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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) <3.2)”. After the week 24, all patients continued to receive LVL in an open-label manner. Due to achieving RA remission (DAS28-ESR<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.

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