Long-term cenobamate retention, efficacy, and safety: outcomes from Expanded Access Programme.

AIM OF THE STUDY: To evaluate the long-term retention rate, efficacy, and tolerability of adjunctive cenobamate (CNB) in patients with drug-resistant epilepsy within the Polish Expanded Access Programme (EAP). CLINICAL RATIONALE FOR THE STUDY: Long-term retention rate is a useful measure of effectiveness including efficacy, safety, and tolerability of antiseizure medications. MATERIAL AND METHODS: We conducted a multicentre retrospective analysis of consecutive patients with focal epilepsy treated with CNB in the EAP between January 2020 and May 2023. All patients who completed the open-label extension phases of the YKP3089C013 and YKP3089C017 trials were offered the opportunity to continue CNB treatment within the EAP. We analysed cenobamate retention, seizure outcomes, and adverse events. RESULTS: 38 patients (18 females; 47.3%) continued CNB treatment within the Expanded Access Programme for 41 months. The mean baseline age of patients was 39.3 years (range: 18-57). All patients were on polytherapy, with the most commonly used antiseizure medications being valproate, levetiracetam, and carbamazepine. Adjunctive CNB treatment resulted in a reduced mean seizure frequency from 8.1 seizures (range: 4-20) per month to 3 seizures (range: 0-8) per month. At the final follow-up, the median CNB dose was 200 mg/day (range: 50-350). Among the patients, 24 (63.1%) achieved ≥ 50% seizure reduction, and eight (21%) remained seizure-free for at least 12 months. One in three patients experienced adverse events, which resolved in half of the subjects. The most frequent adverse events were dizziness, somnolence, and headache. The retention rate after completing the open-label extension phase was 100%. CONCLUSIONS AND CLINICAL IMPLICATIONS: Long-term effectiveness, including ≥ 50% seizure reduction and a 100% retention rate, was sustained over 41 months of CNB treatment within the Expanded Access Programme. No new safety issues were identified. These results provide support for the potential long-term clinical benefits of cenobamate.

Long-term safety of adjunctive cenobamate in patients with uncontrolled focal seizures: Open-label extension of a randomized clinical study.

OBJECTIVE: This study was undertaken to examine long-term (up to 7.8 years) retention rate, safety, and tolerability of the antiseizure medication (ASM) cenobamate as adjunctive treatment in the open-label extension (OLE) of study YKP3089C013 (C013; ClinicalTrials.gov: NCT01397968). METHODS: Patients who completed the 12-week, multicenter, multinational, double-blind, randomized, placebo-controlled C013 study, which examined adjunctive cenobamate treatment of adults with uncontrolled focal seizures, were eligible to enroll in the OLE. During the OLE, dose adjustments of cenobamate and concomitant ASMs were allowed. Safety assessments included frequency of treatment-emergent adverse events (TEAEs) and serious TEAEs, TEAE severity, and TEAEs leading to discontinuation. Probability of patient continuation in the OLE was examined using a Kaplan-Meier analysis. RESULTS: One hundred forty-nine patients entered the OLE (median duration of cenobamate treatment = 6.25 years). As of the data cutoff, 57% of patients (85/149) remained in the OLE (median treatment duration = 6.8 years, range = 6.4-7.8 years). The median modal daily cenobamate dose was 200 mg (range = 50-400 mg). The probability of treatment continuation at 1-6 years of cenobamate treatment was 73%, 67%, 63%, 61%, 60%, and 59%, respectively. Among patients who continued at 1 year (n = 107), the probability of continuing at Years 2-5 was 92%, 87%, 83%, and 82%. The most common discontinuation reasons were patient withdrawal (19.5%, 29/149), adverse event (10.1%, 15/149), and lack of efficacy (5.4%, 8/149). TEAEs leading to discontinuation in 1% or more of patients were fatigue (1.3%, 2/149), ataxia (1.3%, 2/149), and memory impairment or amnesia (1.3%, 2/149). Dizziness (32.9%, 49/149), headache (26.8%, 40/149), and somnolence (21.5%, 32/149) were the most frequently reported TEAEs and were primarily mild or moderate in severity. SIGNIFICANCE: Long-term retention in the C013 OLE study demonstrated sustained safety and tolerability of adjunctive cenobamate treatment up to 7.8 years in adults with treatment-resistant focal seizures taking one to three ASMs.

Clinical course and outcome of SARS-CoV-2 infection in multiple sclerosis patients treated with disease-modifying therapies - the Polish experience.

INTRODUCTION: The aim of this study was to report the course and outcome of SARS-CoV-2 infection in multiple sclerosis (MS) patients treated with disease-modifying therapies (DMTs) in Poland. A major concern for neurologists worldwide is the course and outcome of SARS-CoV-2 infection in patients with MS treated with different DMTs. Although initial studies do not suggest an unfavourable course of infection in this group of patients, the data is limited. MATERIALS AND METHODS: This study included 396 MS patients treated with DMTs and confirmed SARS-CoV-2 infection from 28 Polish MS centres. Information concerning patient demographics, comorbidities, clinical course of MS, current DMT use, as well as symptoms of SARS-CoV-2 infection, need for pharmacotherapy, oxygen therapy, and/or hospitalisation, and short-term outcomes was collected up to 30 January 2021. Additional data about COVID-19 cases in the general population in Poland was obtained from official reports of the Polish Ministry of Health. RESULTS: There were 114 males (28.8%) and 282 females (71.2%). The median age was 39 years (IQR 13). The great majority of patients with MS exhibited relapsing-remitting course (372 patients; 93.9%). The median EDSS was 2 (SD 1.38), and the mean disease duration was 8.95 (IQR 8) years. Most of the MS patients were treated with dimethyl fumarate (164; 41.41%). Other DMTs were less frequently used: interferon beta (82; 20.70%), glatiramer acetate (42; 10.60%), natalizumab (35;8.84%), teriflunomide (25; 6.31%), ocrelizumab (20; 5.05%), fingolimod (16; 4.04), cladribine (5; 1.26%), mitoxantrone (3; 0.76%), ozanimod (3; 0.76%), and alemtuzumab (1; 0.25%). The overall hospitalisation rate due to COVID-19 in the cohort was 6.81% (27 patients). Only one patient (0.3%) died due to SARS-CoV-2 infection, and three (0.76%) patients were treated with mechanical ventilation; 106 (26.8%) patients had at least one comorbid condition. There were no significant differences in the severity of SARS-CoV-2 infection regarding patient age, duration of the disease, degree of disability (EDSS), lymphocyte count, or type of DMT used. CONCLUSIONS AND CLINICAL IMPLICATIONS: Most MS patients included in this study had a favourable course of SARS-CoV-2 infection. The hospitalisation rate and the mortality rate were not higher in the MS cohort compared to the general Polish population. Continued multicentre data collection is needed to increase the understanding of SARS-CoV-2 infection impact on the course of MS in patients treated with DMTs.

Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study.

BACKGROUND: B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19+ B cells. OBJECTIVES: To assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS. METHODS: This phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19+ B-cell count to ⩾80 cells/µL. RESULTS: Complete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively. CONCLUSION: Inebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions.

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial.

BACKGROUND AND OBJECTIVES: Masitinib is a selective tyrosine kinase inhibitor, targeting innate immune cells (mast cells and microglia) that are involved in the pathophysiology of progressive multiple sclerosis (MS). Study AB07002 assessed oral masitinib in patients with progressive MS who were progressing but not clinically active. METHODS: This randomized, double-blind, 2 parallel-group, placebo-controlled trial assessing 2 dose levels of masitinib vs equivalent placebo was conducted at 116 hospital clinics and specialized MS centers in 20 countries. Randomization (2:1) with minimization was performed centrally using an automated system. Patients, physicians, and outcome assessors remained masked to treatment group allocation. Patients with primary progressive MS (PPMS) or nonactive secondary progressive MS (nSPMS) without relapse for ≥2 years, aged 18-75 years, with baseline Expanded Disability Status Scale (EDSS) 2.0-6.0, and regardless of time from onset were treated for 96 weeks. The primary end point was overall EDSS change from baseline using repeated measures (generalized estimating equation, timeframe W12-W96, measured every 12 weeks), with positive values indicating increased clinical deterioration. Efficacy and safety were assessed in all randomly assigned and treated patients. RESULTS: A total of 611 patients were randomized; 301 in the masitinib 4.5 mg/kg/d parallel group and 310 in the uptitrated masitinib 6.0 mg/kg/d parallel group. Masitinib (4.5 mg/kg/d) (n = 199) showed significant benefit over placebo (n = 101) according to the primary end point, 0.001 vs 0.098, respectively, with a between-group difference of -0.097 (97% CI -0.192 to -0.002); p = 0.0256. Safety was consistent with masitinib's known profile (diarrhea, nausea, rash, and hematologic events), with no elevated risk of infection. Efficacy results from the independent uptitrated masitinib 6.0 mg/kg/d parallel group were inconclusive, and no new safety signal was observed. DISCUSSION: Masitinib (4.5 mg/kg/d) can benefit people with PPMS and nSPMS. A confirmatory phase 3 study will be initiated to substantiate these data. TRIAL REGISTRATION INFORMATION: The first participant was randomized to study AB07002 on August 25, 2011. The trial was registered with the European Clinical Trials Database (#EudraCT 2010-021219-17) on July 1, 2011 (clinicaltrialsregister.eu/ctr-search/trial/2010-021219-17/ES) and with ClinicalTrials.gov (#NCT01433497) on September 14, 2011 (clinicaltrials.gov/ct2/show/NCT01433497). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that masitinib 4.5 mg/kg/d decreased progression of disability, measured by the EDSS, in adults with PPMS or patients with nSPMS (with no exacerbations in the last 2 years).

JC Virus Seroprevalence and JCVAb Index in Polish Multiple Sclerosis Patients Treated with Immunomodulating or Immunosuppressive Therapies.

The use of a highly-effective treatment for multiple sclerosis (MS) is associated with a severe risk of developing complications, such as progressive multifocal leukoencephalopathy (PML) caused by the John Cunningham virus (JCV). The aim of this study was to evaluate the correlation between anti-JCV Ab seroprevalence, anti-JCV AI, demographic and clinical factors as well as the type of therapy used in the Polish MS population. This is a multicentre, prospective and cross-sectional study involving 1405 MS patients. The seroprevalence of anti-JCV Ab and anti-JCV AI levels as well as AI categories were analysed with the use of a second-generation two-step ELISA test (STRATIFY JCV DxSelect). The overall prevalence of anti-JCV Ab was 65.8%. It was shown that seroprevalence increases with the patient's age. The seroprevalence was significantly associated with the treatment type, and the highest values (76%) were obtained from immunosuppressant-treated patients. Overall, 63.3% of seropositive patients had an antibody index (AI) level of >1.5. In the seropositive patient group, the mean AI level amounted to 2.09. Similarly to the seroprevalence, AI levels correlated with the patient's age; AI level for patients above 40 years old and from subsequent age quintiles plateaued, amounting to at least 1.55. Patients treated with immunosuppressants and immunomodulatory drugs obtained the highest (1.67) and lowest (1.35) AI levels, respectively. Of the immunosuppressants used, the highest mean AI levels were observed in mitoxantrone and cladribine groups, amounting to 1.75 and 1.69, respectively. In patients treated with immunomodulatory drugs, the lowest AI levels were observed in the dimethyl fumarate (DMF) group (1.11). The seroprevalence rate in the Polish MS population is one of the highest in Europe. The majority of seropositive patients had an anti-JCV Ab level qualifying them for a high-risk category. The highest mean AI levels are observed in patients receiving immunosuppressants, especially mitoxantrone and cladribine. Patients receiving immunomodulatory drugs have lower AI levels compared to treatment-naïve subjects, especially when treated with DMF. Further studies, especially longitudinal studies, are required to determine the impact of MS drugs on the seroprevalence of anti-JCV Ab and AI levels.

JC Virus Seroprevalence and JCVAb Index in Polish Multiple Sclerosis Treatment-Naïve Patients.

Multiple sclerosis (MS) treatment with new agents is associated with the risk of the development of progressive multifocal leukoencephalopathy (PML). The seropositivity and a high index of anti-John Cunningham virus (JCV) antibodies are some of the risk factors for PML development. The aim of this study was to assess the seroprevalence of anti-JCVAb and JCVAb index (AI), as well as its correlations with demographic and clinical characteristics in treatment-naïve Polish MS patients. This is a multicenter, prospective, and cross-sectional study involving 665 MS patients. The overall prevalence of anti-JCVAb was 65.3%, while 63.1% of seropositive patients had an index level of >1.5. The seroprevalence was shown to increase along with the patient's age. Except for age, the prevalence of anti-JCVAb was not associated with demographic or clinical data. No correlations between the index levels and the demographic or clinical data were observed. In Poland, the seroprevalence of anti-JCVAb in treatment-naïve MS patients is one of the highest in Europe. The majority of seropositive patients had an anti-JCV antibody level denoting a high-risk category. This means that we need further studies to be conducted on the individualization of MS treatment in order to provide patients with an appropriate therapeutic safety level.

Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures.

OBJECTIVE: To evaluate the efficacy and safety of adjunctive cenobamate 200 mg/d in patients with uncontrolled focal (partial-onset) seizures despite treatment with 1 to 3 antiepileptic drugs. METHODS: In this multicenter, double-blind, placebo-controlled study, adults 18 to 65 years of age with focal seizures were randomized 1:1 (cenobamate:placebo) after an 8-week baseline period. The 12-week double-blind treatment period consisted of a 6-week titration phase and a 6-week maintenance phase. The primary outcome was percent change in seizure frequency (from baseline) per 28 days during double-blind treatment. RESULTS: Two hundred twenty-two patients were randomized; 113 received cenobamate and 109 received placebo; and 90.3% and 90.8% of patients, respectively, completed double-blind treatment. Median baseline seizure frequency was 6.5 in 28 days (range 0-237). Compared to placebo, cenobamate conferred a greater median percent seizure reduction (55.6% vs 21.5%; p < 0.0001) The responder rate (≥50% reduction in seizure frequency) was 50.4% for cenobamate and 22.2% for placebo (p < 0.0001). Focal seizures with motor component, impaired awareness, and focal to bilateral tonic-clonic seizures were significantly reduced with cenobamate vs placebo. During maintenance, 28.3% of cenobamate-treated and 8.8% of placebo-treated patients were seizure-free. Treatment-emergent adverse events reported in >10% in either group (cenobamate vs placebo) were somnolence (22.1% vs 11.9%), dizziness (22.1% vs 16.5%), headache (12.4% vs 12.8%), nausea (11.5% vs 4.6%), and fatigue (10.6% vs 6.4%). CONCLUSION: Adjunctive treatment with cenobamate 200 mg/d significantly improved seizure control in adults with uncontrolled focal seizures and was well tolerated. CLINICALTRIALSGOV IDENTIFIER: NCT01397968. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for patients with uncontrolled focal seizures, adjunctive cenobamate reduces seizures.

[A case or Leber hereditary optic neuropathy (LHON): differential diagnosis with post inflammatory atrophy of nerve II using the mtDNA analysis]. / Przypadek choroby lebera--róznicowanie z pozapalnym zanikiem nerwu II za pomoca analizy mtDNA.

The Leber hereditary optic neuropathy (LHON) is a disease due to a mtDNA mutation. The disorder results from enzymatic perturbations in the mitochondrial respiratory chain. Clinically the LHON may present as a progressive axonal atrophy of the optic nerves with or without other neurological symptoms. The process of reaching the diagnosis of the LHON by means of the molecular analysis of mtDNA is discussed.