Divozilimab in neuromyelitis optica spectrum disorders: one-year interim analysis of the AQUARELLE clinical trial

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Introduction

Neuromyelitis optica spectrum disorders (NMOSD) are a group of relatively rare autoimmune diseases of the central nervous system characterized by inflammatory lesions predominantly localized in the optic nerves, spinal cord, and brainstem [1]. NMOSDs are characterized by severe relapses that often result in incomplete recovery. This leads to neurological deficits and patient disability up to complete loss of independent ambulation and vision loss, as well as death in rare cases involving brainstem lesions [2]. Treatment for NMOSD includes management of acute relapses with corticosteroids and therapeutic plasma exchange, as well as long-term pathogenetic therapy to prevent relapses.

The primary goal of long-term therapy is to prevent relapses, because disability in NMOSD is exclusively associated with these episodes. Several treatment options that target various pathogenic mechanisms are used. Historically, the therapeutic approach relied on nonselective immunosuppressive therapy. However, its clinical use is declining due to a wide range of adverse events (AEs) and the development of more effective targeted agents, including monoclonal antibodies that affect B-cell immunity, interleukin-6 receptors, and complement system components [3].

B cells play a critical role in NMOSD. Currently, it is thought that trigger factors activate the B-cell immune response, leading to the production of antibodies against the water channel protein aquaporin-4 (AQP4-IgG). These antibodies induce a cascade of events that increases the permeability of the blood-brain barrier, leading to the destruction of astrocytes, which express this target antigen, and the recruitment of inflammatory cells into the central nervous system. CD20⁺ B cells also contribute to the immune response via the upregulation of proinflammatory cytokines and the downregulation of regulatory B cells. This inflammatory cascade causes secondary damage to oligodendrocytes, axons, and neurons [4, 5].

The discovery of the key role of B cells in NMOSD pathogenesis led to the development of anti-B-cell therapies aimed at preventing relapse. Rituximab was the first agent in this class, and it is still used off-label because it lacks regulatory approval for treating neuromyelitis optica, or NMOSD. Rituximab is a chimeric monoclonal antibody that targets the CD20 receptor found on B cells. The efficacy of rituximab in reducing NMOSD relapse rates has been demonstrated in randomized clinical trials (RCTs) with small sample sizes [6, 7] and in several real-world observational studies [8–10]. Although rituximab reduces the relapse rates, severe relapses have been reported in some patients [11]. Additionally, long-term clinical remission needs to be maintained. The tolerability profile of rituximab during prolonged therapy is therefore a concern because the use of chimeric antibodies increases the risk and rate of AEs [12]. This underscores the need for more advanced anti-B-cell agents to treat NMOSD.

Divozilimab, a humanized, afucosylated monoclonal antibody that targets CD20, has been approved to treat relapsing multiple sclerosis, systemic sclerosis, and NMOSD. The BCD-132-6/AQUARELLE clinical trial previously demonstrated a significant reduction in the annualized relapse rate (ARR) in patients with NMOSD after six months of therapy, along with a favourable safety profile [13]. Because these findings need to be confirmed over a longer period, long-term follow-up of patients in this clinical trial is ongoing.

The study aimed to evaluate the one-year efficacy and safety outcomes of divozilimab therapy for patients with NMOSD.

Materials and methods

The AQUARELLE multicenter, open-label, Phase 3 clinical trial (NCT05730699) evaluates the efficacy, safety, pharmacokinetics, pharmacodynamics, and immunogenicity of divozilimab in patients with NMOSD. The trial included patients aged 18 years and older with confirmed diagnosis of NMOSD according to the 2015 International Panel for NMO Diagnosis criteria [2], who had to have experienced at least one relapse within 12 months or at least two relapses within 24 months prior to signing the informed consent form, with Expanded Disability Status Scale (EDSS) score of ≤ 7.0. For AQP4-seronegative patients, the absence of typical multiple sclerosis brain and spinal cord magnetic resonance imaging (MRI) lesions, as well as the absence of intrathecal synthesis of oligoclonal or monoclonal IgG, should be confirmed. During the study, patients received 500 mg of divozilimab via intravenous infusion every 24 weeks. The first dose was divided into two 250-mg infusions administered two weeks apart.

The primary efficacy endpoint in the AQUARELLE trial was the ARR after six months of divozilimab therapy compared with a historical control that used data from the placebo group in the N-MOmentum trial [14]. The primary endpoint was met, and the results have been published [13]. This article presents the results of the analysis of 12 months of treatment efficacy data. Similarly to the primary endpoint, the ARR ratio between the divozilimab group and the historical control group was calculated using the mesially shrunk logit Wald method with a 2-sided 90% CI. The results are presented in both unadjusted and weighted versions. The ARR was calculated for each group as the ratio of confirmed NMOSD relapses to total follow-up duration for the population in person-years. The weight calculation was performed according to the methodology proposed by the National Institute for Health and Care Excellence (UK) [13].

In the AQUARELLE trial, efficacy parameters such as the ARR and time to first relapse were evaluated during the first year of treatment and compared with data from the placebo group in the SAkuraStar trial. The selection of historical control groups was based on the results of a systematic literature search that identified a relevant systematic review with a network meta-analysis [15]. The results of this meta-analysis were deemed applicable to the clinical management of adult patients with NMOSD because it included relevant RCTs. This made it possible to use the findings to establish the historical control group. Of the randomized trials, N-MOmentum (inebilizumab) and SAkuraStar (satralizumab) had the most similar eligibility criteria to those of the AQUARELLE trial. The common inclusion criteria included enrollment of AQP4-seronegative subjects and a prohibition of concomitant immunosuppressive therapy. These criteria applied to both the AQUARELLE trial and the placebo-controlled periods of the historical control studies. The publication reporting the six-month treatment outcomes of the AQUARELLE trial provides a detailed description of the analysis methodology utilizing historical controls [13]. The placebo group from the SAkuraStar study was chosen as the historical control group for the analysis of one-year outcomes because its follow-up period was up to 216 weeks. In contrast, the control group from the N-MOmentum study was only followed for six months [14, 16].

In addition to the ARR at the end of the first year of treatment in the overall AQUARELLE study population, a post hoc subgroup analysis was conducted to evaluate the following:

• AQP4-IgG-seropositive and AQP4-seronegative patients;
• treatment-naïve patients and patients previously treated with relapse-preventing therapies, most commonly azathioprine and rituximab.

Patients with a history of anti-B-cell therapy (rituximab or inebilizumab) were analyzed separately from the latter subgroup. The subgroup analysis of prior therapy excluded patients receiving treatments not indicated for NMOSD, such as glatiramer acetate, interferon beta, and teriflunomide. The ARR and its 95% CI were calculated for each subgroup.

Additionally, the following secondary endpoints were included: analysis of neurological deficit severity using EDSS scores; proportion of patients with confirmed disability worsening; visual acuity assessed by changes in the number of optotypes using high-contrast Early Treatment Diabetic Retinopathy Study (ETDRS) with Landolt-C charts; walking speed evaluated by the Timed 25-Foot Walk (T25FW) test; pain intensity measured by the Numeric Rating Scale (NRS); proportion of patients with neuropathic pain according to the Douleur Neuropathique en 4 Questions (DN4) questionnaire; quality of life assessed by the 36-Item Short Form Survey (SF-36). Descriptive statistics were used to analyze these endpoints.

R software, v.4.3.1, was used to perform the data analysis. Missing data were not imputed.

The safety assessment included the evaluation and reporting AEs, which were graded according to the severity criteria of the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Results

Patient characteristics

The AQUARELLE clinical trial included 105 patients. The median age of the patients was 46 years ([Q₁; Q₃]: [35; 56] years). The majority of the patients were women (٨٩ [84.8%]), and 102 patients (97.1%) were Caucasian. The majority of patients (97 [92.6%]) were seropositive for AQP4-IgG antibodies. The median disease duration was 0.92 [0.25; 3.26] years. The most frequent baseline clinical manifestations were optic neuritis (75 [71.4%]) and acute transverse myelitis (91 [86.7%]). The ARR was 1.210 (95% CI, 1.016–1.439) during the year prior to trial enrollment. The majority of patients (60 [57.1%]) were treatment-naïve (i.e., they had never received relapse-preventing therapies); 9 patients (8.6%) had previously received rituximab, and 4 (3.8%) had received inebilizumab. The most frequently prescribed agents were azathioprine (25 [23.8%]) and mitoxantrone (10 [9.5%]). Satralizumab, eculizumab, methotrexate, mycophenolate mofetil, mycophenolic acid, and human intravenous immunoglobulin were administered in isolated cases. A more detailed description of the baseline characteristics is available in the publication that reports the six-month treatment outcomes of the AQUARELLE trial [13].

A total of 100 patients completed 1 year of divozilimab therapy in the AQUARELLE trial. During this period, 5 patients discontinued the study: 3 due to death, 1 due to an AE, and 1 due to withdrawal of informed consent (Fig. 1). The Safety section provides detailed information about AEs leading to study discontinuation.

 

Fig. 1. Screening, enrollment, and distribution of patients in the AQUARELLE clinical trial.

 

The effect of divozilimab on the probability and rates of NMOSD relapse

The ability of an agent to influence the relapse probability and rates is a key parameter for evaluating its efficacy in NMOSD. During the 48-week treatment period in the AQUARELLE trial, 10 confirmed NMOSD relapses were reported in 10 patients (9.5%). Of these, 5 patients presented with myelitis, 3 with optic neuritis, 1 with both myelitis and optic neuritis, and 1 with cerebral syndrome. The ARR during the first year of treatment was 0.104 (95% CI, 0.056–0.193). The weighted ARR ratio between the divozilimab group and the historical placebo control group (SAkuraStar) was 0.237 (90% CI: 0.084–0.672), demonstrating that divozilimab is superior to placebo after one year.

In the subgroup analysis of ARR after 1 year of treatment, the rates were 0.101 (95% CI, 0.052–0.193) in AQP4-IgG-seropositive patients and 0.141 (95% CI, 0.020–0.999) in AQP4-seronegative patients. In the treatment-naïve subgroup, the ARR was 0.110 (95% CI, 0.050–0.246), whereas in patients with a history of pathogenetic therapy for NMOSD, the ARR was 0.082 (95% CI, 0.027–0.256). The ARR calculated separately for patients with prior exposure to anti-B-cell therapy was 0.041 (95% CI, 0.003–0.658).

An indirect comparison of time to relapse with the historical placebo group from the randomized SAkuraStar trial revealed a statistically significant reduction in the likelihood of relapse in patients receiving divozilimab. The superiority of divozilimab was maintained after population weighting: the hazard ratio (HR) during the first year of treatment was 0.108 (95% CI, 0.036–0.324; p < ٠.٠٠1; Figure 2).

 

Fig. 2. Time to first confirmed relapse in the AQUARELLE study and the historical placebo group (SAkuraStar), presented before (A) and after (B) weighting.

 

Secondary efficacy endpoints

Table 1 presents data regarding secondary efficacy endpoints. During the first year of treatment, no cases of CDW were reported in the AQUARELLE trial. The median EDSS baseline score was 4.0 [3.5; 4.5]. No changes from baseline were observed for this parameter. Similarly, no changes were reported in visual acuity or T25FW.

 

Table 1. Efficacy parameters during 1 year of divozilimab therapy in the AQUARELLE trial

Parameter	n	Value	Change from baseline
Annualized confirmed relapse rate	105	0.104 (95% ДИ 0.056–0.193)
Proportion of relapse-free patients, n (%)	105	95 (90.5%)
EDSS score, Me [Q1; Q3]	100	4.0 [3.5; 4.5]	0.0 [0.0; 0.0]
Proportion of patients with confirmed disability worsening, n (%)	105	0 (0.0)
Visual acuity, number of optotypes, Me [Q1; Q3]
Right eye	78	80 [69; 85]	0 [–5; 4]
Left eye	74	80 [60; 87]	0 [–5; 6]
T25FW, s, Me [Q1; Q3]	97	7.00 [5.6; 9.9]	–0.5 [–1.0; 0.5]
Pain intensity by NRS, scores, Me [Q1; Q3]	100	2.0 [0.0; 5.0]	0.0 [–1.0; 0.0]
Proportion of patients with neuropathic pain by DN4, n (%)	105	34 (32.4)	Initially 45 (42.9)
Quality of life by SF-36, scores, Me [Q1; Q3]
Physical summary score	100	40.45 [29.00; 54.15]	0.75 [–2.65; 4.95]
Mental summary score	100	51.45 [41.50; 56.90]	0.10 [–3.85; 8.10]

 

Pain, which is primarily manifested as neuropathic pain, is one of the clinical features that has the greatest impact on the quality of life of patients with NMOSD. The AQUARELLE trial evaluates two pain parameters: the proportion of patients with neuropathic pain by DN4 score, and pain intensity by NRS. Neuropathic pain was reported in 45 patients (42.9%) at baseline and 34 patients (32.4%) after 1 year of treatment. The AQUARELLE trial evaluated pain intensity after 1 year of treatment in 100 patients. The NRS median was 2 [0; 5.0]. The median change from baseline in pain intensity was 0.0 [−1.0, 0.0]. The study parameters demonstrate no negative changes in pain intensity in patients with NMOSD receiving divozilimab therapy. No significant changes were reported in the physical or mental summary scores by SF-36 to evaluate quality of life during the first year of divozilimab therapy.

Safety

During the first year of divozilimab therapy, AEs were reported in 80 (76.2%) patients. Of them, AEs classified as adverse drug reactions (ADRs) were observed in 45 (42.9%) patients. Most of the reported AEs were mild or moderate in severity. Serious AEs occurred in 9 patients (8.6%), but none were classified as ADRs. During the one-year follow-up period, four severe ADRs were reported in 4 patients (CTCAE, v. 5.0, Grade ≥ 3). All of these reactions were Grade 3 and included infusion-related reactions, decreased lymphocyte, and neutrophil counts. All infusion-related reactions had resolved by the time of data analysis, though some laboratory abnormalities persisted.

Three deaths were associated with the following conditions: suicide, heart failure caused by atherosclerotic cardiovascular disease (ASCVD), and cryptococcal meningitis. These fatal cases were classified by investigators as unrelated to divozilimab. For suicide and ASCVD-related heart failure, a causal relationship to the study treatment was ruled out based on disease pathogenesis and the lack of a pharmacologically plausible mechanism.

In the case of cryptococcal meningitis, symptoms (nausea, vomiting, headache) developed 3 months after the first dose. A differential diagnosis was established to distinguish between a NMOSD relapse and a neuroinfection. Brain MRI revealed leptomeningeal enhancement; cerebrospinal fluid testing demonstrated pleocytosis, elevated protein levels, and the presence of Cryptococcus neoformans. Empirical antibacterial and antifungal therapies were initiated. Death occurred 1.5 months after symptom onset. The sponsor evaluated the possible causal relationship between the serious AEs and the study treatment, considering the temporal relationship with dose administration and the biological plausibility based on the agent’s pharmacological action. The sponsor also considered the significant role of other factors, such as corticosteroid therapy and the underlying disease, in the development of the neuroinfection and its outcome.

In one case, the study was discontinued due to a serious AE: endometrial cancer (stage IA). This cancer was detected during a routine annual gynecological examination of an asymptomatic female patient over 60 years old. The examination was performed two months after a single dose of divozilimab. Due to the short time between dose administration and serious AE, the specific pathogenesis, and the inability to rule out other potential causes, the causal relationship with the treatment was deemed doubtful. However, the patient was withdrawn from the study because pre-existing malignancies (except for basal cell carcinoma of the skin and oncological diseases for which anti-CD20 antibodies are indicated) are a contraindication to the therapy.

The most common ADRs were decreased lymphocyte count (22; 21.0%), decreased neutrophil count (13; 12.4%), decreased white blood cell count (12; 11.4%), and infusion-related reactions (6; 5.7%). Less than 5% of patients had treatment-related infections.

Discussion

The outcomes of the 48-week follow-up period for patients in the AQUARELLE clinical trial showed that divozilimab was superior to the placebo used in the SAkuraStar RCT in terms of both the ARR and time to first relapse. After 1 year of treatment, the changes in disability parameters and other key clinical parameters were evaluated, and no CDW cases were reported. The EDSS score remained stable, and there were no negative changes in T25FW test or visual acuity.

In the subgroup analysis, the ARR after 1 year of divozilimab treatment was low, regardless of the presence or type of prior therapy, including anti-B-cell agents such as rituximab and inebilizumab. The effect of prior exposure to eculizumab and satralizumab was not evaluated because there were very few patients in the AQUARELLE population with such exposure. Low ARR values achieved with divozilimab suggest the potential for effective disease activity control, regardless of prior treatment regimens.

The efficacy of switching from rituximab was previously evaluated in a subgroup analysis for inebilizumab, the anti-B-cell agent (N-MOmentum). In patients with a history of rituximab use, inebilizumab reduced the ARR similarly to the rate observed in patients without a history of rituximab use. In this patient subgroup, the rate of infusion-related reactions did not increase; however, the infection rate was slightly higher than the average study population rate [17].

 

Table 2. Safety profile (AEs and ADRs) during 1st year of divozilimab therapy in the clinical trial (n = 105)

Safety category	Divozilimab, n (%)
AEs
any AEs	80 (76.2)
serious AEs	9 (8.6)
including fatal cases	3 (2.9)
ADRs:
any ADRs	45 (42.9)
severe ADRs	4 (3.8)
serious ADRs	0 (0.0)
Infusion-related reactions	6 (5.7)

 

Unlike inebilizumab, a monoclonal antibody that targets CD19, divozilimab targets the same therapeutic target as rituximab (CD20). However, the different efficacy and safety profiles of rituximab and divozilimab in NMOSD may be due to their structural differences. First, divozilimab is a humanized antibody, whereas rituximab is a chimeric antibody. The first one is associated with lower immunogenicity, which may explain better tolerability and efficacy of divozilimab. Second, divozilimab has an afucosylated Fc region, leading to more efficient binding of the monoclonal antibody to effector cells. Consequently, there is more severe B-cell depletion via antibody-dependent cellular cytotoxicity, which may also contribute to its higher efficacy and better tolerability [18]. Although the number of patients with prior rituximab exposure was limited, data from the AQUARELLE trial suggest that divozilimab is effective in this subgroup and has a favorable safety profile.

The AQUARELLE trial also included a subgroup of AQP4 seronegative patients. The limited number of seronegative patients in the AQUARELLE trial, compared to the available epidemiological data (10–25%) [19–21], was likely due to the strict selection criteria for seronegative patients, including lumbar punctures to rule out intrathecal synthesis of oligoclonal immunoglobulins, independent analysis of MRI data, and diagnostic confirmation by an independent neurological review committee.

For the seronegative subgroup, the ARR during the first year of therapy was similar to that observed in seropositive patients. These findings suggest that divozilimab could be an effective treatment for AQP4-seronegative patients with NMOSD. Although other monoclonal antibodies are only approved for treating AQP4 seropositive patients with NMOSD, seronegative patients were included in the clinical trials for satralizumab (SAkuraStar and SAkuraSky) and inebilizumab (N-MOmentum) [14, 16, 22]. However, none of the clinical trials demonstrated the ability of treatment to reduce risk of relapse in seronegative patients [16, 22]. In the N-MOmentum trial, 3/12 seronegative patients receiving inebilizumab had confirmed NMOSD relapses, whereas none occurred in the placebo group (n = 4) [14]. However, further analysis revealed a reduction in the ARR in the seronegative subgroup.

Pain is a common manifestation of NMOSD that significantly impacts patients’ quality of life. It often results from lesions in the spinothalamic tracts and posterior columns of the spinal cord. Pain in NMOSD is persistent and resistant to treatment [25]. However, the data suggest that relapse-preventive therapy could reduce the pain intensity and its impact on patients’ quality of life. This reduction may be associated with decreased inflammation severity [26]. Therefore, the AQUARELLE clinical trial evaluated changes in the pain intensity by NRS and the proportion of patients experiencing pain after 48 weeks of divozilimab treatment. During divozilimab treatment, pain intensity scores remained stable, but the proportion of patients who had previously experienced neuropathic pain decreased slightly. It is necessary to study the subgroup of patients with the most severe changes and conduct longer follow-ups to better understand pain changes during divozilimab treatment in patients with NMOSD.

The 48-week follow-up of the AQUARELLE trial did not identify any new safety signals. The most common AEs were lymphopenia, neutropenia, and leukopenia. No increase in the severity or rate of these reactions was reported. The rate of infusion-related reactions remained relatively low. The rate of divozilimab-related reactions remained relatively low. Therefore, the safety profile of divozilimab in the AQUARELLE trial is consistent with those observed in other clinical trials for different indications, such as multiple sclerosis and systemic sclerosis, and is comparable to the expected profile of anti-B-cell therapy [27, 28].

The primary limitations of the AQUARELLE trial are its open-label design and use of an external control group. However, as previously discussed, the use of a placebo in patients with this orphan disease, for which relapse-preventing treatment options are available, does not align with the ethical principles of clinical trials, given the high risk of severe patient disability resulting from relapses. Despite this limitation, the validity of the data was ensured by the objective measurement of the primary endpoint, a robust treatment effect in the study group that correlated temporally with its administration, baseline population similarity between the control and study groups, and an evaluation of the treatment effect adjusted for parameters that could influence disease outcomes.

Subsequent analysis of AQUARELLE data over a longer follow-up period will provide additional information regarding the long-term efficacy and safety of divozilimab in NMOSD. It will be crucial to obtain additional data from specific patient subpopulations. Although in the AQUARELLE trial, divozilimab showed positive outcomes in seronegative patients, the subgroup was small, so more data is needed to confirm the divozilimab efficacy in the AQP4-seronegative NMOSD population.

Conclusion

The 48-week follow-up outcomes from the AQUARELLE clinical trial confirm earlier findings demonstrating a favorable efficacy (reduction in both the relapse rate and risk) and safety profile of anti-CD20 therapy for divozilimab in NMOSD. Additionally, these data highlight its therapeutic potential in patients with various types and clinical courses of the disease.

About the authors

Alexey N. Boyko

Federal Center for Brain Research and Neurotechnologies; Pirogov Russian National Research Medical University

Email: boykoan13@gmail.com
ORCID iD: 0000-0002-2975-4151

Dr. Sci. (Med.), Professor, Head, Department of neuroimmunology; Professor, Department of neurology, neurosurgery and medical genetics

Russian Federation, Moscow; Moscow

Mariya N. Zakharova

Russian Center of Neurology and Neurosciences

Email: zakharova@neurology.ru
ORCID iD: 0000-0002-1072-9968

Dr. Sci. (Med.), Professor, chief researcher, Head, 6^th Neurology department, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Taras O. Simaniv

Russian Center of Neurology and Neurosciences

Author for correspondence.
Email: simaniv@neurology.ru
ORCID iD: 0000-0001-7256-2668

Cand. Sci. (Med.), senior researcher, 6^th Neurological department, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Zoya A. Goncharova

Rostov State Medical University

Email: centrms@mail.ru
ORCID iD: 0000-0001-7093-9548

Dr. Sci. (Med.), Professor, Head, Department of nervous diseases and neurosurgery

Russian Federation, Rostov-on-Don

Nikolay N. Spirin

Yaroslavl State Medical University

Email: simaniv@mail.ru
ORCID iD: 0000-0001-9078-589X

Dr. Sci. (Med.), Professor, Head, Department of nervous diseases with medical genetics and neurosurgery

Russian Federation, Yaroslavl

Natalia A. Totolyan

Pavlov First Saint Petersburg State Medical University

Email: ntotolyan@mail.ru
ORCID iD: 0000-0002-6715-8203

Dr. Sci. (Med.), Professor, Department of neurology

Russian Federation, Saint Petersburg

Klara Z. Bakhtiyarova

Bashkir State Medical University

Email: angelika7d@mail.ru

Dr. Sci. (Med.), Professor, Department of neurology

Russian Federation, Ufa

Irina V. Greshnova

Ulyanovsk Regional Clinical Hospital

Email: simaniv@mail.ru
ORCID iD: 0000-0003-3092-5381

deputy chief medical officer

Russian Federation, Ulyanovsk

Vyacheslav A. Dudin

Kirov Center of Cardiology and Neurology

Email: simaniv@mail.ru
ORCID iD: 0000-0002-5624-240X

Head, Department for the provision of primary specialized outpatient medical care in the field of "neurology"

Russian Federation, Kirov

Denis S. Korobko

Novosibirsk State Medical University; Novosibirsk Regional Clinical Hospital

Email: denis.s.korobko@gmail.com
ORCID iD: 0000-0002-7938-3782

Cand. Sci. (Med.), assistant, Department of clinical neurology, Faculty of medicine; Head, Regional Center for Multiple Sclerosis and Other Autoimmune Diseases of the Nervous System

Russian Federation, Novosibirsk; Novosibirsk

Sergey V. Kotov

Moscow Regional Research Institute named after V.F. Vladimirsky

Email: kotovsv@yandex.ru
ORCID iD: 0000-0002-8706-7317

Dr. Sci. (Med.), Professor, Head, Department of neurology, Faculty of advanced medical training, Head, Neurological department for adults

Russian Federation, Moscow

Elena V. Parshina

Privolzhsky Research Medical University

Email: parshina_elena_v@mail.ru
ORCID iD: 0000-0001-7033-053X

Cand. Sci. (Med.), assistant, Department of neurology, psychiatry and narcology

Russian Federation, Nizhny Novgorod

Irina E. Poverennova

Samara State Medical University

Email: i.e.poverennova@samsmu.ru
ORCID iD: 0000-0002-2594-461X
Scopus Author ID: 6506805041

Dr. Sci. (Med.), Professor, Head, Department of neurology and neurosurgery

Russian Federation, Samara

Valeriy M. Lebedev

N.P. Bechtereva Institute of the Human Brain

Email: simaniv@mail.ru
ORCID iD: 0000-0002-3358-5768

Head, Department of neurology

Russian Federation, St. Petersburg

Inna V. Smagina

Altai State Medical University

Email: voroba.nat@mail.ru
ORCID iD: 0000-0002-7947-4529

Dr. Sci. (Med.), Professor, Head, Department of neurology and neurosurgery with a course in advanced medical education

Russian Federation, Barnaul

Diana F. Khairutdinova

City Clinical Hospital No. 1

Email: simaniv@mail.ru
ORCID iD: 0009-0006-7438-9751

Head, Department of neurology

Russian Federation, Chelyabinsk

Tatiana N. Trushnikova

E.A. Vagner Perm State Medical University

Email: simaniv@mail.ru
ORCID iD: 0000-0001-9199-7392

Cand. Sci. (Med.), Associate Professor, Department of neurology and medical genetics,

Russian Federation, Perm

Leonid G. Zaslavsky

I.P. Pavlov First Saint Petersburg State Medical University

Email: simaniv@mail.ru
ORCID iD: 0000-0001-9912-1512

Dr. Sci. (Med.), Professor, Department of neurology

Russian Federation, St. Petersburg

Farit A. Khabirov

Kazan State Medical Academy — Branch of the Russian Medical Academy of Continuous Professional Education

Email: simaniv@mail.ru
ORCID iD: 0000-0002-2572-6970

Dr. Sci. (Med.), Professor, Head, Department of neurology

Russian Federation, Kazan

Stella A. Sivertseva

Medical Sanitary Unit “Neftyanik”; Ural State Medical University; Kirov State Medical University

Email: voroba.nat@mail.ru
ORCID iD: 0000-0002-9293-5932

Dr. Sci. (Med.), Associate Professor, Director, Center for Autoimmune Diseases of the Nervous System and Multiple Sclerosis of the Tyumen region; Professor, Department of neurology and neurosurgery; Professor, Department of neurology, neurosurgery and neurorehabilitation

Russian Federation, Tyumen; Ekaterinburg; Kirov

Daria G. Tolkacheva

The Northwestern Institute of Management — Branch of the Russian Presidential Academy of National Economy and Public Administration

Email: simaniv@neurology.ru
ORCID iD: 0000-0002-6314-4218

independent expert, Project Office's research projects

Russian Federation, Saint Petersburg

Kirill V. Sapozhnikov

S.M. Kirov Military Medical Academy

Email: simaniv@neurology.ru
ORCID iD: 0000-0002-2476-7666

Cand. Sci. (Med.), lecturer, Department of automation of medical service management (with military medical statistics)

Russian Federation, St. Petersburg

Alexandra A. Gorbunova

JSC BIOCAD

Email: simaniv@mail.ru
ORCID iD: 0009-0003-5911-4192

biostatistics

Russian Federation, St. Petersburg, Russia

Marina V. Krasnova

JSC BIOCAD

Email: simaniv@mail.ru
ORCID iD: 0000-0001-8138-6408

Cand. Sci. (Biol.), medical expert

Russian Federation, St. Petersburg

Yulia N. Linkova

JSC BIOCAD

Email: simaniv@mail.ru
ORCID iD: 0000-0002-5463-1022

Cand. Sci. (Med.), Deputy director general for clinical development and research

Russian Federation, St. Petersburg

Arina V. Zinkina

JSC BIOCAD

Email: simaniv@mail.ru
ORCID iD: 0000-0002-8499-2232

Director, Clinical development department

Russian Federation, St. Petersburg

Anastasiya A. Porozova

JSC BIOCAD

Email: simaniv@mail.ru
ORCID iD: 0000-0003-1816-4014

medical expert

Russian Federation, St. Petersburg

References

Supplementary files