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.

. 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. OBJECTIVES: . To evaluate the efficacy and safety of levilimab in combination with methotrexate (MTX) in subjects with MTX resistant active RA. MATERIALS AND 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. Adult subjects (154) aged ≥18 years with confirmed diagnosis of RA1 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 performed 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/EULAR2011 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 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 levilimab maintenance regimen (once every 2 weeks) (Q2W) in those who achieved remission of RA at week 24.

[Long-term efficacy and safety of divozilimab during 2-year treatment of multiple sclerosis patients in randomized double-blind placebo-controlled clinical trial BCD-132-4/MIRANTIBUS]. / Effektivnost' i bezopasnost' dvukhletnei terapii divozilimabom u patsientov s rasseyannym sklerozom v ramkakh randomizirovannogo dvoinogo slepogo platsebo-kontroliruemogo klinicheskogo issledovaniya BCD-132-4/MIRANTIBUS.

OBJECTIVE: To evaluate the efficacy and safety of the anti-CD20 monoclonal antibody divozilimab (DIV) used as an intravenous infusion at a dose of 500 mg every 24 weeks during 100 weeks for the treatment of patients with multiple sclerosis (MS), including relapsing-remitting multiple sclerosis (RRMS) and secondary progressive MS (SPMS) with relapses. MATERIAL AND METHODS: The multicenter, randomized, double-blind and double-masked phase III clinical trial (CT) BCD-132-4/MIRANTIBUS (NCT05385744) included 338 adult patients with MS distributed in a 1:1 ratio into two groups: DIV 500 mg and teriflunomide (TRF) 14 mg. After screening, subjects were included in the main CT period, which consisted of two cycles of therapy over 48 weeks, then entered an additional period from weeks 49 to 100, which included three cycles of therapy. The efficacy was assessed based on the results of brain MRI and registration of data on relapses. RESULTS: 308 subjects completed 5 therapy cycles according to the study protocol. An analysis of the effectiveness of DIV therapy over 2 years showed a persistent suppression of MRI and clinical activity of the disease in comparison with TRF, which was confirmed by all the studied MRI indicators (including CUA; total number of gadolinium-enhancing (GdE) lesions on T1-weighted scans ; number of new or enlarged lesions on T2-weighted scans; lesions volume change on T2-weighted scans; change in the volume of hypointense lesions on T1-weighted scans). The use of DIV was associated with a statistically significant decrease in ARR compared to TRF (p=0.0001). The ARR in the DIV group was 0.057, in the TRF group - 0.164 with 95% confidential interval for the frequency ratio [0.202; 0.593]. The incidence of GdE lesions on T1-weighted scans in the DIV group was significantly lower than in the TRF group. The average number of such lesions was 0.0±0.08 and 1.0±4.46 in the DIV and TRF groups, respectively (p<0.0001). Progression of EDSS was detected in 18 (10.7%) and 36 (21.3%) patients in the DIV and TRF groups, respectively (p=0.0075). The proportion of patients with relapses was 11.2% (n=19) in the DIV group and 23.1% (n=39) in the TRF group (p=0.0039). In the subpopulation of patients with SPMS, no cases of increase in EDSS were detected, and not a single case of exacerbation was recorded over 2 years of using DIV. Also, DIV has shown a favorable safety profile. Among the adverse reactions (AR), infusion reactions and laboratory abnormalities, such as a decrease in the number of leukocytes, neutrophils, and lymphocytes, were most often recorded. Identified AR were expected, had mild to moderate severity, and resolved without any negative consequences. CONCLUSION: The results of the BCD-132-4/MIRANTIBUS CT indicate a high sustained efficacy and safety of long-term use of DIV in comparison with TRF during 2 years of therapy.

[Efficacy and safety of antiCD20 monoclonal antibody divozilimab during 48-week treatment of multiple sclerosis patients in randomized double-blind placebo-controlled clinical trial BCD-132-4/MIRANTIBUS]. / Effektivnost' i bezopasnost' 48 nedel'nogo primeneniya monoklonal'nogo antitela protiv CD20 divozilimaba u patsientov s rasseyannym sklerozom: rezul'taty randomizirovannogo dvoinogo slepogo platsebo-kontroliruemogo klinicheskogo issledovaniya BCD-132-4/MIRANTIBUS.

OBJECTIVE: To evaluate the efficacy and safety of the anti-CD20 monoclonal antibody divozilimab (DIV) used as an intravenous infusion at a dose of 500 mg for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS) in comparison with the teriflunomide (TRF). The study of the efficacy and safety of the use of the drug DIV was carried out for 48 weeks of therapy. MATERIAL AND METHODS: The multicenter, randomized, double-blind and double-masked phase III clinical trial (CT) BCD-132-4/MIRANTIBUS included 338 adult patients with RRMS distributed in a 1:1 ratio into two groups: DIV 500 mg and TRF 14 mg. After screening, subjects were included in the main CT period, which consisted of two cycles of therapy over 48 weeks. The primary end point was «Mean annualized relapse rate 48 weeks after the last patient is randomized in the study¼. RESULTS: 321 subjects completed 48 weeks of therapy according to the study protocol. The analysis of the of efficacy data for the primary endpoint successively proved the hypothesis of superiority of the test drug DIV at a dose of 500 mg over the reference drug TRF. A rapid suppression of acute disease activity according to the brain MRI and clinical manifestations of the disease was shown after the first infusion of DIV in patients with RRMS. Thus, after 48 weeks of therapy in patients treated with DIV, there were no T1 gadolinium-enhancing lesions, while in the TRF group such lesions were observed in 20.7% (35/169) of subjects. Evaluation of the CUA per scan showed that the mean values for the estimated period were statistically significantly lower in the DIV drug group compared to the TRF group: the ratio of the adjusted per scan rates (DIV/TRF) was 0.125 [95% CI: 0.089; 0.177]. Over the 48 weeks of therapy, the proportion of subjects with relapses was 9.5% (n=16/169) in the DIV group and 19.5% (33/169) in the TRF group (p=0.0086). DIV has shown a favorable safety profile. Among the adverse reactions (AR), infusion reactions and deviations of laboratory data, such as a decrease in the number of leukocytes, neutrophils, and lymphocytes, were most often recorded. Identified AR were expected, had mild to moderate severity, and resolved without any negative consequences. CONCLUSION: The results of the clinical study indicate the high efficacy and safety of DIV in comparison with TRF.

[Cholelithiasis and cholesterosis of a gallbladder: a comparison of pheno-genetypic characteristics of patients].

A study was and comparison was carried out of the phenotypical and genotypical features in 115 patients with cholelythiasis and 97 patients with cholesterosis of the gallbladder. The received data proves that cholelythiasis is characterized by the domination of (prevalence) of type O I blood type, decrease of blood types B III and AB IV in comparison to the control group and to the group with cholesterosis of the gallbladder (p < 0.05), increase of the frequency of gene O decrease of frequency of gene B, decrease of heterozygosis. Patients with cholesterosis of the gallbladder are characterized by the increase of frequency of gene A, decrease of ratio of patients with blood type B III and increase of patients with AB IV blood type (p < 0.05). The received data (results) show the presence of different and multidirectional phenotypical and genotypical characteristics in patients with cholelythiasis and cholesterosis of the gallbladder, and therefore differ genotypically.

[Duodenal atresia in the newborn].

The specific features of intrauterine development and pheno- and genotypic characteristics were studied in newborn infants with duodenal atresia. Main anthropometric parameters at birth (weight, height, and head and chest circumferences), concomitant developmental malformations, gene frequencies and phenotypic combinations of ABO and Rhesus factor blood groups were analyzed. The babies with duodenal atresia were found to have considerably impaired intrauterine development, multiple concomitant hypoplastic developmental abnormalities, significantly higher frequencies of the ORh+ phenotype, and lower frequencies of the ARh+ phenotype.

[Intestinal malrotation: genetics features and other congenital malformations in children].

The article is devoted to features of prenatal development of children with intestinal malrotation. Mass, height, head and chest circumferences of children after birth have been studied. In addition all associated malformations, a blood group (ABO system) and the rhesus-factor have been investigated. In comparison to the control group of newborn the disorders of prenatal development have included associated malformations, low anthropometric data after birth, decreasing of pA gene frequency. Notable, children with intestinal malrotation have had high frequency of malformations as in the abdominal and thoracic cavities as outside intestinal innervations: the small pelvis, the facial skeleton, the upper and lower extremity.