[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.

[Efficacy and safety of divozilimab during 24-week treatment of multiple sclerosis patients in randomized double-blind placebo-controlled clinical trial BCD-132-2]. / Effektivnost' i bezopasnost' 24 nedel' primeneniya divozilimaba sredi patsientov s rasseyannym sklerozom v ramkakh randomizirovannogo dvoinogo slepogo platsebo-kontroliruemogo klinicheskogo issledovaniya BCD-132-2.

OBJECTIVE: To find the optimal therapeutic dose of the anti-B cell mAb divozilimab (DIV) based on the efficacy and safety data of intravenous administration at a dose of 125 mg or 500 mg in patients with relapsing remitting multiple sclerosis (RRMS) compared to placebo (PBO) and teriflunomide (TRF). To study the efficacy and safety of DIV within 24 weeks of treatment. MATERIAL AND METHODS: A multicenter, randomized, double-blind and double-masked, placebo-controlled phase 2 clinical trial (CT) BCD-132-2 involved 271 adult patients with RRMS from 25 centres In Russia. Patients were randomly assigned (2:2:2:1) into 4 groups: TRF, DIV 125 mg, DIV 500 mg and PBO. After screening patients entered to the main period, which consisted of one cycle of therapy for 24 weeks. The primary endpoint was the total number of gadolinium-enhancing T1 lesions (Gd+) observed on brain MRI scans after 24 weeks (per scan - involves estimating the mean value of the score from all the MRI assessments performed for each participant in the study). RESULTS: 263 patients completed 24 weeks of treatment. Most of the patients in the DIV groups had no lesions on T1-weighted MRI after 24 weeks of treatment (94.44% on 125 mg and 93.06% on 500 mg). In the TRF and PBO groups the values were significantly lower: 68.06% and 56.36% respectively (both p<0.05). The proportions of relapse-free patients in the DIV groups were 93.06% and 97.22% (125 mg and 500 mg, respectively). As expected, DIV reduced the CD19+ B-cells. However, the repopulation rate of CD19+ B-cells in the 125 mg group was more pronounced (mainly due to the recovering pool of CD27-naive B-cells) compared to the 500 mg group. DIV showed a favorable safety profile at both doses. CONCLUSION: Thus, the assessment of 24 weeks treatment demonstrated that DIV is a highly effective, safe and convenient option for the treatment of RRMS patients, both naive and previously treated with disease modifying therapy. A dose of 500 mg is recommended for further efficacy and safety evaluation during phase 3 CT.

[Long-term Efficacy and Safety of Sampeginterferon-ß1a in the Treatment of Relapsing Remitting Multiple Sclerosis: a Randomized, Double-Blind Clinical Trial 104-Week Results]. / Dolgosrochnye dannye po effektivnosti i bezopasnosti preparata sampeginterferon-ß1a u patsientov s remittiruyushchim rasseyannym sklerozom: rezul'taty 104-nedel'nogo randomizirovannogo dvoinogo slepogo klinicheskogo issledovaniya.

OBJECTIVE: To assess the efficacy and safety of sampeginterferon-ß1a (samPEG-IFN-ß1a) 180 µg and 240 µg administered once every 2 weeks compared to placebo and low dose interferon beta-1a (LIB) 30 µg administered once weekly. MATERIAL AND METHODS: Patients with relapsing-remitting multiple sclerosis aged 18-60 years, with Expanded Disability Status Scale score ≤5.5 were randomized at a ratio of 2:2:2:1 to the following groups: samPEG-IFN-ß1a 180 µg, samPEG-IFN-ß1a 240 µg, LIB, placebo. After 20 weeks, the placebo group completed the study. After week 52, the final analysis was performed, which included the primary endpoint analysis, the LIB group patients completed their participation in the study. The patients in samPEG-IFN-ß1a groups continued to receive therapy with samPEG-IFN-ß1a 240 µg until week 100 inclusive. The results of the final analysis after 52 weeks have been previously published. The current article presents a long-term efficacy and safety of samPEG-IFN-ß1a after 104 weeks of the trial. RESULTS: The annualized relapse rate over the second year was 0.16 in the samPEG-IFN-ß1a 180 µg group and 0.09 in the samPEG-IFN-ß1a 240 µg group. By week 104, the proportion of relapse-free patients was 77.0% (87/113) and 83.3% (95/114) in the samPEG-IFN-ß1a 180 µg and 240 µg groups, respectively. There were no negative dynamics of MRI markers, neurological deficit parameters and cognitive functions by scales and tests. The safety profile of samPEG-IFN-ß1a was consistent with the known safety profile of IFN-ß therapy. CONCLUSION: Treatment with samPEG-IFN-ß1a is an effective and safe first-line therapy for relapsing-remitting multiple sclerosis patients.

[Efficacy and safety of sampeginterferon ß-1a in the treatment of relapsing remitting multiple sclerosis: results of 52 weeks of therapy in a randomized, double-blind clinical trial]. / Effektivnost' i bezopasnost' sampeginterferona ß-1a dlya lecheniya remittiruyushchego rasseyannogo skleroza: rezul'taty 52-nedel'nogo randomizirovannogo dvoinogo slepogo klinicheskogo issledovaniya.

OBJECTIVE: To evaluate the efficacy and safety of samPEG-IFN-ß1a 180 µg and 240 µg administered once every 2 weeks for the treatment of relapsing remitting multiple sclerosis (RRMS) compared to placebo and low dose interferon beta-1a (LIB) 30 µg administered once weekly. The primary endpoint after 52 weeks of therapy was the time to first relapse, the hypotheses of non-inferiority and superiority to LIB were tested. MATERIAL AND METHODS: This international, multicenter, double blind, comparative, placebo-controlled clinical study enrolled 399 patients with the diagnosis of RRMS, randomized in 4 groups: samPEG-IFN-ß1a180 µg (n=114), samPEG-IFN-ß1a 240 µg (n=114), LIB (n=114) and placebo (n=57). Placebo group patients participated in the study for 20 weeks. After 52 weeks of therapy and 4 weeks of follow-up, LIB group patients completed their participation in the study, patients from PEG-IFN-ß1a groups continued to receive therapy until week 100 inclusive. The article presents the results of an analysis conducted after the end of 52 weeks of a double-blind, comparative, randomized, placebo-controlled clinical trial. RESULTS: Final analysis of the efficacy and safety was performed after 52 weeks of study. Main statistical hypothesis testing proved that both doses of samPEG-IFN-ß1a were equally effective when compared to LIB by the primary endpoint - «Time to first relapse¼. Due to detection of statistically significant differences in the primary endpoint between the study drug and the reference drug, indicating a greater efficacy of the study drug, an additional testing was carried out and the hypothesis of superiority of samPEG-IFN-ß1a at a dose of 240 µg over the reference LIB was proved. Evaluation of the dynamics of certain key parameters of magnetic resonance imaging (MRI) of the brain and clinical outcomes demonstrated a positive effect of samPEG-IFN-ß1a therapy in the form of decreased activity of the demyelinating process in the brain and reduce the number of relapses. The proportion of patients without new T2 lesions after 52 weeks was 87.6% and 90.4% in 180 µg and 240 µg samPEG-IFN-ß1a groups, versus 72.6% in the LIB group (p=0.0199 and p=0.0033). No progression of multiple sclerosis was shown based on EDSS scale evaluation. During the study, the most common adverse reactions were flu-like symptoms and injection site reactions. CONCLUSION: The new drug samPEG-IFN-ß1a is an effective and safe agent for relapsing remitting multiple sclerosis treatment, while having an advantage over other low-dose interferons in the form of reduced frequency of intramuscular injections.

[Results of a phase 1 clinical study of anti-CD20 monoclonal antibody (BCD-132): pharmacokinetics, pharmacodynamics and safety]. / Rezul'taty I fazy klinicheskogo issledovaniia monoklonal'nogo antitela protiv CD20 (BCD-132): farmakokinetika, farmakodinamika i bezopasnost'.

AIM: To study the pharmacokinetics, pharmacodynamics, and immunogenicity of two intravenous dosing regimens of the new anti-B-cells drug BCD-132 (JSC BIOCAD, Russia) at ascending doses in patients with remitting multiple sclerosis. MATERIAL AND METHODS: Twenty-four patients with multiple sclerosis were sequentially randomized in the multicenter open-label uncontrolled multicohort phase I study (3+3 design) and assigned to 4 cohorts (8 groups). Patients in each cohort received an intravenous infusion of BCD-132 at a predefined dose ranging from 100 to 1000 mg based on the planned algorithm of dose escalation if no dose-limiting toxicities occurred. RESULTS: The assessment of the number of cells positive for the main B-cell antigens over time demonstrated a direct effect of BCD-132 on B lymphocytes when used at a wide range of doses (100 to 1000 mg) in patients with remitting multiple sclerosis. No significant variation of the number of T-cells was observed, which clearly proves strict specificity of BCD-132 exclusively to B lymphocytes. CONCLUSION: BCD-132 has an expected pharmacodynamic effect of long-term depletion of CD19+ and CD20+ B lymphocytes and an acceptable safety profile when used to treat patients with remitting multiple sclerosis at all tested doses.

[Experience of using interferon Β-1a biosimilans (cinnovex and genfaxon-44) in the Moscow Multiple Sclerosis Center]. / Opyt primeneniia bioanalogov Β-interferona-1a - sinnoveksa i genfaksona-44 v Moskovskom gorodskom tsentre rasseiannogo skleroza.

OBJECTIVE: To study the efficacy and tolerability of generics (interferon beta-1a biosimilans) cinnovex for intramascular introduction and genfaxon-44 for subcutaneous injections in multiple sclerosis (MS). MATERIAL AND METHODS: One hundred patients were treated with cinnovex and 104 patients were treated with genfaxon-44 during one year. Patient's status was assessed using clinical approach, psychometric scales and MRI. RESULTS AND CONCLUSION: The high percentage of withdrawal of treatment due to the lack of clinical effect and intolerance to the drugs was identified during the treatment. Positive effect with respect to stabilization of MS course was found only in patients who earlier did not receive disease-modifying drugs. Double-blind studies are needed to resolve the question of the adequacy of brand-name drugs and generics.

[The first experience of the use the Russian Β-interferon-1b biosimilar (infibeta) in the daily practice of the Moscow Center of Multiple Sclerosis].

We summarized the 1-year experience of using the Russian Β-interferon-1b biosimilar (infibeta) in 123 patients including 65 patients with relapsing-remitting multiple sclerosis (RMS) and 58 patients with secondary progressive multiple sclerosis (SPMS). The significant decrease in the frequency of exacerbations per year was seen during the first year of treatment. We also noted the stabilization of the process of disability without the rise in EDSS scores in more than 50% of patients. Good tolerability comparable to that of the original drug was observed during the first year of treatment. There was no refusal from therapy with infibeta, which indicated sufficiently strong adherence to this type of treatment.

[Results of a comparative clinical trial of the Russian Β - interferon-1b bioanalogue (infibeta)].

Results of annual comparative clinical research of the Russian biosimilar of beta-IFN - 1в at 122 patients with multiple sclerosis are presented. There were positive dynamics on EDSS scores in both groups (in the main group and group of control) in a year of treatment. There were positive dynamics in frequency of relapses in the main group (with 1.5 to 0.4 in a year) and in group of control (with 1.4 to 0.37 in a year). Positive dynamics according to MRI was also fixed in both groups. In both groups, good tolerability of the treatment was noted. This research didn't reveal essential distinctions on efficiency and safety parameters in both groups.

[Efficacy and tolerability of long-term using of glatimer acetate (copaxone): a 10 year-study in the Moscow Municipal Multiple Sclerosis center].

Experience of 10-year administration of glatimer acetate (copaxone) in 74 patients with active remitting multiple sclerosis is summarized. The significant decrease in the frequency of exacerbations was seen over these ten years. Disease severity on the EDSS was stable and decreased only to the end of the 10-year period. The positive stable clinical dynamics did not depend on the disease severity at baseline. The drug was well-tolerated that allowed to control the course of multiple sclerosis: 64.8% of patients had no more than one exacerbation over 10 years and in 71.6% patients, the disease progression was absent or minimal (less than one score on EDSS). It has been concluded, that the long-term 10-year treatment with copaxone enables to control the development of disease in many patients.

[The comparative study of efficacy and tolerability of intramuscular introduction of beta-interferon-1a in adults and adolescents with remitting multiple sclerosis].

The experience of the treatment of patients with remitting multiple sclerosis (MS) with intramuscular introduction of beta-interferon-1a (avonex) is presented. Seventeen children and adolescents, aged from 11 to 18 years, and 55 adults, aged over 55 years, were treated for at least one-year period. Results revealed a significant reduction of exacerbations in both groups (from 1.35 to 0.06 in average in adolescents and from 0.86 to 0.17 in adults). The changes were accompanied by the stabilization of MS severity index: EDSS scores have decreased in 23.6% of adults and in 17.6% of adolescents. In both groups, good tolerability of the treatment was noted. There was a low probability of side-effects with the exception of increased frequency of a flu-like syndrome (47% cases) in patients younger than 18 years that demands special attention from children neurologists. The high efficacy and good tolerability and safety profile of beta-interferon-1a give grounds for administering this drug to children and adolescents with MS.

[Data of MRI and neuropsychological tests predict the course of typical remitting multiple sclerosis during five years].

A complex study of 50 patients with active typical remitting multiple sclerosis (MS) was carried out. Neuropsychological testing using Wechsler and Stroop tests and MRI of the brain with the morphometric analysis of focal and diffusive changes were used in the study. Patients were stratified into two subgroups by the changes in the performance of neuropsychological tests. The disease course was assessed during five years. In all cases, the natural course of the disease, i.e. when patients did not receive disease modifying drugs, was analyzed. The transition to secondary progressive MS and the marked increase in MS severity on the EDSS were found in the subgroup of patients who demonstrated changes in the neuropsychological test performance. The strongest correlation was observed between EDSS scores and the diffusive atrophy of the brain white matter on MRI. The data of neuropsychological testing and some brain MRI parameters may be recommended as a predictive test in remitting MS.

[The use of rebif in the Moscow Municipal Multiple Sclerosis Center].

We summarized the 3-year experience of using beta-interferon 1a (44 mcg, subcutaneously) in the form of the preparation rebif in 141 patients including 120 patients with active remitting multiple sclerosis (RMS) and 21 patients with secondary progressive MS (SPMS). All patients were examined every three months. The significant decrease in the frequency of exacerbations per year was seen already during the first year of treatment. EDSS scores remained stable in 47.37% of all RMS cases and in 57.14% of all SPMS cases during the first year. A one point and more increase of EDSS was found only in 5.26% patients during three years of treatment. The drug was well tolerated during the long period, adverse effects were found in 16.31%, with a flu-like syndrome in the first place. Only 1.42% of patients refused treatment. All other patients were highly motivated and adherent to treatment.

[Pharmacogenomics of multiple sclerosis: association of immune response genes polymorphism with copaxone treatment efficacy].

Complex association analysis of copaxone (glatiramer acetate) immunotherapy efficacy with allelic polymorphism in the number of immune response genes, which encode interferone beta (IFNB1), transforming growth factor beta1 (TGFB1), interferone gamma (IFNG), tumor necrosis factor (TNF), interferon alpha/beta receptor 1 (IFNAR1), CC chemokine receptor 5 (CCR5), interleukin 7 receptor alpha subunit (IL7RA), cytotoxic T-lymphocyte antigen 4 (CTLA4) and HLA class II histocompatibility antigen beta chain (DRB1) was performed with APSampler algorithm for 285 multiple sclerosis patients of Russian ethnicity. The results show evidence for the contribution of polymorphic variants in CCRS, DRB1, IFNG, TGFB1, IFNAR1, IL7RA and, probably, TNF and CTLA4 genes to copaxone treatment response. Single alleles of CCR5 and DRB1 genes are reliably associated with treatment efficacy. Carriage of allelic variants of other above mentioned genes contribute with reliable effect to copaxone treatment response as part of bi- and three-allelic combinations only. Present investigation may support basis toward the future possibility of prognostic test realization, which can provide a personal choice of immunomodulatory treatment for a patient with multiple sclerosis.

[The results of longitudinal use of copaxone and betaferon in Moscow Multiple Sclerosis Center: issues of efficacy and adherence to therapy].

In last decades, practical neurologists are able to use DMT in multiple sclerosis (MS) in every day practice. This paper presents data of 3-year study of DMT (copaxone and betaferon) treatment of 280 patients with definite diagnosis of multiple sclerosis (MS), 166 patients regularly receiving DMT (104--copaxone and 62--betaferon) for, at least, 3 years. Clinical symptoms of the patients, reasons of treatment withdrawal (48--copaxone and 31--betaferon) and the features of MS course after the withdrawal are analyzed. Patients who received betaferon previously had more severe MS course with frequent relapses, half of them had secondary progressive MS course (SPMS) with relapses. This made impossible a direct comparison of the data of two treatment groups. Treatment with copaxone reduced 5 times annual relapse rate, from 1.45 before DMT to 0.27 during these 3 years (p < 0.001), and this reduction remained stable. For 36 months, 40.4% of patients were relapse-free though all of them had, at least, one relapse per year before the treatment. No EDSS progression was observed in 80% of these patients. Treatment with betaferon caused the reduction of relapse rate from 1,84 to 0,69 per year (2.7 times), 8 patients (26%) with previously active RMS being relapse-free for 36 months. In 31 patients with SPMS, the reduction of relapse rate was also significant, from 1.89 to 0.49 (3.8 times, p < 0.001). Twenty-two patients (71%) with previous SPMS did not have EDSS progression for 36 months that indicate the positive effect of the therapy. Side-effects were moderate and were not the main cause of the treatment withdrawal. The latter was caused mainly by clinical un efficacy, most frequently by the increase of EDSS due to transformation of the MS course to SPMS without relapses and poor understanding by the patient of the goals and the possibilities of DMT. These facts stress the significance of improving compliance, motivation and adherence to DMT in everyday neurological practice.