Interleukin 6 (IL-6) plays a key role in the immunopathogenesis of rheumatoid arthritis (RA), with the pleiotropic effect on organs and tissues. Blocking IL-6 receptors is of interest both in terms of correcting joint syndrome and alleviating systemic inflammation. Levilimab (LVL) is a monoclonal antibody drug against the interleukin 6 receptor, which has demonstrated efficacy and safety in patients with active RA when administered 162 mg subcutaneously (SC) every week. The article presents data obtained from the two-phase clinical study (CS) LUNAR (NCT05800327), in which the first stage was a CS phase I, and the second – CS phase III. The aim is to study the tolerability, safety, immunogenicity and main pharmacokinetic and pharmacodynamic parameters of the LVL after its single SC or intravenous (IV) administration in increasing doses to healthy volunteers, as well as to confirm the efficacy and safety of new dosing regimens of LVL at a dose of 648 mg IV once every 4 weeks (Q4W) in combination with methotrexate (MT) and at a dose of 324 mg SC once every 2 weeks (Q2W) in combination with MT in patients with active RA resistant to MT monotherapy. Materials and methods. During the first stage of clinical trial, the safety and tolerance of new regimens of LVL 648 mg Q4W IV and 324 mg Q2W SC were demonstrated in healthy volunteers and these doses have also been shown to provide the required therapeutic concentration throughout the entire interdose interval. In the phase III study, patients with active RA (according to American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) 2010 criteria) resistant to MT therapy at a stable dose of 15–25 mg/week for ≥12 weeks were included.The study had a double-blind design until week 24, evaluation of the efficacy of LVL new dosing regimens with the standard regimen of 162 mg SC QW was conducted at week 24 based on the parameter “Proportion of patients achieving low RA activity according to DAS28-ESR (Disease Activity Score with Erythrocyte Sedimentation Rate) &lt;3.2)”. After the week 24, all patients continued to receive LVL in an open-label manner. Due to achieving RA remission (DAS28-ESR&lt;2.6) at week 24, patients were switched to a maintenance regimen depending on the group: 324 mg IV Q4W for patients previously receiving LVL at a dose of 648 mg IV Q4W, and 162 mg SC Q2W for patients previously receiving LVL at doses of 324 mg SC Q2W and 162 mg SC QW. Patients who did not achieve RA remission at week 24 continued to receive LVL in the initial regimen.The efficacy analysis included the assessment of achieving remission and low RA activity according to DAS28-ESR, DAS28-CRP (DAS28 with C-reactive protein), CDAI (Clinical Disease Activity Score), and SDAI (Simplified Disease Activity Score) indices, achieving 20%/50%/70% improvement according to ACR criteria (ACR20/ACR50/ACR70), moderate and good response according to EULAR criteria, as well as the dynamics of laboratory markers (CRP and ESR). Safety was assessed by the frequency and profile of adverse events (AEs) and adverse reactions (ARs). Results. 232 patients were randomized into one of the LVL application groups: 162 mg SC QW (n=78), 324 mg SC Q2W (n=77), and 648 mg IV Q4W (n=77). At week 24, the groups with 324 mg SC Q2W and 648 mg IV Q4W demonstrated non-inferior efficacy in terms of the “Percentage of patients achieving low activity according to DAS28- ESR”: 68.8% and 63.4%, respectively, compared to 62.6% in the 162 mg SC QW group (p=0.8277 and p=0.3954). The efficacy analysis for secondary endpoints (achievement of remission and low RA activity according to DAS28- ESR, DAS28-CRP, CDAI, SDAI, achievement of ACR20/ACR50/ACR70, dynamics of ESR and CRP) also demonstrated comparable efficacy of the new dose regimens of LVL.At week 24, more than 39% of patients in all groups achieved RA remission according to DAS28-ESR and were switched to a maintenance regimen of the drug, while by week 52 of therapy, the vast majority of patients maintained RA remission according to DAS28-ESR, as well as the relative number of patients with RA remission according to DAS28-CRP, CDAI, and SDAI indices increased. In cases where RA remission according to DAS28-ESR was not achieved at week 24, continuation of initial LVL therapy led to achieving low activity and RA remission in a significant number of cases (up to 45.8% according to DAS28-ESR) by week 52. The most of AEs and ARs were mild and moderate according to CTCAE 5.0 (Common Terminology Criteria for Adverse Events). The use LVL new dosing regimens was accompanied by a favorable and predictable safety profile. Conclusion. The efficacy and safety of LVL at a dose of 648 mg IV once every 4 weeks and 324 mg SC once every 2 weeks are comparable to the previously approved dosing regimen. Transitioning to maintenance therapy upon achieving RA remission is accompanied by the retention rate of clinical response. 

Extract of oak bark as a selective natural reagent for the spectrophotometric determination of iron (II) in pharmaceutical preparations and blood serum

The efficacy and safety of levilimab (LVL) in patients with active rheumatoid arthritis (RA) has been confirmed in controlled clinical trials. This article presents the results of a preliminary analysis of a non-interventional observational study of LVL in RA patients. Objective: to evaluate the efficacy and safety of LVL in the treatment of patients with RA in real-world clinical practice. Materials and methods. The HELIOS study is a retrospective-prospective, multicenter, non-interventional study of retention rate of LVL therapy and the safety of LVL in patients with RA in real-world clinical practice. Patients received medical care, including LVL, according to routine clinical practice for the treatment of RA and Russian instructions for medical use of the drug. This article presents the results of an analysis of the efficacy and safety of LVL after 12 and 24 weeks of treatment. Efficacy was assessed using the DAS28-CRP/ESR, SDAI, CDAI and patient assessment of pain, fatigue and morning stiffness according to VAS (0–100 mm). Results and discussion. 524 patients from 42 medical centers in the Russian Federation were enrolled in the study from June 2022 to November 2023. The majority of patients were female (83.2 %) and the mean age of patients was 53 years. A statistically significant decrease in DAS28-CRP/ESR, SDAI, CDAI, patient assessment of pain, fatigue and morning stiffness (VAS) was observed after 12 and 24 weeks of treatment, regardless of previous treatment with biologics or Jak inhibitors (JAKi). LVL was well tolerated by patients, the most frequently reported adverse events were infections, changes in peripheral blood and laboratory abnormalities characteristic of treatment with IL-6R inhibitors. Conclusion. In real-world clinical practice, LVL has been shown to be highly effective and well tolerated in patients with RA when prescribed as the first biologic disease-modifying antirheaumatic drus (bDMARD) and after switching from other bDMARDs or JAKi. 

pdf/efficacy-and-safety-of-levilimab-in-the-treatment-of-41zjklyhpd.pdf

Efficacy and safety of levilimab in the treatment of rheumatoid arthritis in real-life clinical practice: first results of the HELIOS observational study

Background. Previously, 24-week results of phase III double-blind, placebo-controlled randomized clinical study (SOLAR) of levilimab in subjects with active rheumatoid arthritis (RA) proved a superiority of levilimab over placebo. Here we present 1-year efficacy and safety data of the SOLAR study.Objective – to evaluate the efficacy and safety of levilimab in combination with methotrexate (MTX) in subjects with MTX resistant active RA.Methods. The study was conducted at 21 clinical sites in Russia and Belarus. All randomized subjects have completed the study between November 2019 and October 2021.154 adults, aged ≥18 years with confirmed diagnosis of RA were randomly assigned (2:1) to receive either levilimab (162 mg, SC, QW) + MTX (n=102) or placebo + MTX (n=52).After W24 of the study all subjects continued to receive open label levilimab. Subjects who have achieved DAS28-CRP≤2.6 at W24 were switched to maintenance (Q2W) regimen of levilimab at W28 (LVL QW/Q2W and PBO/LVL Q2W arms). Those with DAS28-CRP>2.6 at W28 continued with QW regimen (LVL QW and PBO/LVL QW arm). The PBO/LVL Q2W arm contained only one subject, thus not included in the analysis. The efficacy analysis was done in a population of all randomized subjects. Those with missing data due to study discontinuation or rescue therapy prescription were considered non-responders. Otherwise, the analysis was performed on complete cases.Safety was assessed through monitoring of adverse events (AEs) in a population of those, who received at least on dose of LVL (n=152).Results. Better response to treatment was observed in LVL QW/Q2W as it composed of those who reach DAS28-CRP≤2.6 at W24. At this time point 15/27 (55.6%) of them achieved ACR70; 23/27 (85.2%) achieved DAS28-CRP remission (<2.6) and 7/27 (25.9%) achieved ACR/EULAR 2011 remission of RA. After switching to LVL Q2W, rates of ACR70 and DAS28-CRP<2.6 did not significantly changed until W52: 17/27 (63.0%) and 21/27 (77.8%), respectively, yet the proportion of subject with ACR/EULAR 2011 remission further increased and reached 12/27 (44.4%).LVL QW arm was diminished by subjects who achieved high response to treatment at W24 and composed LVL QW/Q2W arm. Thus, ACR70, and remissions rate in this arm was close to zero at W24. However, continuation of LVL QW in those who not achieved DAS28-CRP≤2.6 at W24 induced ACR70 response in 37/75 (36.0%), DAS28-CRP remission in 35/75 (46.7%) and ACR/EULAR 2011 remission in 8/75 (10.7%) at W52.The most common adverse events (reported in ≥5% of subjects) were blood cholesterol increase (30.3%), ALT increase (23.0%), lymphocyte count decrease (17.1%), ANC decrease (16.4%). blood triglycerides increase (13.8%), bilirubin increase (11.2%), AST increase (9.9%), WBC decrease (9.9%), IGRA with Mycobacterium tuberculosis antigen positive (7.2%) and injection site reactions (5.9%). No deaths were occurred.Conclusions. Open label period confirmed the lasting efficacy and safety of levilimab in combination with MTX in subjects with MTX resistant active RA and suggested the possibility of switching to maintenance (Q2W) regimen in those who achieved remission of RA at week 24.

Efficacy and safety of levilimab in combination with methotrexate in patients with active rheumatoid arthritis: 56-week results of phase III randomized double-blind placebo-controlled trial SOLAR

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Efficacy and safety of levilimab in combination with methotrexate in patients with active rheumatoid arthritis: 56-week results of phase III randomized double-blind placebo-controlled trial SOLAR