Simulating the Impact of Elevated Levels of Interleukin-6 on the Pharmacokinetics of Various CYP450 Substrates in Patients with Neuromyelitis Optica or Neuromyelitis Optica Spectrum Disorders in Different Ethnic Populations

Background: The international panel for neuromyelitis optica (NMO) diagnosis has proposed diagnostic criteria for neuromyelitis optica spectrum disorders (NMOSD). Objectives: We assessed the impact of these criteria on diagnostic rates in a large cohort of patients. Methods: We identified and applied the 2006 and 2015 criteria to all patients ( n = 176) seen in the NMO and non-multiple sclerosis central nervous system demyelination clinic (part of the UK NMO service) from January 2013 to May 2015. Results: The 2006 criteria classified 63 of 176 (36%) patients as NMO. A total of 42 patients (67%) were aquaporin 4 (AQP4) immunoglobulin G (IgG) +ve and 21 (33%) AQP4 IgG −ve. The 2015 criteria classified 111 of 176 (63%) patients as NMOSD, of which 81 (73%) were AQP4 IgG +ve and 30 (27%) were AQP4 IgG −ve. There was an increase of 48 patients (76%) diagnosed as NMOSD using the new criteria. Conclusion: Application of the 2015 criteria led to a rise in diagnosis of NMOSD by 76%. The rise in the AQP4 IgG +ve group contributed 62% and the seronegative group contributed 14%.

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Pharmacodynamic modeling and exposure-response assessment of inebilizumab in subjects with neuromyelitis optica spectrum disorders

10.22541/au.163676321.19163981/v1 ◽

2021 ◽

Author(s):

Li Yan ◽

Bing Wang ◽

Dewei She ◽

Ben Mitchel ◽

Ryan Criste ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Neuromyelitis Optica ◽

Drug Exposure ◽

Response Assessment ◽

Pharmacodynamic Modeling ◽

Neuromyelitis Optica Spectrum Disorders ◽

Spectrum Disorders ◽

Disease Attack ◽

The Impact

AIM: Neuromyelitis optica spectrum disorders (NMOSD) is an autoantibody-mediated, B cell-driven disease. Inebilizumab is a humanized, affinity-optimized, afucosylated IgG1 kappa monoclonal antibody that binds to the B cell specific surface antigen CD19, resulting in rapid, profound, and sustained depletion of circulating peripheral B cells in NMOSD subjects (pivotal study). The objective of this study was to conduct population modeling of B cell response following inebilizumab treatment in adult subjects with NMOSD, and to assess the impact of drug exposure to outcome. METHODS: A hematopoietic transit model was developed to describe the joint effects of reducing influx from pro-B cells and accelerating CD20+ B cell depletion in the blood by inebilizumab. Furthermore, the relationships between inebilizumab pharmacokinetic (PK) exposure and the primary efficacy endpoint and key secondary efficacy endpoints were evaluated. KEY RESULTS: At the 300 mg dose, there was no apparent relationship between efficacy (reduction in disease attack risk, risk of worsening from baseline in Expanded Disability Status Scale, cumulative total active MRI lesions, and the number of NMOSD-related in-patient hospitalizations) and PK exposure. Subjects with low, medium, and high PK exposure had a similar hazard ratio of NMOSD attack vs placebo group. CONCLUSIONS: The pharmacodynamic modeling confirmed effective depletion of B cells is achieved with a 300 mg intravenous dose of inebilizumab administered on Day 1 and Day 15 and every 6 months thereafter. The PK variability between patients had no apparent effect on clinical efficacy.

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Satralizumab for the Treatment of Neuromyelitis Optica Spectrum Disorders

Annals of Pharmacotherapy ◽

10.1177/1060028020976669 ◽

2020 ◽

pp. 106002802097666

Author(s):

Yanli Gao ◽

Baoqi Zhang ◽

Junyi Yang

Keyword(s):

Treatment Option ◽

Neuromyelitis Optica ◽

Interleukin 6 ◽

English Language ◽

Data Extraction ◽

Data Sources ◽

Phase Iii ◽

Neuromyelitis Optica Spectrum Disorders ◽

Valuable Treatment ◽

Spectrum Disorders

Objective To review the pharmacological characteristics, clinical evidence, and place in therapy of satralizumab for the treatment of neuromyelitis optica spectrum disorders (NMOSDs). Data Sources A comprehensive literature search was conducted in PubMed (January 2000 to October 15, 2020). Key search terms included satralizumab and neuromyelitis optica spectrum disorders. Other sources were derived from product labeling and ClinicalTrials.gov. Study Selection and Data Extraction All English-language articles identified from the data sources were reviewed and evaluated. Phase I, II, and III clinical trials were included. Data Synthesis NMOSD is an autoimmune disease characterized by inflammatory lesions in the optic nerves and spinal cord. Interleukin-6 is involved in the pathogenesis of the disorder. Satralizumab is a humanized monoclonal antibody targeting the interleukin-6 receptor. Phase III trials showed that protocol-defined relapse was 30% for satralizumab and 50% for placebo ( P = 0.018) when patients with NMOSD were treated with satralizumab monotherapy; protocol-defined relapse was 20% for satralizumab and 43% for placebo ( P = 0.02) when satralizumab was added to immunosuppressant treatment. Satralizumab is generally well tolerated, with common adverse effects including injection-related reaction. Relevance to Patient Care and Clinical Practice Satralizumab has the potential to become a valuable treatment option for patients with NMOSD. Conclusion Satralizumab appears to be safe and effective as monotherapy or in combination with an immunosuppressant for patients with NMOSD and has the potential to become a valuable treatment option for these patients.

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Targeting interleukin-6 to treat neuromyelitis optica spectrum disorders: Implications from immunology, the FcRn pathway and clinical experience

Drug Discovery Today ◽

10.1016/j.drudis.2021.03.018 ◽

2021 ◽

Author(s):

Johann Sellner ◽

Harald H. Sitte ◽

Paulus S. Rommer

Keyword(s):

Clinical Experience ◽

Neuromyelitis Optica ◽

Interleukin 6 ◽

Neuromyelitis Optica Spectrum Disorders ◽

Spectrum Disorders

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Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG–Associated Disease and Neuromyelitis Optica Spectrum Disorders

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000001100 ◽

2021 ◽

Vol 9 (1) ◽

pp. e1100

Author(s):

Marius Ringelstein ◽

Ilya Ayzenberg ◽

Gero Lindenblatt ◽

Katinka Fischer ◽

Anna Gahlen ◽

...

Keyword(s):

Neuromyelitis Optica ◽

Interleukin 6 ◽

Neuromyelitis Optica Spectrum Disorders ◽

Class Iii ◽

Disability Status ◽

Interleukin 6 Receptor ◽

Spectrum Disorders ◽

The Brain

Background and ObjectivesTo evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti–interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein–IgG–associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD).MethodsAnnualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab.ResultsPatients received TCZ for 23.8 months (median; interquartile range 13.0–51.1 months), with an IV dose of 8.0 mg/kg (median; range 6–12 mg/kg) every 31.6 days (mean; range 26–44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5–5) to 0 (range 0–0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0–5] to 0 [range 0–4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0–3.0] to 0.2 [range 0–2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy.DiscussionThis study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

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Satralizumab: an interleukin-6 (IL-6) receptor antagonist for the treatment of neuromyelitis optica spectrum disorders

Drugs of Today ◽

10.1358/dot.2021.57.3.3251715 ◽

2021 ◽

Vol 57 (3) ◽

pp. 209

Author(s):

D.M. Paton

Keyword(s):

Receptor Antagonist ◽

Neuromyelitis Optica ◽

Interleukin 6 ◽

Neuromyelitis Optica Spectrum Disorders ◽

Spectrum Disorders

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COVID-19 in Patients With Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody Disease in North America

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000001057 ◽

2021 ◽

Vol 8 (5) ◽

pp. e1057

Author(s):

Scott D. Newsome ◽

Anne H. Cross ◽

Robert J. Fox ◽

June Halper ◽

Pamela Kanellis ◽

...

Keyword(s):

Health Care Providers ◽

Neuromyelitis Optica ◽

Myelin Oligodendrocyte Glycoprotein ◽

Small Sample ◽

Clinical Severity ◽

Categorical Variables ◽

Neuromyelitis Optica Spectrum Disorders ◽

Care Providers ◽

Spectrum Disorders ◽

The Impact

Background and ObjectiveTo describe the impact of coronavirus disease 2019 (COVID-19) on people with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD).MethodsThe COVID-19 Infections in Multiple Sclerosis (MS) and Related Diseases (COViMS) Registry collected data on North American patients with MS and related diseases with laboratory-positive or highly suspected SARS-CoV-2 infection. Deidentified data were entered into a web-based registry by health care providers. Data were analyzed using t-tests, Pearson χ2 tests, or Fisher exact tests for categorical variables. Univariate logistic regression models examined effects of risk factors and COVID-19 clinical severity.ResultsAs of June 7, 2021, 77 patients with NMOSD and 20 patients with MOGAD were reported in the COViMS Registry. Most patients with NMOSD were laboratory positive for SARS-CoV-2 and taking rituximab at the time of COVID-19 diagnosis. Most patients with NMOSD were not hospitalized (64.9% [95% CI: 53.2%–75.5%]), whereas 15.6% (95% CI: 8.3%–25.6%) were hospitalized only, 9.1% (95% CI: 3.7%–17.8%) were admitted to the ICU and/or ventilated, and 10.4% (95% CI: 4.6%–19.5%) died. In patients with NMOSD, having a comorbidity was the sole factor identified for poorer COVID-19 outcome (OR = 6.0, 95% CI: 1.79–19.98). Most patients with MOGAD were laboratory positive for SARS-CoV-2, and almost half were taking rituximab. Among patients with MOGAD, 75.0% were not hospitalized, and no deaths were recorded; no factors were different between those not hospitalized and those hospitalized, admitted to the ICU, or ventilated.DiscussionAmong the reported patients with NMOSD, a high mortality rate was observed, and the presence of comorbid conditions was associated with worse COVID-19 outcome. There were no deaths reported in the patients with MOGAD, although these observations are limited due to small sample size.

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