[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].

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.

XTX301, a Tumor-Activated Interleukin-12 Has the Potential to Widen the Therapeutic Index of IL12 Treatment for Solid Tumors as Evidenced by Preclinical Studies.

IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells in tumors. However, the systemic administration of IL12 has been accompanied by considerable toxicity, prompting interest in researching alternatives to drive preferential IL12 bioactivity in the tumor. Here, we have generated XTX301, a tumor-activated IL12 linked to the human Fc protein via a protease cleavable linker that is pharmacologically inactivated by an IL12 receptor subunit beta 2 masking domain.

[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].

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.

[POEMS-syndrome].

POEMSsyndrome (polyneuropathy - P, organomegaly - O, endocrinopathy - E, M-protein - M, skin changes - S) is a paraneoplastic syndrome caused by underlying dyscrasia of plasma cells. The main criteria of the syndrome are polyradiculoneuropathy, clonal proliferation of plasma cells, sclerotic bone lesions, elevated levels of vascular endothelial growth factor and the presence of Castleman disease. Additional signs include organomegaly, endocrinopathy, characteristic skin changes, edema of the optic disc, extravascular volume overload (edema) and thrombocytosis.

[Efficacy and safety of divozilimab during 24-week treatment of multiple sclerosis patients in randomized double-blind placebo-controlled clinical trial 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.

5-Alkoxy-1-aryl-3-polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels.

Chemoselective O-alkylation of 1-aryl-3-polyfluoroalkylpyrazol-5-oles under basic conditions resulted in a series of 5-alkoxypyrazoles (26 derivatives). They showed an acceptable ADME profile (in silico) and can be considered as drug-like. In experiments in vivo (CD-1 mice), it was found that the obtained compounds do not have toxic properties at a dose of more than 150 mg/kg (for most compounds at a dose of >300 mg/kg, and for lead compounds - >600 mg/kg).

[Long-term treatment for multiple sclerosis with interferon beta-1b. Outcomes of an open, retrospective, observational study].

Objective: To assess the outcomes of long-term treatment in multiple sclerosis (MS) patients with Infibeta (interferon beta-1b).

Material And Methods: The article presents the results a real-world, multicenter, retrospective, observational study of treatment with interferon beta-1b. We enrolled 332 patients with MS who had been receiving Infibeta for at least 8 years.

[Efficacy and safety of sampeginterferon β-1a in the treatment of relapsing remitting multiple sclerosis: results of 52 weeks of therapy in a randomized, double-blind clinical trial].

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 (=114), samPEG-IFN-β1a 240 μg (=114), LIB (=114) and placebo (=57).

Local delivery of mRNA-encoded cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models.

Local immunotherapy ideally stimulates immune responses against tumors while avoiding toxicities associated with systemic administration. Current strategies for tumor-targeted, gene-based delivery, however, are limited by adverse effects such as off-targeting or antivector immunity. We investigated the intratumoral administration of saline-formulated messenger (m)RNA encoding four cytokines that were identified as mediators of tumor regression across different tumor models: interleukin-12 (IL-12) single chain, interferon-α (IFN-α), granulocyte-macrophage colony-stimulating factor, and IL-15 sushi.

Survey of diagnostic and treatment practices for multiple sclerosis in Russian Federation in comparison to European data.

Introduction: The data of the survey of European (EU) neurologists on the methods of diagnosis and treatment of multiple sclerosis in Europe were compared with the data of the similar survey of neurologists of the Russian Federation (RF).

Method: Seventy-five neurologists specialized in MS from RF completed questionnaires on radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS) multiple sclerosis.

Results: In the case of RIS, only 46% of neurologists from the RF recommended CSF analysis for oligoclonal IgG and only 54.

An experimental model of anti-PD-1 resistance exhibits activation of TGFß and Notch pathways and is sensitive to local mRNA immunotherapy.

Immune checkpoint blockade elicits durable anti-cancer responses in the clinic, however a large proportion of patients do not benefit from treatment. Several mechanisms of innate and acquired resistance to checkpoint blockade have been defined and include mutations of MHC I and IFNγ signaling pathways. However, such mutations occur in a low frequency of patients and additional mechanisms have yet to be elucidated.

Pan-TGFβ inhibition by SAR439459 relieves immunosuppression and improves antitumor efficacy of PD-1 blockade.

TGFβ is a pleiotropic cytokine that may have both tumor inhibiting and tumor promoting properties, depending on tissue and cellular context. Emerging data support a role for TGFβ in suppression of antitumor immunity. Here we show that SAR439459, a pan-TGFβ neutralizing antibody, inhibits all active isoforms of human and murine TGFβ, blocks TGFβ-mediated pSMAD signaling, and TGFβ-mediated suppression of T cells and NK cells.

[The efficacy and safety of siponimod in the Russian population of patients with secondary progressive multiple sclerosis].

Aim: To study the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis (SPMS) in the Russian population of the EXPAND study.

Material And Methods: Ninety-four patients with SPMS from Russia were included in the analysis. Sixty-three patients received siponimod and 31 patients received placebo.

[The new pegylated interferon beta-1a (sampeginterferon beta-1a, BCD-054) in the treatment of remitting multiple sclerosis].

Aim: To evaluate the efficacy and safety of BCD 054 180 μg and 240 μg administered once every 2 weeks for the treatment of remitting multiple sclerosis compared to placebo and low dose interferon beta-1a (LIB) 30 μg administered once weekly. Results of a 20 week blinded interim analysis from a double blind, comparative, randomised, placebo-controlled clinical study are included.

Material And Methods: This multinational, multicentre, double blind, comparative, placebo-controlled study enrolled 399 patients with the diagnosis of remitting multiple sclerosis: 114 patients in the sampeginterferon beta 1a and LIB groups each and 57 patients in the placebo group.

[Susac syndrome, review and clinical case].

Susac syndrome (SS) is an extremely rare neurological disorder characterized by symptoms of a clinical triad: encephalopathy, retinopathy and hearing loss. These problems arise from the microangiopathy of blood vessels that supply blood to the brain, the retina and the cochlea. SS is more common in young women.

Real-world study of efficacy, risk management and reasons for discontinuation of natalizumab for treatment of multiple sclerosis in Russia.

Background: NTZ is approved in Russia for the treatment of highly active relapsing remitting multiple sclerosis and is reimbursed via federal budget program. However, no data about NTZ treatment in Russia and the effect of federal reimbursement have been performed so far.

Objective: To characterize the population of patients receiving natalizumab and assess the efficacy and risk-management plan (RMP) implementation of NTZ therapy in routine clinical practice in Russia.

[Provision of alemtuzumab safety is one of the main components of pharmacovigilance].

Modern multiple sclerosis therapy with disease-modifying drugs is characterized by the risks of dangerous infectious complications. In the last 5 years, there have been several reports of severe, sometimes lethal, listeriosis infection in patients treated with alemtuzumab. This article presents a clinical case of lethal listeriosis meningoencephalitis, which developed within 7 days after the completion of the first cycle of alemtuzumab therapy.

[Primary-progressive multiple sclerosis in Russia: a medical-sociological study involving patients and neurologists].

The main results of a medical-sociological study aimed at the evaluation of the level of satisfaction with treatment in patients with primary progressive multiple sclerosis (PPMS) are presented. The survey was conducted in 19 regions of the Russian Federation and involved 437 patients with confirmed diagnosis of PPMS and 80 neurologists specialized in multiple sclerosis. The research was carried out by the All-Russian Public Organization of Disabled People with Multiple Sclerosis with the participation of the Russian Committee for Treatment and Research in Multiple Sclerosis.

A kinetic investigation of interacting, stimulated T cells identifies conditions for rapid functional enhancement, minimal phenotype differentiation, and improved adoptive cell transfer tumor eradication.

For adoptive cell transfer (ACT) immunotherapy of tumor-reactive T cells, an effective therapeutic outcome depends upon cell dose, cell expansion in vivo through a minimally differentiated phenotype, long term persistence, and strong cytolytic effector function. An incomplete understanding of the biological coupling between T cell expansion, differentiation, and response to stimulation hinders the co-optimization of these factors. We report on a biophysical investigation of how the short-term kinetics of T cell functional activation, through molecular stimulation and cell-cell interactions, competes with phenotype differentiation.

[Primary progressive multiple sclerosis: current issues of timely diagnosis].

This article presents a review of international data on primary progressive multiple sclerosis (PPMS) and an analysis of factors influencing timely diagnosis of PPMS in a number of regions of the Russian Federation.

[Polymorphic variants of the immune response genes as risk factors for primary progressive multiple sclerosis].

Aim: To analyze the involvement of immune response genes in the pathogenesis of primary progressive multiple sclerosis (PPMS).

Material And Methods: This multicenter study included 111 patients with PPMS from the Russian ethnic group. The association of PPMS with genes of immune system was analyzed by the study of polymorphic variants of genes of cytokines and genes of antigen-presenting cells.

[Clinical guidelines for the use of dimethyl fumarate in relapsing-remitting multiple sclerosis].

Multiple sclerosis is a chronic demyelinating and neurodegenerative disease of the central nervous system, in which autoimmune inflammation and oxidative stress play essential pathogenetic roles. Activation and infiltration of immune cells in brain tissues, lipid peroxidation products, mitochondrial dysfunction, defective antioxidant protection, and many other pathological factors result in demyelination, axonal injury and death, and apoptosis of oligodendrocytes and neurons, all of which causes constant progression of the disease. The new oral agent for the treatment of relapsing-remitting multiple sclerosis (RRMS), dimethyl fumarate (DMF), helps change the pathogenetic mechanisms of the disease, thus decreasing the rate of exacerbations, slowing down disease progression, and reducing the risk of radiological progression of the disease.