.0005) and AEs leading to drug discontinuation (RR: 1.86 with 95% CI [1.05, 3.29], P = 0.03). OKZ is effective and with acceptable safety profile when administrated with methotrexate in patients with RA not adequately controlled by tumor necrosis factor inhibitors; however, more large-scale RCTs are still required to investigate the optimal dosing, long-term effects, and comparative efficacy versus established biological DMARDs. Key Points • OKZ is effective especially with methotrexate in RA patients.

Genetic and Clinical Factors Associated with Olokizumab Treatment in Russian Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease and its treatment is an urgent problem of rheumatology. Olokizumab (OKZ) is a new humanized monoclonal antibody targeting IL-6 and is one of the few promising drugs for RA therapy. One-hundred-and-twenty-five DNA samples from Russian patients with RA, treated with olokizumab, were genotyped with an NGS panel containing 60 single nucleotide polymorphisms (SNPs) and the whole coding sequences of IL6, IL6R, TNFRSF1A, CTLA4, IL10, IL23R, and PADI4; and by RT-PCR for HLA-DRB1 and HLA-B. Associations of polymorphic variants with olokizumab efficacy according to the scores ACR20, ACR50, and DAS28-CRP were determined. We analyzed the obtained data by using logistic regression, ROC curves, and multivariate ANOVA. A high predictive value of the response to olokizumab therapy at 24 weeks was found for the combination of HLA-DRB1*04 and HLA-B*27 alleles with SNPs located in non-HLA genes (IL1B, IL17A, PADI4, DHODH, GLCCI1, IL23R, and TNFAIP3), and clinical characteristics (age, RA duration, and intensity) according to ACR20. Thus, the comprehensive assessment of polymorphic variants of HLA and non-HLA genes considering population characteristics in combination with clinical parameters allows for the elaboration of an RA prognostic panel.

Rheumatoid arthritis: new monoclonal antibodies.

Rheumatoid arthritis (RA) is an immune-mediated condition which primarily affects the joints, but with critical extra-articular manifestations, including a significantly increased cardiovascular risk. Patients suffering from RA can develop deforming and disabling alterations of the affected joints. Their quality of life can be substantially affected, and their life expectancy is shorter compared to that of healthy subjects. Fortunately, several pathogenic mechanisms characterizing RA have been identified, leading to the development of targeted drugs. Inhibitors of tumor necrosis factor (TNF) were the first developed among biological medications and they dramatically changed the therapeutic perspectives of RA patients. Now, 20 years after the licensing of etanercept (the first anti-TNF drug), more than 10 different biological agents have been approved by the U.S. Food and Drug Administration (FDA). Additionally, more and more drugs are under investigation in clinical trials. This review will focus on the more recently approved monoclonal antibodies and the more promising antibodies under investigation.

Safety and pharmacokinetics of olokizumab, an anti-IL-6 monoclonal antibody, administered to healthy male volunteers: A randomized phase I study.

Interleukin-6 (IL-6) is implicated in the pathophysiology of several inflammatory conditions. Olokizumab, a humanized anti-IL-6 monoclonal antibody, selectively blocks the final assembly of the IL-6 signaling complex. A randomized, double-blind, placebo-controlled, phase I dose-escalation study assessed the safety and tolerability of escalating single doses of olokizumab administered intravenously (iv) or subcutaneously (sc) to 67 healthy male volunteers. The pharmacokinetics, pharmacodynamics and immunogenicity of olokizumab were also assessed. Olokizumab was tolerated at doses up to 3.0 mg/kg sc and 10.0 mg/kg iv; the maximum tolerated dose was not reached. No serious adverse events or withdrawals as a result of treatment-emergent adverse events were reported. Pharmacokinetic analysis showed that both maximum serum concentration and area under the concentration-time curve increased linearly with increasing dose. Mean terminal half-life was 31.5 days (standard deviation 12.4 days). The bioavailability of the sc doses ranged from 84.2% to 92.5%. Rapid decreases in C-reactive protein concentrations were observed, with no dose dependency.

Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130-signaling.

Interleukin-6 (IL-6) is a critical regulator of the immune system and has been widely implicated in autoimmune disease. Here, we describe the discovery and characterization of olokizumab, a humanized antibody to IL-6. Data from structural biology, cell biology and primate pharmacology demonstrate the therapeutic potential of targeting IL-6 at "Site 3", blocking the interaction with the signaling co-receptor gp130.