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Eculizumab: A Review in Neuromyelitis Optica Spectrum Disorder.

ABSTRACT: The terminal complement protein (C5) inhibitor eculizumab (Soliris®) is the first agent to be specifically approved in the EU, USA, Canada and Japan for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults who are aquaporin-4 water channel autoantibody (AQP4-IgG) seropositive and (in the EU only) for those with a relapsing course of disease. In the phase III PREVENT trial, eculizumab significantly reduced the risk of adjudicated relapse relative to placebo in patients with AQP4-IgG-seropositive NMOSD, approximately a quarter of whom did not receive concomitant immunosuppressive therapies. The beneficial effect of eculizumab was seen across all patient subgroups analysed and was accompanied by improvements in neurological and functional disability assessments, as well as generic health-related quality of life measures; it was sustained through 4 years of treatment, according to combined data from the PREVENT trial and an interim analysis of its ongoing open-label extension study. The safety profile of eculizumab in AQP4-IgG-seropositive NMOSD was consistent with that seen for the drug in other approved indications. Thus, eculizumab provides an effective, generally well tolerated and approved treatment option for this rare, disabling and potentially life-threatening condition.

SUBMITTER: Frampton JE

PROVIDER: S-EPMC7183484 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Eculizumab: A Review in Neuromyelitis Optica Spectrum Disorder.

Frampton James E JE

Drugs 20200501 7

The terminal complement protein (C5) inhibitor eculizumab (Soliris<sup>®</sup>) is the first agent to be specifically approved in the EU, USA, Canada and Japan for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults who are aquaporin-4 water channel autoantibody (AQP4-IgG) seropositive and (in the EU only) for those with a relapsing course of disease. In the phase III PREVENT trial, eculizumab significantly reduced the risk of adjudicated relapse relative to placebo in pati ...[more]

PMID: 32266705

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Project description:BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system. Although complement-dependent astrocyte damage mediated by anti-aquaporin 4 autoantibody (AQP4-Ab) is well acknowledged to be the core of NMOSD pathogenesis, additional inflammatory cascades may contribute to the establishment of lesion formation. Thus, in this study, we investigated the possible pathogenic role of immune-reactive mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) of NMOSD patients.MethodsUsing quantitative polymerase chain reaction, we measured extracellular mtDNA levels in CSF of NMOSD patients positive for AQP4-Ab. Patients with multiple sclerosis or other neurological diseases were examined as controls. Pre- and post-treatment extracellular mtDNA levels were also compared in the NMOSD group. Extracellular mtDNA release from human astrocytes was analyzed in vitro utilizing NMOSD sera, and interleukin (IL)-1? production was measured in supernatants of mixed glial cells stimulated with DNA fraction of CSF derived from NMOSD patients. Furthermore, specific innate immune pathways mediating the IL-1? production by mtDNA were investigated in peripheral blood mononuclear cells with selective inhibitors of Toll-like receptor 9 (TLR9) and NOD-like receptor protein 3 (NLRP3) inflammasomes.ResultsExtracellular mtDNA level was specifically elevated in acute phase of NMOSD CSF. In vitro studies provided the evidence that mtDNA is released from human astrocytes by NMOSD sera. In addition, DNA fraction isolated from NMOSD CSF promoted secretion of IL-1? from mixed glial cells. Selective inhibition of TLR9 and NLRP3 inflammasomes revealed that mtDNA-mediated IL-1? production depends on specific innate immune pathways.ConclusionExtracellular mtDNA is specifically elevated in the CSF of patients with acute phase NMOSD, and mtDNA released by AQP4-Ab-mediated cellular damage elicits the innate immune cascades via TLR9 and NLRP3 inflammasomes pathways. Our study highlights mtDNA-mediated innate immune pathways as a novel therapeutic target for future treatment of NMOSD patients.

Dataset Information

Eculizumab: A Review in Neuromyelitis Optica Spectrum Disorder.

Publications

Eculizumab: A Review in Neuromyelitis Optica Spectrum Disorder.

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