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.

OBJECTIVE:To assess the efficacy and safety of sampeginterferon-β1a (samPEG-IFN-β1a) 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-β1a 180 µg, samPEG-IFN-β1a 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-β1a groups continued to receive therapy with samPEG-IFN-β1a 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-β1a after 104 weeks of the trial.RESULTS:The annualized relapse rate over the second year was 0.16 in the samPEG-IFN-β1a 180 μg group and 0.09 in the samPEG-IFN-β1a 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-β1a 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-β1a was consistent with the known safety profile of IFN-β therapy.CONCLUSION:Treatment with samPEG-IFN-β1a is an effective and safe first-line therapy for relapsing-remitting multiple sclerosis patients.

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.

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 study».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.

Hereditary inclusion body myopathy (IBM) is a variant of multisystem proteinopathy. It is a generalized progressive disease with autosomal recessive or autosomal dominant inheritance, characterized by the development of a degenerative process in muscle fi bers due to the accumulation of rimmed vacuoles and nuclear intermediate fi laments. This article presents a clinical observation of a rare variant of IBM — HNRNPA2B1-associated myopathy with a phenotypically diverse picture in representatives of one family from diff erent generations.

Introduction. Asthenia, vegetative manifestations, sleep disturbances and psycho-emotional background are companions of the coronavirus infection, the issue of drug correction of which is especially relevant. These symptoms disrupt the habitual way of life of patients for a long time, and in special cases lead to disability.Aim. To study the mental, somatoform and cognitive aspects of anxiety disorders after coronavirus infection during treatment with tofisopam (Grandaxin®) 150 mg/day.Materials and methods. The study included patients who had experienced a new coronavirus infection, who, after the end of treatment for the underlying disease, had complaints suggesting the presence of an anxiety disorder. The Hamilton scale was used to assess the level of anxiety. Examination of patients was carried out before the start of treatment, after 2, 4 and 6 weeks of therapy.Results and discussion. Prior to the start of therapy, all patients had an overall high level of anxiety: the average HAM-A score was 31.4 ± 2.92 points. At the end of Grandaxin® therapy, all patients showed a decrease in the level of anxiety: the average HAM-A score was 12.08 ± 2.27 points (p < 0.001). The maximum decrease in the severity of vegetative disorders was noted by the end of the 6th week of therapy with Grandaxin®. Thus, the indicator of this subscale decreased by more than 2 times – from 2.46 ± 0.54 to 1.05 ± 0.28 points (p < 0.001). The severity of insomnia during six weeks of therapy with Grandaxin® decreased from 2.56 ± 0.54 to 0.96 ± 0.45 points (p < 0.001).Conclusion. Psycho-emotional disorders (more often in the form of increased personal anxiety), sleep disorders, vegetative disorders, asthenic syndrome significantly affect the quality of life of patients who have had a new coronavirus infection. Involvement of the structures of the autonomic nervous system and central structures that regulate GABAergic transmission leads to significant vegetative failures, which requires pathogenetically substantiated drug correction of these disorders.

OBJECTIVE To evaluate the efficacy and safety of samPEG-IFN-β1a 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-β1a180 μg (n=114), samPEG-IFN-β1a 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-β1a 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-β1a were equally effective when compared to LIB by the primary endpoint - «Time to first relapse». 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-β1a 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-β1a 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-β1a 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-β1a 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.

Introduction. In addition to acute manifestations, coronavirus infection is characterized by long-lasting symptoms: asthenia, somatic vegetative manifestations, sleep disorders and psychoemotional background, the question of therapeutic correction of which is especially relevant.The aim of the study was to study the mental, somatoform and cognitive aspects of anxiety disorders after coronavirus infection during treatment with tofizopam (Grandaxin®) at 150 mg / day.Materials and methods. The study involved patients who had a new coronavirus infection, who 4 weeks after the end of treatment for the underlying disease had complaints that suggest the presence of an anxiety disorder. The Hamilton scale was used to assess the level of anxiety. The patients were examined before the start of treatment, after 2, 4 and 6 weeks of therapy.Results. Prior to the start of therapy, all patients had an overall high level of anxiety: the average HAM-A score was 31.72 ± 2.24 points. At the end of Grandaxin® therapy, all patients showed a decrease in the level of anxiety: the average score for HAM-A was 12.68 ± 2.04 points (p < 0.001). At the end of the course of therapy, patients noted an increase in mental performance, improved memory and attention, that is, a decrease in the severity of cognitive disorders associated with anxiety was> distinct – the average score on the “cognitive disorders” subscale decreased three times – from 1.6 ± 0.12 to 0.5 ± 0.09 (p˂0.001).Conclusions. Disorders of the psychoemotional background (more often in the form of increased personal anxiety), sleep disorders, autonomic disorders, asthenic syndrome significantly affect the quality of life of patients who have suffered a new coronavirus infection. A comprehensive approach is needed in the clinical diagnosis of the long-term consequences of a new coronavirus infection and their subsequent correction with drug therapy.

OBJECTIVES:To evaluate efficacy, safety, and tolerability of the treatment with teberif/interferon β-1a, to analyze safety, tolerability and dynamics of key efficacy variables after switching from referent drug rebif to biosimilar teberif in patients with remitting multiple sclerosis (RMS).MATERIAL AND METHODS:During the main period of the international multicenter randomized study patients were randomized to receive treatment with teberif for 52 weeks, or rebif for 52 weeks, or placebo for 16 weeks to evaluate efficacy and safety of treatment. After the main study period, patients were group-independently switched to take open-label teberif treatment during the next 48 weeks.RESULTS AND CONCLUSION:The analysis of multiple evaluation parameters of the efficiency during the 1st study period (blinded) and the 2nd study period (open-label) has shown that teberif and rebif demonstrate equivalent efficacy and stable 2-year efficacy of teberif was proven. There were no significant differences between teberif and rebif for all safety, and tolerability parameters. Switching from rebif to teberif didn't influence treatment efficacy. The 2-year study results confirmed a biosimilar teberif's benign tolerability and expected safety profile to other interferons β-1a in patients with RMS.

Objectives. To demonstrate equivalence of the efficacies of the drugs Teberif (BCD-033, interferon β-1a) and Rebif (interferon β-1a) in patients with remitting multiple sclerosis (RMS). Materials and methods. A multicenter, double-blind, placebo-controlled, comparative, randomized phase III trial included 163 patients with diagnoses of MS. Patients were randomized to the Teberif, Rebif, and placebo groups at a ratio of 1:1:1. Results and conclusions. Analysis of efficacy after 52 weeks of the trial demonstrated equivalence between the study drug Teberif and the original formulation Rebif in patients with RMS. Evaluation of primary endpoint results – CUA (combined unique active lesions, i.e., the total number of MRI T1 plaques and new T2 plaques or cases of increases in T2 plaques without double counting) – demonstrated that there were no significant differences (0.727 ± 1.042 and 0.652 ± 1.059, p = 0.7354, Student’s t test) between the Teberif and Rebif groups. There were no statistically significant between-group differences in other MRI indicators or measures associated with exacerbations. The safety profile and tolerance of Teberif were satisfactory and comparable with the safety and tolerance profile of Rebif. These data provide evidence of therapeutic equivalence of these drugs, which may provide grounds for the use of the interferon β-1a bioanalog in patients with RMS.

AIM:To prove the equivalent efficacy of teberif (BCD-033, interferon beta-1) and rebif (interferon beta-1a) in patients with remitting multiple sclerosis (RMS).MATERIAL AND METHODS:A multicenter double blind placebo-controlled comparative randomized III phase study included 163 patients with RMS. Patients were randomized into three equal groups (teberif, rebif or placebo).RESULTS AND CONCLUSION:After 52 weeks, the equivalent efficacy of teberif and the brand drug rebif was shown. The result of assessment of the primary endpoint, which was combined unique active (CUA) lesion (the total of MRI T1-weighted lesions and new or newly enlarging T2-weighted lesions, without double counting of lesions with both activities), showed no significant differences (0.727±1.042 and 0.652±1.059 (p=0.7354, t-Student test) in the teberif and rebif groups, respectively. No between-group differences were found for other MRI indices and clinical parameters related with relapses. Teberif was shown to have a favorable safety and tolerability profile comparable to that of rebif. The results suggest the therapeutic equivalency of the drugs and form the basis for using the bioanalogue of interferon-beta 1 in patients with RMS.

withdrawn PP4118 The FAB fails to discriminate PSP from FTD and to capture disease progression in frontal disorders M. Stamelou1,2, J. Diehl-Schmidt3, D. Kontaxopoulou1, A. Hapfelmeier4, K. Bhatia5, W. Oertel2, L. Stefanis1, S. Papageorgiou1, G. Hoeglinger2,6 1University of Athens, Medical School, Attikon University Hospital, Athens, Greece, 2Philipps-University of Marburg, Marburg, 3Department of Psychiatry, 4Department of Medical Statistics and Epidemiology, Technische Universität München, Munich, Germany, 5UCL Institute of Neurology, London, United Kingdom, 6Department of Neurology, Technische Universität München, Munich, Germany Introduction: The frontal assessment battery (FAB) has been suggested as a useful tool in the differential diagnosis of progressive supranuclear palsy (PSP) from Parkinson’s disease (PD) and multiple system atrophy with parkinsonism (MSA-P). However, the utility of the FAB in the differential diagnosis of PSP from frontotemporal dementia (FTD) phenotypes is still under research. Methods: We performed the FAB, in a large multi-centre cohort of probable PSP (N=70), FTD (N=76 behavioral variant FTD, N=10 semantic dementia, N=9 progressive non-fluent aphasia), as well as PD (N=26) and MSA-P (N=11) patients, according to established criteria. Patients were also rated with the mini mental state examination and motor scales. Results: The FAB total score and subscores failed to discriminate PSP from bvFTD and PNFA patients. Moreover, the FAB did not correlate with disease duration and was insufficient to capture disease progression in these disorders. In contrast, we confirmed that the FAB was useful in differentiating PSP from PD and MSA-P. In fact, two FAB subscores together (verbal fluency and Luria motor series) were sufficient and better than the total score in differentiating PSP from PD and MSA-P. Conclusions: The FAB can neither differentiate PSP from FTD related disorders, nor can capture disease progression in PSP and FTD. This should be taken into consideration in clinical practice but also in planning clinical trials. When used to differentiate PSP from PD and MSA-P, verbal fluency and motor series are sufficient and the total score is redundant. Disclosure: Nothing to disclose 668 Paper Poster Sessions © 2014 EFNS European Journal of Neurology 21 (Suppl. 1), 388–713 PP4119 Clinical and genetic characteristics of dopa-responsive dystonia in a Serbian population M. Svetel1, V. Dobricic2, I. Novakovic2, N. Dragasevic1, I. Petrovic1, V.S. Kostic1 1Movement Disorders Department, 2Genetic Laboratory, Clinic of Neurology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia Introduction: Dopa-responsive dystonia (DRD) is neuromethabolic disorders inherited in 2 ways: autosomaldominant (AD) with heterozygous mutations in GPTcyclohydrolase 1 gene (GCH1-DYT5a) and autosomalrecessive (AR) with homozygous or compound heterozygous mutations in genes for thyrosin-hydrolase (TH) or sepiapterin-reductase (SPR) (DYT5b). AD form is characterized by reduced penetrance and excellent and permanent response to levodopa, while AR form is more severe, with developmental delay and cognitive impairment. The aim was to assess genetic and clinical characteristics of DYT5a mutations carriers in patients with dystonia-plus syndrome in Serbia. Methods: Study comprised 66 patients with dystonia-plus syndrome and 60 healthy controls. Genetical analysis was performed by method of direct sequencing of coding exones of GCH1 gene. Clinical characteristics of patients were evaluated using standardized rating scales for assessment of dystonia and parkinsonism. Results: We found 5 mutations of GCH1 gene (L157P, 209delA, c.C08G>A , c.558c>T, ex+1G>C) in 10 carriers. The most frequent mutation (L157P) was demonstrated in a family with 5 affected members, all with spastic paraparesis as initial presentation and excellent levodopa responsiveness. Phenotype spectrum was wide in our group of patients, from lower extremities dystonia to hemiparkinsonim, dystonia-parkinsonism complex and spastic paraparesis. All patients were on continuous levodopa treatment. DAT was normal in all patients, while 2 of them had pathological finding on TCS. Conclusions: Our results showed GCH1 mutations in 15% of patients with dystonia-plus syndrome. It is important to stress phenotypic heterogeneity of the disease with wide spectrum of clinical expressions in forms of dystonia, parkinsonism and spastic paraparesis. Disclosure: Nothing to disclose PP4120 Frequency of non-motor symptoms in patients with Parkinson’s disease K. Tanveer1, I. Attique1, W. Sadiq1, F. Rao2, A. Ahmed1 1Shifa College of Medicine, Shifa Tameer-e-Millat University, 2Shifa Int Hospital, Islamabad, Pakistan Introduction: In multiple studies around the globe, nonmotor symptoms have been identified as a source of immense disability in patients of Parkinson’s disease. However there is scarcity of data from Asia. This is the first study from Pakistan assessing the impact of non-motor symptoms on patients with Parkinson ’s disease. Objectives: To investigate the frequency of non-motor symptoms of Parkinson’s disease in Pakistani population and compare it with the Western data. Methods: In this cross-sectional survey, data was retrospectively collected from Shifa International Hospital Neurology database. This study comprised of 97 patients at different stages of Parkinson’s disease who were questioned at neurology OPD or through telephonic interviews. Disease severity was assessed using ’Hoehn & Yahr’s staging’ while ’NMS Quest’ was employed to identify the non-motor symptoms present. Medical records were reviewed for demographic data and recent treatment history. Results: The mean age was 67.33 years (adult onset=76.3%, young onset=23.7%). No correlation was found between the disease duration and the disease stage. The most frequent non-motor symptoms were nocturia (77.3%), urinary urgency (61.9%), constipation (59.8%), forgetfulness (58.8%), insomnia (52.6%) and orthostatic hypotension (52.6%). The earliest manifestations of non-motor symptoms were nocturia, forgetfulness, low mood and orthostatic hypotension. Sleep abnormalities, falling episodes & hallucinations are prevalent amongst patients of advanced disease. Conclusion: There is a direct correlation between disease progression and number of non-motor symptoms present. Disclosure: Nothing to disclose