Treatment of demyelinating diseases of the central nervous system (CNS) with satralizumab

Abstract

The present invention provides means for the treatment of demyelinating diseases of the central nervous system (CNS) characterized by the presence of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies, including anti-IL-6 receptor antibodies or antigen-binding fragments thereof, and also for reducing the risk of relapse in demyelinating diseases. TIFF2024543147000005.tif85170

Description

[Technical field]

[0001] The present invention relates to a medicine or pharmaceutical composition for treating or reducing the risk of recurrence of a demyelinating disease of the central nervous system (CNS) characterized by the presence of an anti-myelin oligodendrocyte glycoprotein (MOG) antibody, the composition comprising an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. The present invention also relates to a method of treating or reducing the risk of recurrence of said demyelinating disease by administering an anti-IL-6 receptor antibody or an antigen-binding fragment thereof to a subject in need thereof. [Background technology]

[0002] Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare autoimmune demyelinating disease of the CNS characterized by the presence of anti-myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) in adults and children. MOG is a transmembrane protein expressed on oligodendrocytes and the outer layer of the myelin sheath

[19] . The disease is characterized by attacks of optic neuritis, transverse myelitis, inflammation of the brain or brainstem, or a combination thereof (1). A combination of a compatible clinical and radiological phenotype and seropositivity for MOG-IgG is required to establish the diagnosis. In approximately 80% of adult patients, the disease is chronic and characterized by a relapsing course (2, 3, and 4). The proportion of adolescents with a relapsing disease course appears to be similar to adults (5 and 6). MOGAD-related disorders are seizure / relapse driven, and therefore relapse prevention is important. There is no approved treatment for MOGAD, and no consensus-based treatment guidelines exist. MOGAD is exacerbated by several multiple sclerosis (MS) disease-modifying treatments, including interferon-β (IFN-β), glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, fingolimod, natalizumab, and alemtuzumab (Non-Patent Document 7, Non-Patent Document 8, Non-Patent Document 9, and Non-Patent Document 6). Current MOGAD treatment paradigms include corticosteroids with or without intravenous immunoglobulin (IVIg) or plasma exchange (PLEX) for acute treatment of attacks, and the use of empirically selected conventional steroid-sparing immunosuppressant therapy (IST) and rituximab (RTX) for relapse prevention (Non-Patent Document 10, Non-Patent Document 9, Non-Patent Document 11, Non-Patent Document 12, and Non-Patent Document 13). Current literature indicates that these medications are often only partially effective, with numerous short-term and long-term adverse effects (Non-Patent Document 9, Non-Patent Document 14, Non-Patent Document 15, and Non-Patent Document 6). There remains a need for safe, proven effective, and convenient chronic treatments for MOGAD.

[0003] There is no approved treatment for MOGAD or for the prevention of MOGAD recurrence. IST used empirically off-label is often only partially effective, and many are associated with numerous short-term and long-term adverse effects. Recently, elevated interleukin (IL)-6 levels in cerebrospinal fluid (CSF) and serum have been reported in patients with MOGAD (Non-Patent Document 16). There have been several reports on the off-label use of tocilizumab, an anti-IL-6 receptor antibody, in patients with MOGAD. However, the exact role of IL-6 in MOGAD is unclear (Non-Patent Document 17, Non-Patent Document 18, and Non-Patent Document 19).

[0004] Humanized antibodies such as tocilizumab are first-generation antibody drugs. Second-generation antibody drugs have been developed with improved efficacy, convenience, and cost by improving the first-generation antibody drugs (Patent Document 2 and Patent Document 3). Among the second-generation antibody drugs, there is satralizumab (SA237), a novel anti-IL-6 receptor antibody to which improvement techniques such as enhanced antigen binding ability, pharmacokinetics, and stability, and reduced immunogenicity risk have been applied (Patent Document 3 and Patent Document 4).

[0005] Satralizumab is a humanized anti-IL-6 receptor monoclonal antibody with pH-dependent antigen binding. It specifically targets the human IL-6 receptor (IL-6R) and inhibits IL-6 signaling by inhibiting the binding of IL-6 to membrane-bound IL-6R and soluble IL-6R. Satralizumab was constructed by modifying the amino acid sequence of tocilizumab to extend its plasma half-life. Satralizumab also exhibits a reduced antibody molecule isoelectric point and stronger binding to FcRn compared to tocilizumab. In addition, its Fc region has been modified to minimize antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity effector activity compared to tocilizumab. The following literature information on prior art related to the invention of this application is provided below. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] US2012 / 0039840 [Patent Document 2] WO2009 / 041621 [Patent Document 3] WO2010 / 035769 [Patent Document 4] WO2016 / 136933 [Non-patent literature]

[0007] [Non-Patent Document 1] Lopez-Chiriboga AS, Majed M, Fryer J, et al. Association of MOG-IgG Serostatus With Relapse After Acute Disseminated Encephalomyelitis and Proposed Diagnostic Criteria for MOG-IgG-Associated Disorders. JAMA Neurol. 2018 Nov 1;75(11):1355-1363. [Non-Patent Document 2] Jarius S, Ruprecht K, Kleiter I, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflammation. 2016;13(1):280. [Non-Patent Document 3] Hyun JW, Woodhall MR, Kim SH, et al. Longitudinal analysis of myelin oligodendrocyte glycoprotein antibodies in CNS inflammatory diseases. J Neurol Neurosurg Psychiatry. 2017;88(10):811-817. [Non-Patent Document 4] Salama S, Pardo S, Levy M. Clinical characteristics of myelin oligodendrocyte glycoprotein antibody neuromyelitis optica spectrum disorder. Mult Scler Relat Disord. 2019;30:231-235. [Non-Patent Document 5] Bruijstens AL, Breu M, Wendel E-M, et al. E.U. paediatric MOG consortium consensus: Part 4 - Outcome of paediatric myelin oligodendrocyte glycoprotein antibody- associated disorders. Eur J Paediatr Neurol 2020b;29:32-40. [Non-Patent Document 6] Cobo-Calvo A, Ruiz A, Rollot F, et al. Clinical Features and Risk of Relapse in Children and Adults with Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease. Ann Neurol. 2021;89(1):30-41. [Non-Patent Document 7] Wildemann B, Jarius S, Schwarz A, et al. Failure of alemtuzumab therapy to control MOG encephalomyelitis. Neurology. 2017;89(2):207-209. [Non-Patent Document 8] Wynford-Thomas R, Jacob A, et al. Neurological update: MOG antibody disease. J Neurol. 2019;266(5):1280-1286. [Non-Patent Document 9] Chen JJ, Flanagan EP, Bhatti MT, et al. Steroid-sparing maintenance immunotherapy for MOG-IgG associated disorder. Neurology. 2020;95(2):e111-e120. [Non-Patent Document 10] Stiebel-Kalish H, Hellmann MA, Mimouni M, et al. Does time equal vision in the acute treatment of a cohort of AQP4 and MOG optic neuritis? Neurol Neuroimmunol Neuroinflamm. 2019;6(4):e572. [Non-Patent Document 11] Chen JJ and Bhatti MT. Clinical phenotype, radiological features, and treatment of myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) optic neuritis. Curr Opin Neurol. 2020;33(1):47-54. [Non-Patent Document 12] Hegen H, Reindl M. Recent developments in MOG-IgG associated neurological disorders. Ther Adv Neurol Disord. 2020;13:1756286420945135. [Non-Patent Document 13] Whittam DH, Karthikeayan V, Gibbons E, et al. Treatment of MOG antibody associated disorders: results of an international survey. J Neurol. 2020a;267(12):3565-3577. [Non-Patent Document 14] Whittam DH, Cobo-Calvo A, Lopez-Chiriboga AS, et al. Treatment of MOG-IgG-associated disorder with rituximab: An international study of 121 patients. Mult Scler Relat Disord. 2020b;44:102251. [Non-Patent Document 15] Durozard P, Rico A, Boutiere C, et al. Comparison of the Response to Rituximab between Myelin Oligodendrocyte Glycoprotein and Aquaporin-4 Antibody Diseases. Ann Neurol. 2020;87(2):256-266. [Non-Patent Document 16] Hofer LS, Mariotto S, Wurth S, et al. Distinct serum and cerebrospinal fluid cytokine and chemokine profiles in autoantibody-associated demyelinating diseases. Mult Scler J Exp Transl Clin. 2019;5(2):2055217319848463. [Non-Patent Document 17] Mult Scler Relat Disord. 2021 Feb;48:102696 [Non-Patent Document 18] Mult Scler Relat Disord. 2020 Nov;46:102483 [Non-Patent Document 19] Neurology. 2019 Apr 16;92(16):765-767 Summary of the Invention [Problem to be solved by the invention]

[0008] There are no approved treatments for MOGAD or for preventing MOGAD recurrence. Empirically used off-label IST is often only partially effective, and many are associated with numerous short-term and long-term adverse effects. There is a substantial unmet need for treatments for MOGAD and also for preventing MOGAD recurrence that can subsequently improve long-term prognosis in patients with MOGAD. [Means for solving the problem]

[0009] To solve the above problems, the inventors designed a Phase III, randomized, double-blind (DB), placebo-controlled, multicenter study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab compared with placebo as monotherapy or as an add-on to baseline / background IST for preventing MOGAD relapse. The Phase III study herein is expected to effectively treat MOGAD, prevent MOGAD attacks / relapses, and reduce the risk of MOGAD attacks / relapses.

[0010] The present disclosure includes, but is not limited to, the embodiments described below. [A1.1] A pharmaceutical product comprising an IL-6 inhibitor as an active ingredient for treating a demyelinating disease of the central nervous system (CNS) characterized by the presence of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in a subject who is anti-MOG antibody-positive, or for reducing the risk of relapse in a relapsing demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies. [A1.2] The pharmaceutical agent according to A1.1, wherein the IL-6 inhibitor is an anti-IL-6 antibody or an antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [A1.3] The pharmaceutical agent according to A1.1 or A1.2, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [A1.4] Any one of the pharmaceutical agents A1.1 to A1.3, wherein the IL-6 inhibitor is a humanized antibody. [A1.5] Any one of the pharmaceuticals A1.1 to A1.4, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [A1.6] The pharmaceutical of A1.5, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2. [A1.7] A pharmaceutical agent according to A1.5 or A1.6, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4. [A1.8] Any one of the pharmaceuticals A1.5 to A1.7, wherein the IL-6 inhibitor is satralizumab. [A1.9] Any one of A1.1 to A1.8 for delaying relapses, reducing the frequency of relapses, or reducing the severity of relapses of a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies. [A1.10] Any one of A1.1 to A1.9 for which the CNS demyelinating disease characterized by the presence of anti-MOG antibodies is a disease other than anti-aquaporin-4 (AQP4) antibody-positive NMOSD and multiple sclerosis (MS). [A1.11] Any one of A1.1 to A1.10, for which the CNS demyelinating disease characterized by the presence of anti-MOG antibodies is a disease other than anti-aquaporin-4 (AQP4) antibody-positive NMOSD, multiple sclerosis (MS), and anti-NMDAR autoimmune encephalitis. [A1.12] Any one of A1.1 to A1.11, wherein the demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies is myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). [A1.13] The drug product of A1.12, wherein MOGAD is characterized by (i) seropositivity for MOG-IgG by cell-based assay and (ii) two or more episodes of encephalitis selected from the group consisting of optic neuritis (ON); transverse myelitis (TM); or acute disseminated encephalomyelitis (ADEM), brain stem encephalitis, cortical encephalitis; demyelinating brain stem syndrome, demyelinating cerebellar syndrome, and demyelinating cerebral syndrome. [A1.14] Any one of A1.1 to A1.13, wherein (i) the subject is MOG-IgG seropositive by a cell-based assay, and (ii) the subject has experienced two or more attacks of encephalitis selected from the group consisting of optic neuritis (ON); transverse myelitis (TM); or acute disseminated encephalomyelitis (ADEM), brain stem encephalitis, cortical encephalitis, brain stem syndrome with demyelination, cerebellar syndrome with demyelination, and cerebral syndrome with demyelination. [A1.15] Any one of the medicines A1.1 to A1.14, wherein the subject is anti-aquaporin-4 (AQP4) antibody negative. [A1.16] Any one of the pharmaceuticals A1.1 to A1.15, wherein the subject is 12 years of age or older. [A1.17] Any one of A1.1 to A1.16, wherein the subject is not receiving any ongoing chronic immunosuppressive therapy. [A1.18] Any one of A1.1 to A1.16, where the subject is receiving ongoing treatment with a stable dose of azathioprine (AZA), mycophenolate mofetil (MMF), oral corticosteroids (OCS), or a combination of AZA or MMF and OCS. [A1.19] Any one of the pharmaceuticals of A1.5 to A1.18, characterized in that the pharmaceutical is used such that, for each administration, 60 mg or 120 mg, 120 mg or 180 mg, and 180 mg or 240 mg of an anti-IL-6 receptor antibody or antigen-binding fragment thereof are administered subcutaneously to a subject having a body weight of less than 40 kg, 40 to 100 kg, and more than 100 kg, respectively. [A1.20] Any one of the pharmaceuticals of A1.5 to A1.18, characterized in that the pharmaceutical is used such that, for each administration, 60 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered subcutaneously to a subject having a body weight of less than 40 kg. [A1.21] Any one of the pharmaceuticals of A1.5 to A1.18, characterized in that the pharmaceutical is used such that, for each administration, 120 mg of an anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered subcutaneously to a subject having a body weight of less than 40 kg. [A1.22] Any one of the pharmaceuticals of A1.5 to A1.18, characterized in that the pharmaceutical is used such that, for each administration, 120 mg of the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered subcutaneously to a subject having a body weight of 40 to 100 kg. [A1.23] Any one of the pharmaceuticals of A1.5 to A1.18, characterized in that the pharmaceutical is used such that, for each administration, 180 mg of the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered subcutaneously to a subject having a body weight of 40 to 100 kg. [A1.24] Any one of the pharmaceuticals of A1.5 to A1.18, characterized in that the pharmaceutical is used such that, for each administration, 180 mg of an anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered subcutaneously to a subject having a body weight of more than 100 kg. [A1.25] Any one of the pharmaceuticals of A1.5 to A1.18, characterized in that the pharmaceutical is used such that, for each administration, 240 mg of an anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered subcutaneously to a subject having a body weight of more than 100 kg. [A1.26] Any one of the pharmaceuticals A1.5 to A1.25, characterized in that the pharmaceutical is used so that the anti-IL-6 receptor antibody or its antigen-binding fragment is administered subcutaneously to the subject. [A1.27] Any one of the pharmaceuticals A1.5 to A1.26, characterized in that the pharmaceutical is used so that the anti-IL-6 receptor antibody or its antigen-binding fragment is administered to a subject three times at two-week intervals (Q2W) and then four-weekly (Q4W) intervals. [A1.28] Any one of the pharmaceuticals A1.1 to A1.27, characterized in that the pharmaceutical is used in combination with immunosuppressant therapy (IST). [A1.29] The pharmaceutical product of A1.28, wherein the IST is a treatment with one or more immunosuppressants selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and oral corticosteroids (OCS). [A1.30] The pharmaceutical product of A1.29, wherein the immunosuppressant comprises prednisone or prednisolone. [A1.31] Any one of A1.1 to A1.30 that delays the time from administration of an IL-6 inhibitor to the first occurrence of a relapse of a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies. [A1.32] Medicinal products according to A1.31 that reduce one or more of the following: (a) Rate of relapse of demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies; (b) proportion of active lesions on MRI of the neuraxis; (c) the proportion of subjects receiving salvage therapy; or (d) Rate of hospitalization. [A1.33] Any one of A1.1 to A1.32 that increases a subject's high-contrast best-corrected visual acuity (BCVA), low-contrast visual acuity (LCVA), National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) composite or subscale score, EuroQol EQ-5D-5L score, or SF-36v2 Health Survey (SF-36v2) score; or reduces a subject's Expanded Disability Status Scale (EDSS) score, EDSS Functional System Score (FSS), Short-Form McGill Pain Questionnaire (SF-MPQ-2) score, or MOG-IgG titer. [A2.1] A pharmaceutical composition comprising an IL-6 inhibitor as an active ingredient for treating a demyelinating disease of the central nervous system (CNS) characterized by the presence of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in a subject who is anti-MOG antibody positive, or for reducing the risk of relapse in a recurrent demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies. [A2.2] The pharmaceutical composition of A2.1, wherein the IL-6 inhibitor is an anti-IL-6 antibody or an antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [A2.3] The pharmaceutical composition of A2.1 or A2.2, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [A2.4] Any one of the pharmaceutical compositions of A2.1 to A2.3, wherein the IL-6 inhibitor is a humanized antibody. [A2.5] Any one of the pharmaceutical compositions of A2.1 to A2.4, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [A2.6] The pharmaceutical composition of A2.5, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:1 and a VL comprising the amino acid sequence of SEQ ID NO:2. [A2.7] A pharmaceutical composition of A2.5 or A2.6, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4. [A2.8] Any one of the pharmaceutical compositions of A2.5 to A2.7, wherein the IL-6 inhibitor is satralizumab. [A2.9] Any one of the pharmaceutical compositions of A2.1-A2.8 for delaying relapses, reducing the frequency of relapses, or reducing the severity of relapses of a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies. [A2.10] Any one of the pharmaceutical compositions of A2.1 to A2.9, wherein the demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies is a disease other than anti-aquaporin-4 (AQP4) antibody-positive NMOSD and multiple sclerosis (MS). [A2.11] Any one of the pharmaceutical compositions of A2.1 to A2.10, wherein the demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies is a disease other than anti-aquaporin-4 (AQP4) antibody-positive NMOSD, multiple sclerosis (MS), and anti-NMDAR autoimmune encephalitis. [A2.12] Any one of the pharmaceutical compositions of A2.1 to A2.11, wherein the demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies is myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). [A2.13] The pharmaceutical composition of A2.12, wherein MOGAD is characterized by (i) seropositivity for MOG-IgG by a cell-based assay and (ii) two or more episodes of optic neuritis (ON); transverse myelitis (TM); or encephalitis selected from the group consisting of acute disseminated encephalomyelitis (ADEM), brain stem encephalitis, cortical encephalitis, brain stem syndrome with demyelination, cerebellar syndrome with demyelination, and cerebral syndrome with demyelination. [A2.14] Any one of the pharmaceutical compositions of A2.1 to A2.13, wherein (i) the subject is MOG-IgG seropositive by a cell-based assay, and (ii) the subject has experienced two or more attacks of any one or more of the following encephalomyelitis selected from the group consisting of optic neuritis (ON); transverse myelitis (TM); or acute disseminated encephalomyelitis (ADEM), brain stem encephalitis, cortical encephalitis; brain stem syndrome with demyelination, cerebellar syndrome with demyelination, and cerebral syndrome with demyelination. [A2.15] Any one of the pharmaceutical compositions of A2.1 to A2.14, wherein the subject is anti-aquaporin-4 (AQP4) antibody negative. [A2.16] Any one of the pharmaceutical compositions of A2.1 to A2.15, wherein the subject is 12 years of age or older. [A2.17] Any one of the pharmaceutical compositions of A2.1 to A2.16, wherein the subject is not receiving any ongoing chronic immunosuppressive therapy. [A2.18] Any one of the pharmaceutical compositions of A2.1 to A2.16, wherein the subject is receiving ongoing treatment with a stable dose of azathioprine (AZA), mycophenolate mofetil (MMF), oral corticosteroids (OCS), or a combination of AZA or MMF and OCS. [A2.19] Any one of the pharmaceutical compositions of A2.5 to A2.18, wherein the pharmaceutical composition is used such that, for each administration, 60 mg or 120 mg, 120 mg or 180 mg, and 180 mg or 240 mg of an anti-IL-6 receptor antibody or antigen-binding fragment thereof are subcutaneously administered to a subject having a body weight of less than 40 kg, 40 to 100 kg, and more than 100 kg, respectively. [A2.20] Any one of the pharmaceutical compositions of A2.5 to A2.18, wherein the pharmaceutical composition is used such that, for each administration, 60 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of less than 40 kg. [A2.21] Any one of the pharmaceutical compositions of A2.5 to A2.18, wherein the pharmaceutical composition is used such that, for each administration, 120 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of less than 40 kg. [A2.22] Any one of the pharmaceutical compositions of A2.5 to A2.18, wherein the pharmaceutical composition is used such that, for each administration, 120 mg of the anti-IL-6 receptor antibody or antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of 40 to 100 kg. [A2.23] Any one of the pharmaceutical compositions of A2.5 to A2.18, wherein the pharmaceutical composition is used such that, for each administration, 180 mg of the anti-IL-6 receptor antibody or antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of 40 to 100 kg. [A2.24] Any one of the pharmaceutical compositions of A2.5 to A2.18, wherein the pharmaceutical composition is used such that, for each administration, 180 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of more than 100 kg. [A2.25] Any one of the pharmaceutical compositions of A2.5 to A2.18, wherein the pharmaceutical composition is used such that, for each administration, 240 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of more than 100 kg. [A2.26] Any one of the pharmaceutical compositions A2.5 to A2.25, characterized in that the pharmaceutical composition is used so that the anti-IL-6 receptor antibody or its antigen-binding fragment is administered subcutaneously to the subject. [A2.27] Any one of the pharmaceutical compositions A2.5 to A2.26, characterized in that the pharmaceutical composition is used so that the anti-IL-6 receptor antibody or its antigen-binding fragment is administered to a subject three times at two-week intervals (Q2W) and then four-weekly (Q4W) intervals. [A2.28] Any one of the pharmaceutical compositions of A2.1 to A2.27, characterized in that the pharmaceutical composition is used in combination with immunosuppressant therapy (IST). [A2.29] The pharmaceutical composition of A2.28, wherein the IST is a treatment with one or more immunosuppressants selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and oral corticosteroids (OCS). [A2.30] The pharmaceutical composition of A2.29, wherein the immunosuppressant comprises prednisone or prednisolone. [A2.31] Any one of the pharmaceutical compositions of A2.1 to A2.30, which delays the time from administration of an IL-6 inhibitor to the first occurrence of a relapse of a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies. [A2.32] A pharmaceutical composition of A2.31 that reduces one or more of the following: (a) Rate of relapse of demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies; (b) proportion of active lesions on MRI of the neuraxis; (c) the proportion of subjects receiving salvage therapy; or (d) Rate of hospitalization. [A2.33] Any one of the pharmaceutical compositions of A2.1 to A2.32 that increases a subject's high contrast best corrected visual acuity (BCVA), or low contrast visual acuity (LCVA), National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) composite or subscale score, EuroQol EQ-5D-5L score, or SF-36v2 Health Survey (SF-36v2) score; or reduces a subject's Expanded Disability Status Scale (EDSS) score, EDSS Functional System Score (FSS), Short McGill Pain Questionnaire (SF-MPQ-2) score, or MOG-IgG titer. [B1] Use of an IL-6 inhibitor in the preparation of a medicine for treating a demyelinating disease of the central nervous system (CNS) characterized by the presence of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in a subject who is anti-MOG antibody-positive, or for reducing the risk of relapse in a recurrent demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies. [B2] Use of B1, wherein the IL-6 inhibitor is an anti-IL-6 antibody or an antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [B3] Use of B1 or B2, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [B4] Use of any one of B1 to B3, wherein the IL-6 inhibitor is a humanized antibody. [B5] Use of any one of B1 to B4, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [B6] Use of B5, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2. [B7] Use of B5 or B6, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4. [B8] Use of any one of B5 to B7, wherein the IL-6 inhibitor is satralizumab. [B9] The use of any one of B1 to B8, wherein the pharmaceutical agent is for delaying relapses, reducing the frequency of relapses, or reducing the severity of relapses of a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies. [B10] Use of any one of B1 to B9, wherein the CNS demyelinating disease characterized by the presence of anti-MOG antibodies is a disease other than anti-aquaporin-4 (AQP4) antibody-positive NMOSD and multiple sclerosis (MS). [B11] Use of any one of B1 to B10, wherein the CNS demyelinating disease characterized by the presence of anti-MOG antibodies is a disease other than anti-aquaporin-4 (AQP4) antibody-positive NMOSD, multiple sclerosis (MS), and anti-NMDAR autoimmune encephalitis. [B12] The use of any one of B1 to B11, wherein the demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies is myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). [B13] Use of B12, wherein MOGAD is characterized by (i) seropositivity for MOG-IgG by a cell-based assay and (ii) two or more episodes of encephalitis selected from the group consisting of optic neuritis (ON); transverse myelitis (TM); or acute disseminated encephalomyelitis (ADEM), brain stem encephalitis, cortical encephalitis; brain stem demyelinating syndrome, cerebellar demyelinating syndrome, and cerebral demyelinating syndrome. [B14] Use of any one of B1-B13, wherein (i) the subject is determined to be MOG-IgG seropositive by a cell-based assay, and (ii) the subject has experienced two or more attacks of any one or more of the following encephalitides selected from the group consisting of optic neuritis (ON); transverse myelitis (TM); or acute disseminated encephalomyelitis (ADEM), brain stem encephalitis, cortical encephalitis; brain stem syndrome with demyelination, cerebellar syndrome with demyelination, and cerebral syndrome with demyelination. [B15] Use of any one of B1 to B14, wherein the subject is anti-aquaporin-4 (AQP4) antibody negative. [B16] Use of any one of B1 to B15, wherein the subject is aged 12 years or older. [B17] The use of any one of B1 to B16, wherein the subject is not receiving any ongoing chronic immunosuppressive therapy. [B18] The use of any one of B1 to B16, wherein the subject is receiving ongoing treatment with a stable dose of azathioprine (AZA), mycophenolate mofetil (MMF), oral corticosteroids (OCS), or a combination of AZA or MMF and OCS. [B19] The use of any one of B5 to B18, wherein the pharmaceutical is used such that, for each administration, 60 mg or 120 mg, 120 mg or 180 mg, and 180 mg or 240 mg of an anti-IL-6 receptor antibody or antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of less than 40 kg, 40 to 100 kg, and more than 100 kg, respectively. [B20] The use of any one of B5 to B18, characterized in that the pharmaceutical agent is used so that, for each administration, 60 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of less than 40 kg. [B21] The use of any one of B5 to B18, characterized in that the pharmaceutical agent is used so that, for each administration, 120 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of less than 40 kg. [B22] The use of any one of B5 to B18, wherein the pharmaceutical is used so that, for each administration, 120 mg of the anti-IL-6 receptor antibody or antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of 40 to 100 kg. [B23] The use of any one of B5 to B18, characterized in that the pharmaceutical agent is used so that, for each administration, 180 mg of the anti-IL-6 receptor antibody or its antigen-binding fragment is subcutaneously administered to a subject having a body weight of 40 to 100 kg. [B24] The use of any one of B5 to B18, wherein the pharmaceutical agent is used such that, for each administration, 180 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of more than 100 kg. [B25] The use of any one of B5 to B18, wherein the pharmaceutical agent is used such that, for each administration, 240 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of more than 100 kg. [B26] Use of any one of B5 to B25, wherein the pharmaceutical is used so that the anti-IL-6 receptor antibody or its antigen-binding fragment is subcutaneously administered to the subject. [B27] The use of any one of B5 to B26, wherein the pharmaceutical is used such that the anti-IL-6 receptor antibody or its antigen-binding fragment is administered to a subject three times at two-week intervals (Q2W) and then four weeks apart (Q4W). [B28] The use of any one of B1 to B27, wherein the pharmaceutical is used in combination with immunosuppressive therapy (IST). [B29] The use of B28, wherein the IST is a treatment with one or more immunosuppressants selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and oral corticosteroids (OCS). [B30] The use of B29, wherein said immunosuppressant comprises prednisone or prednisolone. [B31] The use of any one of B1 to B30, wherein the pharmaceutical agent delays the time from administration of an IL-6 inhibitor to the first occurrence of a relapse of a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies. [B32] Use of B31, wherein said medicament reduces one or more of the following: (a) Rate of relapse of demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies; (b) proportion of active lesions on MRI of the neuraxis; (c) the proportion of subjects receiving salvage therapy; or (d) Rate of hospitalization. [B33] Use of any one of B1 to B32, wherein the pharmaceutical product increases the subject's high contrast best corrected visual acuity (BCVA), or low contrast visual acuity (LCVA), National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) composite or subscale score, EuroQol EQ-5D-5L score, or SF-36v2 Health Survey (SF-36v2) score; or reduces the subject's Expanded Disability Status Scale (EDSS) score, EDSS Functional System Score (FSS), Short McGill Pain Questionnaire (SF-MPQ-2) score, or MOG-IgG titer. [C1] An IL-6 inhibitor for use in treating a demyelinating disease of the central nervous system (CNS) characterized by the presence of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in a subject who is anti-MOG antibody positive, or for use in reducing the risk of relapse in a relapsing demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies. [C2] An IL-6 inhibitor for use in C1, which is an anti-IL-6 antibody or an antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [C3] An IL-6 inhibitor of C1 or C2 which is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [C4] An IL-6 inhibitor which is a humanized antibody, any one of C1 to C3. [C5] An IL-6 inhibitor comprising any one of C1 to C4, which is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [C6] An IL-6 inhibitor for use with C5, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:1 and a VL comprising the amino acid sequence of SEQ ID NO:2. [C7] An IL-6 inhibitor for use with C5 or C6, which is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4. [C8] Satralizumab, an IL-6 inhibitor for use with any one of C5 to C7. [C9] An IL-6 inhibitor for use of any one of C1-C8 for delaying relapses, reducing the frequency of relapses, or reducing the severity of relapses of a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies. [C10] An IL-6 inhibitor for use in any one of C1 to C9, wherein the CNS demyelinating disease characterized by the presence of anti-MOG antibodies is a disease other than anti-aquaporin-4 (AQP4) antibody-positive NMOSD and multiple sclerosis (MS). [C11] An IL-6 inhibitor for use in any one of C1 to C10, wherein the CNS demyelinating disease characterized by the presence of anti-MOG antibodies is a disease other than anti-aquaporin-4 (AQP4) antibody-positive NMOSD, multiple sclerosis (MS), and anti-NMDAR autoimmune encephalitis. [C12] An IL-6 inhibitor for use in any one of C1 to C11, wherein the CNS demyelinating disease characterized by the presence of anti-MOG antibodies is myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). [C13] An IL-6 inhibitor for use in C12, wherein MOGAD is characterized by (i) seropositivity for MOG-IgG by a cell-based assay and (ii) two or more episodes of optic neuritis (ON); transverse myelitis (TM); or encephalitis selected from the group consisting of acute disseminated encephalomyelitis (ADEM), brain stem encephalitis, cortical encephalitis, brain stem syndrome with demyelination, cerebellar syndrome with demyelination, and cerebral syndrome with demyelination. [C14] An IL-6 inhibitor for use of any one of C1 to C13, wherein (i) the subject has been determined to be MOG-IgG seropositive by a cell-based assay, and (ii) the subject has experienced two or more attacks of any one or more of encephalitis selected from the group consisting of optic neuritis (ON); transverse myelitis (TM); or acute disseminated encephalomyelitis (ADEM), brain stem encephalitis, cortical encephalitis; brain stem syndrome with demyelination, cerebellar syndrome with demyelination, and cerebral syndrome with demyelination. [C15] An IL-6 inhibitor for use according to any one of C1 to C14, wherein the subject is anti-aquaporin-4 (AQP4) antibody negative. [C16] An IL-6 inhibitor for use according to any one of C1 to C15, wherein the subject is aged 12 years or older. [C17] An IL-6 inhibitor for use in any one of C1 to C16, wherein the subject is not receiving any ongoing chronic immunosuppressive therapy. [C18] An IL-6 inhibitor for use in any one of C1 to C16, wherein the subject is receiving ongoing treatment with a stable dose of azathioprine (AZA), mycophenolate mofetil (MMF), oral corticosteroids (OCS), or a combination of AZA or MMF and OCS. [C19] An IL-6 inhibitor for use according to any one of C5 to C18, characterized in that for each administration, 60 mg or 120 mg, 120 mg or 180 mg, and 180 mg or 240 mg of an anti-IL-6 receptor antibody or antigen-binding fragment thereof are subcutaneously administered to a subject weighing less than 40 kg, 40 to 100 kg, and more than 100 kg, respectively. [C20] An IL-6 inhibitor for use according to any one of C5 to C18, characterized in that for each administration, 60 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of less than 40 kg. [C21] An IL-6 inhibitor for use according to any one of C5 to C18, characterized in that for each administration, 120 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of less than 40 kg. [C22] An IL-6 inhibitor for use according to any one of C5 to C18, characterized in that for each administration, 120 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of 40 to 100 kg. [C23] An IL-6 inhibitor for use according to any one of C5 to C18, characterized in that for each administration, 180 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of 40 to 100 kg. [C24] An IL-6 inhibitor for use in any one of C5 to C18, characterized in that for each administration, 180 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of more than 100 kg. [C25] An IL-6 inhibitor for use in any one of C5 to C18, characterized in that for each administration, 240 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject having a body weight of more than 100 kg. [C26] An IL-6 inhibitor for use in any one of C5 to C25, characterized in that the anti-IL-6 receptor antibody or its antigen-binding fragment is administered subcutaneously to the subject. [C27] An IL-6 inhibitor for use in any one of C5 to C26, characterized in that the anti-IL-6 receptor antibody or its antigen-binding fragment is administered to a subject three times at two-week intervals (Q2W) and then at four-week intervals (Q4W). [C28] An IL-6 inhibitor for use in combination with immunosuppressive therapy (IST), any one of C1 to C27. [C29] The IL-6 inhibitor for use in C28, wherein the IST is a treatment with one or more immunosuppressants selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and oral corticosteroids (OCS). [C30] The IL-6 inhibitor for use in C29, wherein the immunosuppressant comprises prednisone or prednisolone. [C31] An IL-6 inhibitor for use in any one of C1 to C30, which delays the time from administration of the IL-6 inhibitor to the first occurrence of a relapse of a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies. [C32] An IL-6 inhibitor for use in C31 that reduces one or more of the following: (a) Rate of relapse of demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies; (b) proportion of active lesions on MRI of the neuraxis; (c) the proportion of subjects receiving salvage therapy; or (d) Rate of hospitalization. [C33] An IL-6 inhibitor for use in any one of C1 to C32 to increase a subject's high contrast best corrected visual acuity (BCVA), or low contrast visual acuity (LCVA), National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) composite or subscale score, EuroQol EQ-5D-5L score, or SF-36v2 Health Survey (SF-36v2) score; or to reduce a subject's Expanded Disability Status Scale (EDSS) score, EDSS Functional System Score (FSS), Short McGill Pain Questionnaire (SF-MPQ-2) score, or MOG-IgG titer. [D1] A kit for treating a demyelinating disease of the central nervous system (CNS) characterized by the presence of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in a subject who is anti-MOG antibody-positive, or for reducing the risk of relapse in a recurrent demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies, comprising: (1) any one of the pharmaceutical compositions of A2.1 to A2.33; and (2) a package insert or labeling instructing administration of the pharmaceutical composition to a subject; The kit comprising: [D2] A subcutaneous administration device containing a fixed dose of 60 mg of satralizumab in a pharma- ceutically acceptable excipient. [D3] A subcutaneous administration device containing a fixed dose of 240 mg of satralizumab in a pharma- ceutically acceptable excipient. [D4] A subcutaneous administration device of D2 or D3 that is a prefilled syringe. [D5] A subcutaneous administration device of D2 or D3 that is an autoinjector. [E1] A method of treating a subject having a demyelinating disease of the central nervous system (CNS) characterized by the presence of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies, comprising: administering to the subject an effective amount of an IL-6 inhibitor. The method comprising: [E2] The method of E1, wherein the IL-6 inhibitor is an anti-IL-6 antibody or an antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [E3] The method of E1 or E2, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [E4] Any one of the methods E1 to E3, wherein the IL-6 inhibitor is a humanized antibody. [E5] Any one of the methods E1 to E4, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [E6] The method of E5, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2. [E7] The method of E5 or E6, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4. [E8] Any one of the methods E5 to E7, wherein the IL-6 inhibitor is satralizumab. [E9] Any one of the methods of E1-E8, wherein the demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies is a disease other than anti-aquaporin-4 (AQP4) antibody-positive NMOSD and multiple sclerosis (MS). [E10] Any one of the methods E1-E9, wherein the CNS demyelinating disease characterized by the presence of anti-MOG antibodies is a disease other than anti-aquaporin-4 (AQP4) antibody-positive NMOSD, multiple sclerosis (MS), and anti-NMDAR autoimmune encephalitis. [E11] Any one of the methods of E1-E10, wherein the disease is myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). [E12] The method of E11, wherein the subject's MOGAD is characterized by (i) seropositivity for MOG-IgG by a cell-based assay and (ii) two or more episodes of optic neuritis (ON); transverse myelitis (TM); or encephalitis selected from the group consisting of acute disseminated encephalomyelitis (ADEM), brain stem encephalitis, cortical encephalitis, brain stem syndrome with demyelination, cerebellar syndrome with demyelination, and cerebral syndrome with demyelination. [E13] Any one of the methods of E1-E12, wherein (i) the subject is determined to be MOG-IgG seropositive by a cell-based assay, and (ii) the subject has experienced two or more attacks of any one or more of the following encephalomyelitis selected from the group consisting of optic neuritis (ON); transverse myelitis (TM); or acute disseminated encephalomyelitis (ADEM), brain stem encephalitis, cortical encephalitis; brain stem syndrome with demyelination, cerebellar syndrome with demyelination, and cerebral syndrome with demyelination. [E14] Any one of the methods E1 to E13, wherein the subject has been determined to be anti-aquaporin-4 (AQP4) antibody negative. [E15] Any one of the methods E1-E15, wherein the subject is 12 years of age or older. [E16] Any one of the methods of E1-E16, wherein said subject is not receiving any ongoing chronic immunosuppressive therapy. [E17] Any one of the methods of E1-E16, wherein the subject is receiving ongoing treatment with a stable dose of azathioprine (AZA), mycophenolate mofetil (MMF), oral corticosteroids (OCS), or a combination of AZA or MMF and OCS. [E18] Any one of the methods E5 to E17, wherein the subject is determined to have a body weight of less than 40 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 60 mg. [E19] Any one of the methods E5 to E17, wherein the subject is determined to have a body weight of less than 40 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 120 mg. [E20] Any one of the methods E5 to E17, wherein the subject is determined to have a body weight of 40 to 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 120 mg. [E21] Any one of the methods E5 to E17, wherein the subject is determined to have a body weight of 40 to 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 180 mg. [E22] Any one of the methods E5 to E17, wherein the subject is determined to have a body weight of more than 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 180 mg. [E23] Any one of the methods E5 to E17, wherein the subject is determined to have a body weight of more than 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 240 mg. [E24] Any one of the methods E5 to E23, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered subcutaneously to the subject. [E25] Any one of the methods E5 to E24, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered to the subject once every two weeks (Q2W) for three times and then once every four weeks (Q4W). [E26] Any one of the methods E1-E25, wherein an immunosuppressant therapy (IST) is administered to the subject simultaneously with the IL-6 inhibitor. [E27] The method of E26, wherein the IST comprises one or more immunosuppressants, including at least one selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and oral corticosteroids (OCS). [E28] The method of E16, wherein the immunosuppressant comprises prednisone or prednisolone. [E29] Any one of the methods of E1-E28, wherein administering to the subject an IL-6 inhibitor delays the time from administration of the IL-6 inhibitor to the first occurrence of a relapse of a CNS demyelinating disease characterized by the presence of anti-MOG antibodies. [E30] The method of E29, wherein administering to said subject an IL-6 inhibitor reduces one or more of the following: (a) Rate of relapse of demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies; (b) proportion of active lesions on MRI of the neuraxis; (c) the proportion of subjects receiving salvage therapy; or (d) Rate of hospitalization. [E31] Any one of the methods of E1-E30, wherein administering an IL-6 inhibitor to the subject increases the subject's high contrast best corrected visual acuity (BCVA), or low contrast visual acuity (LCVA), National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) composite or subscale score, EuroQol EQ-5D-5L score, or SF-36v2 Health Survey (SF-36v2) score; or reduces the subject's Expanded Disability Status Scale (EDSS) score, EDSS Functional System Score (FSS), Short McGill Pain Questionnaire (SF-MPQ-2) score, or MOG-IgG titer. [F1] A method for reducing the risk of relapse in a recurrent demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies in a subject who is anti-MOG antibody positive, comprising: administering to the subject an amount of an IL-6 inhibitor effective to reduce the risk of recurrence. The method comprising: [F2] The method of F1, wherein the IL-6 inhibitor is an anti-IL-6 antibody or an antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [F3] The method of F1 or F2, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [F4] Any one of the methods F1 to F3, wherein the IL-6 inhibitor is a humanized antibody. [F5] Any one of the methods F1 to F4, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [F6] The method of F5, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2. [F7] The method of F5 or F6, wherein the IL-6 inhibitor is an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4. [F8] Any one of the methods F5 to F7, wherein the IL-6 inhibitor is satralizumab. [F9] Any one of the methods F1-F8, wherein the demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies is a disease other than anti-aquaporin-4 (AQP4) antibody-positive NMOSD and multiple sclerosis (MS). [F10] Any one of the methods F1 to F9, wherein the demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies is a disease other than anti-aquaporin-4 (AQP4) antibody-positive NMOSD, multiple sclerosis (MS), and anti-NMDAR autoimmune encephalitis. [F11] Any one of the methods of F1-F10, wherein reducing the risk of recurrence comprises delaying recurrence of disease in the subject, reducing the frequency of said recurrence, reducing the severity of said recurrence, or reducing the need for salvage therapy for said recurrence. [F12] Any one of the methods F1 to F11, wherein the disease is myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). [F13] The method of F10, wherein the subject's MOGAD is characterized by (i) seropositivity for MOG-IgG by a cell-based assay and (ii) two or more episodes of encephalitis selected from the group consisting of optic neuritis (ON); transverse myelitis (TM); or acute disseminated encephalomyelitis (ADEM), brain stem encephalitis, cortical encephalitis; brain stem syndrome with demyelination, cerebellar syndrome with demyelination, and cerebral syndrome with demyelination. [F14] Any one of the methods of F1-F12, wherein (i) the subject is determined to be MOG-IgG seropositive by a cell-based assay, and (ii) the subject has experienced two or more attacks of any one or more of the following encephalomyelitis selected from the group consisting of optic neuritis (ON); transverse myelitis (TM); or acute disseminated encephalomyelitis (ADEM), brain stem encephalitis, cortical encephalitis; brain stem syndrome with demyelination, cerebellar syndrome with demyelination, and cerebral syndrome with demyelination. [F15] Any one of the methods F1 to F14, wherein the subject has been determined to be negative for anti-aquaporin-4 (AQP4) antibodies. [F16] Any one of the methods F1 to F15, wherein the subject is 12 years of age or older. [F17] Any one of the methods of F1-F16, wherein said subject is not receiving any ongoing chronic immunosuppressive therapy. [F18] Any one of the methods of F1-F17, wherein the subject is receiving ongoing treatment with a stable dose of azathioprine (AZA), mycophenolate mofetil (MMF), oral corticosteroids (OCS), or a combination of AZA or MMF and OCS. [F19] Any one of the methods F5 to F18, wherein the subject is determined to have a body weight of less than 40 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 60 mg. [F20] Any one of the methods F5 to E18, wherein the subject is determined to have a body weight of less than 40 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 120 mg. [F21] Any one of the methods F5 to F18, wherein the subject is determined to have a body weight of 40 to 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 120 mg. [F22] Any one of the methods F5 to F18, wherein the subject is determined to have a body weight of 40 to 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 180 mg. [F23] Any one of the methods F5 to F18, wherein the subject is determined to have a body weight of more than 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 180 mg. [F24] Any one of the methods F5 to F18, wherein the subject is determined to have a body weight of more than 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 240 mg. [F25] Any one of the methods F5 to F24, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered subcutaneously to the subject. [F26] Any one of the methods F5 to F25, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered to a subject once every two weeks (Q2W) for three times and then once every four weeks (Q4W). [F27] Any one of the methods F1-F26, wherein an immunosuppressant therapy (IST) is administered to the subject simultaneously with the IL-6 inhibitor. [F28] The method of F27, wherein the IST comprises one or more immunosuppressants, including at least one selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and oral corticosteroids (OCS). [F29] The method of F28, wherein the immunosuppressant comprises prednisone or prednisolone. [F30] Any one of the methods F1 to F29, wherein administration of an IL-6 inhibitor to the subject delays the time from administration of the IL-6 inhibitor to the first occurrence of a relapse of a CNS demyelinating disease characterized by the presence of anti-MOG antibodies. [F31] The method of F30, wherein administering to said subject an IL-6 inhibitor reduces one or more of the following: (a) Rate of relapse of demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies; (b) proportion of active lesions on MRI of the neuraxis; (c) the proportion of subjects receiving salvage therapy; or (d) Rate of hospitalization. [F32] Any one of the methods of F1 to F31, wherein administering an IL-6 inhibitor to the subject increases the subject's high contrast best corrected visual acuity (BCVA), or low contrast visual acuity (LCVA), National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) composite or subscale score, EuroQol EQ-5D-5L score, or SF-36v2 Health Survey (SF-36v2) score; or reduces the subject's Expanded Disability Status Scale (EDSS) score, EDSS Functional System Score (FSS), Short McGill Pain Questionnaire (SF-MPQ-2) score, or MOG-IgG titer. Effect of the Invention

[0011] The present invention can provide a pharmaceutical agent (pharmaceutical composition) comprising satralizumab for treating MOGAD, preventing attacks / recurrences of MOGAD, or reducing the risk of attacks / recurrences of MOGAD. [Brief description of the drawings]

[0012] [Figure 1]The study design for this Phase III, randomized, double-blind, placebo-controlled, multicenter study is shown. DB = double-blind; IST = (baseline / background) immunosuppressant treatment; LA = final assessment; LO = last observation; PK = pharmacokinetics; RA = relapse assessment; RFA = relapse follow-up assessment. Note: Arms A and B: Randomized 1:1 to satralizumab + / - IST or placebo + / - IST. Satralizumab or matching placebo will be administered based on a tiered dosing scheme based on body weight <40 kg: 60 mg or 120 mg; 40-100 kg: 120 mg or 180 mg; >100 kg: 180 mg or 240 mg. [Diagram 2] Predicted steady-state exposure parameters (maximum concentration (Cmax), trough concentration (Ctrof)), and receptor occupancy (RO) values ​​in serum after dosing with 60 mg, 120 mg, and 180 mg satralizumab at 4-week intervals in patients weighing <40 kg (30-40 kg), ≤100 kg (40-100 kg), and >100 kg (100-160 kg), respectively. Simulations are based on 2000 individuals. Predicted values ​​of Cmax are shown in the top panel, Ctrof in the middle panel (Ctr = steady-state concentration at the end of the dosing interval), and RO in the bottom panel. Dots are simulated data assuming anti-drug antibody (ADA) positivity in a similar proportion of participants as observed in a neuromyelitis optica spectrum disorder (NMOSD) trial. Dashed horizontal lines have been added for reference. The assumption in setting the initial dose in this Phase III trial is that the pharmacokinetics of satralizumab in MOGAD are similar to those in NMOSD. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Description of the Aspects The present invention relates to a pharmaceutical product (pharmaceutical composition) comprising an IL-6 inhibitor as an active ingredient for treating demyelinating diseases of the central nervous system (CNS) characterized by the presence of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in subjects who are anti-MOG antibody positive, or for reducing the risk of relapse in recurrent demyelinating diseases of the CNS characterized by the presence of anti-MOG antibodies. Relapse is defined as a new clinical episode (new or worsening acute symptoms and clinical signs, possibly accompanied by MRI evidence of acute demyelination) that appears at least 30 days after the last attack (90 days if the last attack was ADEM). In another aspect, the present invention also relates to the use of an IL-6 inhibitor in the preparation of a medicament for treating a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies or for reducing the risk of relapse in a recurrent demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies in a subject who is anti-MOG antibody-positive. In yet another aspect, the present invention relates to an IL-6 inhibitor for use in treating a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies in a subject who is anti-MOG antibody positive, or in reducing the risk of relapse in a relapsing demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies. Furthermore, the present invention also relates to a kit for treating a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies or reducing the risk of relapse in a recurrent demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies in a subject who is anti-MOG antibody-positive, the kit comprising a pharmaceutical composition comprising an IL-6 inhibitor and a package insert or label instructing administration of the pharmaceutical composition to the subject. Furthermore, the present invention also relates to a method for treating a subject having a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies, or for reducing the risk of relapse in a recurrent demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies, in a subject who is anti-MOG antibody-positive, comprising the step of administering to the subject an effective amount of an IL-6 inhibitor. The "IL-6 inhibitor" of the present disclosure is a substance that blocks signal transduction by IL-6 and inhibits the biological activity of IL-6. The IL-6 inhibitor is preferably a substance that inhibits the binding between IL-6 and the IL-6 receptor, and / or between the IL-6 / IL-6 receptor complex and gp130. Examples of the IL-6 inhibitor of the present disclosure include, but are not limited to, an anti-IL-6 antibody or an antigen-binding fragment thereof, an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, an anti-gp130 antibody or an antigen-binding fragment thereof, an IL-6 variant, a soluble IL-6 receptor variant, or a partial peptide of IL-6 or IL-6 receptor, and a low molecular weight substance exhibiting similar activity. Examples of the IL-6 inhibitor of the present disclosure may be preferably an anti-IL-6 antibody or an antigen-binding fragment thereof or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, more preferably an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, and optionally a humanized antibody.

[0014] In some embodiments of the present disclosure, the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO:5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO:8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:10. In certain embodiments of the present disclosure, the anti-IL-6 receptor antibody or an antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:1 and a VL comprising the amino acid sequence of SEQ ID NO:2. In certain embodiments of the present disclosure, the IL-6 inhibitor is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4. In certain embodiments of the present disclosure, the IL-6 inhibitor is satralizumab, an anti-IL-6 receptor antibody.

[0015] In certain embodiments of the present disclosure, the demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies is myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). In certain embodiments, MOGAD is characterized by (i) seropositivity for MOG-IgG by a cell-based assay and (ii) two or more attacks of any one or more of the following: optic neuritis (ON) (e.g., chronic relapsing inflammatory optic neuropathy (CRION)), transverse myelitis (TM) (e.g., longitudinally extensive transverse myelitis (LETM), short segment transverse myelitis (STM)), acute disseminated encephalomyelitis (ADEM), brainstem encephalitis, cortical encephalitis, brainstem demyelination syndrome, cerebellar demyelination syndrome, and cerebral demyelination syndrome. In certain embodiments, the MOGAD is a disease other than at least one selected from the group consisting of anti-aquaporin-4 (AQP4) antibody-positive NMOSD, multiple sclerosis (MS), and anti-NMDAR autoimmune encephalopathy.

[0016] Although many of the above symptoms overlap with the typical presentation of AQP4-positive NMOSD and MS, MOGAD is differentiated from these alternative autoimmune diseases by the detection of anti-MOG-IgG in serum or CSF. Thus, in certain embodiments, the present invention can be applied to subjects who are anti-aquaporin-4 (AQP4) antibody negative. MOG-IgG seropositivity can be determined using a cell-based assay (CBA) as described in Lopez-Chiriboga AS et al., JAMA Neurol. 2018 Nov 1;75(11):1355-1363. The combination of a compatible clinical and radiological phenotype (e.g., as described in Jarius S et al., J Neuroinflammation. 2016;13(1):280 and Chen JJ et al., Curr Opin Neurol. 2020;33(1):47-54) and MOG-IgG seropositivity is required to establish the diagnosis.

[0017] Although some patients, particularly children, may have a monophasic course, approximately 80% of adult patients exhibit a highly relapsing course (Jarius et al. J Neuroinflammation. 2016;13(1):280; Hyun et al. J Neurol Neurosurg Psychiatry. 2017;88(10):811-817; Mult Scler Relat Disord. 2019;30:231-235). The proportion of adolescents with a relapsing disease course is thought to be similar to adults (Bruijstens et al. Eur J Paediatr Neurol 2020b;29:32-40; Cobo-Calvo et al. Ann Neurol. 2021;89(1):30-41), and MOGAD-associated disability is driven by attacks / relapses, therefore relapse prevention is important. Current MOGAD treatment paradigms include the use of corticosteroids with or without intravenous immunoglobulin (IVIg) or plasma exchange (PLEX) for acute treatment of attacks, and empirically selected conventional steroid-sparing IST and rituximab (RTX) for relapse prevention (Stiebel-Kalish et al. Neurol Neuroimmunol Neuroinflamm. 2019;6(4):e572; Chen et al. Neurology. 2020;95(2):e111-e120; Chen and Bhatti Curr Opin Neurol. 2020;33(1):47-54; Hegen and Reindl, Ther Adv Neurol Disord. 2020;13:1756286420945135; Whittam et al. J Neurol. 2020a;267(12):3565-3577).Current literature indicates that these medications are often only partially effective with numerous short-term and long-term adverse effects (Chen et al. 2020;95(2):e111-e120, Whittam et al. Mult Scler Relat Disord. 2020b;44:102251; Durozard et al. Ann Neurol. 2020;87(2):256-266; Cobo-Calvo et al. Ann Neurol. 2021;89(1):30-41).

[0018] In certain embodiments, the medicament or pharmaceutical composition of the present invention is used in combination with immunosuppressive therapy (IST).In certain embodiments, the IST is one or more immunosuppressants, such as azathioprine (AZA), mycophenolate mofetil (MMF), and oral corticosteroids (OCS), such as prednisone and prednisolone.

[0019] In certain embodiments, the medicaments or pharmaceutical compositions of the present invention can delay the time from administration of an IL-6 inhibitor to the first occurrence of a relapse of a CNS demyelinating disease characterized by the presence of anti-MOG antibodies. In certain embodiments, the medicaments or pharmaceutical compositions of the present invention can further reduce one or more of the following: (a) Rate of relapse of demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies; (b) proportion of active lesions on MRI of the neuraxis; (c) the proportion of subjects receiving salvage therapy; or (d) Rate of hospitalization.

[0020] CNS demyelinating disease characterized by the presence of anti-MOG antibodies (MOGAD) is an autoimmune disease that is difficult to achieve complete remission. Therefore, even if complete remission is not achieved, alleviating or improving symptoms to a level where minimal manifestation (MM) can be maintained, or maintaining such a state, are also included in "treating CNS demyelinating disease characterized by the presence of anti-MOG antibodies".

[0021] The severity of MOGAD can be assessed, for example, using MOG-IgG titers (e.g., in serum samples), as well as EDSS, FSS, BCVA, HCVA, LCVA, NEI VFQ-25, EQ-5D-5L, SF-36v2, and / or SF-MPQ-2. Details of these assessments are described in the following examples. For example, for NEI VFQ-25, the composite score and subscale scores range from 0 to 100, with higher scores indicating better vision-related function. Thus, the pharmaceutical composition of the present invention can increase the subject's NEI VFQ-25 score. For EQ-5D-5L, higher scores indicate better health. Thus, the pharmaceutical composition of the present invention can increase the EQ-5D-5L score. For SF-36v2, higher scores indicate better health. Thus, the pharmaceutical composition of the present invention can increase the SF-36v2 score. For SF-MPQ-2, lower score is equivalent to less pain, and higher score is equivalent to more pain.Therefore, the pharmaceutical composition of the present invention can reduce SF-MPQ-2 score.Higher MOG-IgG titer (e.g., in serum sample) can be regarded as higher risk of MOGAD attack / recurrence. Thus, in certain embodiments, the present invention can reduce MOG-IgG titers and / or improve one or more scores or points in the EDSS, FSS, BCVA, LCVA, NEI VFQ-25, EQ-5D-5L, SF-36v2, and / or SF-MPQ-2 in a subject to which the present invention is applied compared to a subject to which the present invention is not applied.

[0022] The effectiveness of the present invention for treating MOGAD or reducing the risk of recurrence in recurrent MOGAD can be evaluated by using the above-mentioned evaluation items and by quantitatively measuring the severity of MOGAD before and after applying the present invention to a subject (e.g., a patient) and checking whether the change in severity is statistically significant. Alternatively, the change or difference in the patient group to which the present invention is applied and the group to which the present invention is not applied (i.e., a placebo group) can be compared. For example, one or more of the scores or points for measuring the severity of MOGAD as described above can be determined in the patient as a baseline before applying the present invention; after applying the present invention for a certain period of time, the patient's MOGAD severity can be determined, and then the improvement of severity compared to the baseline can be determined. The above-mentioned evaluation criteria can be used as the standard for quantitative evaluation. In any of the above-mentioned evaluation criteria, if the change in score or points in a given patient after administration compared to before application of the present invention (baseline), or the difference in score or points between the group of patients to which the present invention is applied and the group to which the present invention is not applied, is statistically significant, the present invention can be said to be effective in treating MOGAD or preventing MOGAD recurrence (or reducing its risk).When the degree of MOGAD in a patient is severe, some MOGAD evaluation scores or points, such as EDSS score, FSS of EDSS, SF-MPQ-2 score, and / or MOG-IgG titer, will be considered high, and others will be considered low, and when the degree is mild, they will be considered low.Therefore, it is desirable to reduce the change or difference in these scores or points in the evaluation criteria. On the other hand, if the patient's MOGAD is severe, other MOGAD assessment scores or points, such as high contrast BCVA, LCVA, NEI VFQ-25 composite or subscale scores, EuroQol EQ-5D-5L score, and / or SF-36v2 score, will be considered low, whereas if the patient's MOGAD is mild, they will be high. Therefore, it is desirable to increase the change or difference in these scores or points of the assessment criteria.

[0023] The given period of time over which the invention is applied (e.g., a medicament or pharmaceutical composition of the invention is administered) to assess efficacy is not particularly limited and includes 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 48 ​​weeks, 1 year, 2 years, 3 years, 4 years, and 5 years, and the period of time may be shorter or longer than the exemplified periods.

[0024] In the present invention, a patient having a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies may receive the treatment (e.g., medicaments, pharmaceutical compositions, methods, etc.) of the present invention, for example, three times at two-week intervals (Q2W) (i.e., at time zero, and further at weeks 2 and 4), and then at four-week intervals (Q4W). In some embodiments, the patient may receive the anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the medicament or composition of the present invention via a subcutaneous administration route.

[0025] In addition to treating demyelinating diseases of the central nervous system (CNS) characterized by the presence of anti-MOG antibodies in subjects who are anti-MOG antibody positive, the present invention is also used to reduce the risk of relapse in recurrent demyelinating diseases of the CNS characterized by the presence of anti-MOG antibodies in subjects who are anti-MOG antibody positive, such as MOGAD. In the present invention, reducing the risk of relapse includes, but is not limited to, delaying relapse of a demyelinating disease of the CNS characterized by the presence of anti-MOG antibodies, reducing the frequency of the relapse, or reducing the severity of the relapse, or reducing the need for rescue therapy for the relapse.

[0026] The anti-IL-6 receptor antibody or antigen-binding fragment thereof used in the present invention binds to the IL-6 receptor, inhibits the binding of IL-6 to the IL-6 receptor, blocks signal transduction by IL-6, and inhibits the biological activity of IL-6.

[0027] The anti-IL-6 receptor antibody used in the present invention can be obtained using known methods. In particular, the anti-IL-6 receptor antibody used in the present invention is preferably a monoclonal antibody derived from a mammal. Mammalian-derived monoclonal antibodies include those produced by hybridomas and those produced by hosts transformed with an expression vector containing an antibody gene using genetic engineering techniques.

[0028] Preferred examples of the "IL-6 receptor antibody" of the present invention include humanized anti-IL-6 receptor antibodies produced by modifying the variable and constant regions of tocilizumab, specifically antibodies comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

[0029] More preferred antibodies of the present invention include antibodies comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. Even more preferred are antibodies comprising a heavy chain (satralizumab (generic name); SA237 (informal name) heavy chain) comprising the amino acid sequence of SEQ ID NO: 3, and a light chain (satralizumab light chain) comprising the amino acid sequence of SEQ ID NO: 4. Satralizumab (informal name: SA237) is particularly preferred.

[0030] Government marketing approval for satralizumab has been obtained in many countries, including Japan, the United States, and Europe, based on the indication of "prevention of relapses of neuromyelitis optica spectrum disorder (including neuromyelitis optica)." The safety profile identified during international Phase III clinical trials (SA-307JG / BN40898 and SA-309JG / BN40900 studies) targeting patient populations with neuromyelitis optica spectrum disorder (NMOSD) and / or neuromyelitis optica (NMO) was generally adequate. No deaths were reported. The percentage of patients who experienced severe adverse events in the satralizumab group was similar to that in the placebo group. There was no significant difference between the two groups in the frequency of adverse events that led to discontinuation of study drug administration or to drug withdrawal. The safety profile was similar between the SA-309JG study, which was a monotherapy trial, and the SA-307JG study, which was a combination trial with existing therapy (oral steroids and / or immunosuppressants).

[0031] Such antibodies can be obtained according to the methods described in WO2010 / 035769, WO2010 / 107108, WO2010 / 106812, etc. Specifically, the antibodies can be produced based on the above-mentioned IL-6 receptor antibody sequences using gene recombination techniques known to those skilled in the art (see, for example, Borrebaeck CAK and Larrick JW, THERAPEUTIC MONOCLONAL ANTIBODIES, published in the UK by MACMILLAN PUBLISHERS LTD in 1990). Recombinant antibodies can be obtained by cloning DNA encoding the antibody from a hybridoma or an antibody-producing cell, such as an antibody-producing sensitized lymphocyte, inserting the DNA into an appropriate vector, and introducing the vector into a host (host cell) to produce the antibody.

[0032] Such antibodies can be isolated and purified using, but not limited to, isolation and purification methods conventionally used for antibody purification. For example, antibodies can be isolated and purified by appropriately selecting and combining column chromatography, filtration, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, recrystallization, and the like.

[0033] The antibody used in the present invention may be a conjugated antibody, which is bound to various molecules such as polyethylene glycol (PEG), radioactive substances, and toxins. Such conjugated antibodies can be obtained by chemically modifying the obtained antibody. Methods for antibody modification have already been established in this field. Therefore, the term "antibody" in the present invention includes such conjugated antibodies.

[0034] The antibody used in the present invention may be an antibody fragment (also called an antigen-binding fragment of an antibody) or a modified product thereof, so long as it can be suitably used in the present invention. For example, the antibody fragment includes Fab, F(ab')2, Fv, and single chain Fv (scFv) in which the Fv of the H chain and the Fv of the L chain are linked via a suitable linker. Specifically, antibody fragments are produced by treating antibodies with enzymes such as papain or pepsin, or alternatively, by constructing genes encoding these antibody fragments and introducing them into expression vectors and then expressing the vectors in suitable host cells (see, e.g., Co, MS et al., J. Immunol. (1994) 152, 2968-2976; Better, M. & Horwitz, AH, Methods in Enzymology (1989) 178, 476-496; Plueckthun, A. & Skerra, A., Methods in Enzymology (1989) 178, 497-515; Lamoyi, E., Methods in Enzymology (1989) 121, 652-663; Rousseaux, J. et al., Methods in Enzymology (1989) 121, 652-663). 663-666; and Bird, RE et al., TIBTECH (1991) 9, 132-137).

[0035] An scFv can be obtained by linking the H chain V region and the L chain V region of an antibody. In this scFv, the H chain V region and the L chain V region are linked via a linker, preferably via a peptide linker (Huston, JS et al., Proc. Natl. Acad. Sci. USA (1988) 85, 5879-5883). The H chain and L chain V regions in the scFv may be derived from any of the above antibodies. The peptide linker for linking the V regions includes, for example, any single-chain peptide consisting of 12 to 19 amino acid residues.

[0036] DNA encoding an scFv can be obtained by amplifying a DNA portion encoding the desired amino acid sequence in a template sequence by PCR using a primer pair that defines the ends of the portion, in which a DNA encoding the H chain or H chain V region and a DNA encoding the L chain or L chain V region of the above-mentioned antibody are used as templates, and then further amplifying the amplified DNA portion using a DNA encoding a peptide linker portion and a primer pair that defines both ends of the linker so that it can be linked to each of the H chain and the L chain. Once the DNA encoding the scFv has been prepared, an expression vector containing the DNA and a host transformed with the expression vector can be obtained according to a conventional method. In addition, the host can be used to obtain the scFv according to a conventional method. Similarly as above, antibody fragments can be produced by obtaining and expressing the genes themselves and then using a host.

[0037] In the present invention, "as an active ingredient" means that the ingredient is contained in the pharmaceutical composition as a major active ingredient, and the content thereof is not limited unless specifically indicated, so long as the antibody or antigen-binding fragment thereof used in the present invention is included as a medicinal ingredient.

[0038] The dose of the anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention is not particularly limited, and examples include 50 to 800 mg of antibody per administration, preferably 60 to 240 mg of antibody per administration, and more preferably 60 mg, 120 mg, 180 mg, or 240 mg of antibody. The dose of the anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention may vary depending on the patient's body weight. In certain embodiments of the present invention, the dose of the anti-IL-6 receptor antibody or antigen-binding fragment suitable for a subject having a body weight of less than 40 kg is 60 mg or 120 mg; the dose suitable for a subject having a body weight of 40 kg to 100 kg is 120 mg or 180 mg; and the dose suitable for a subject having a body weight of more than 100 kg is 180 mg or 240 mg. The pharmaceutical or composition containing the anti-IL-6 receptor antibody or antigen-binding fragment thereof of the present invention is administered to a subject via any route, including but not limited to subcutaneous, intravenous, intramuscular, and injection. The preferred embodiment is subcutaneous administration.

[0039] In a particular embodiment of the present invention, two or more consecutive doses of an anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention are administered to a subject during an initial period, wherein the doses administered during the initial period are spaced apart by a first administration interval (also referred to as an administration interval shorter than a conventional administration interval), for example, 20 weeks, 8 weeks, 4 weeks, or 2 weeks; and after the administration of the final dose in the initial period, a second administration interval longer than the first administration interval is provided, and then a dose of an anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention is administered to a human patient, wherein, optionally, multiple consecutive doses are administered after the administration of the final dose in the initial period and are spaced apart by a second administration interval (also referred to as a "conventional administration interval") that is not particularly limited except that it is longer than the first administration interval. Examples of the second administration interval include 1 day to 24 weeks, preferably 2 weeks to 8 weeks, more preferably 3 to 5 weeks, and even more preferably 4 weeks. In a specific embodiment of the present invention, the anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention is administered to a subject three times at two-week intervals (Q2W) and then four-weekly (Q4W) intervals.

[0040] A preferred administration schedule for the anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention can be adjusted, for example, by appropriately extending the administration interval by monitoring changes in the disease state and blood test values.

[0041] The present invention also provides a product, such as a kit, device, etc., for use in the method of the present invention, containing the pharmaceutical composition or medicament of the present invention. The pharmaceutical composition or medicament of the present invention comprises an IL-6 inhibitor as described herein. The product may be packaged with additional pharma- ceutically acceptable carriers or vehicles, or instructions for use in the kit, etc.

[0042] In one embodiment, the product comprises a container and a label on the container or a package insert associated with the container. Suitable containers include, for example, bottles, vials, syringes (including prefilled syringes and autoinjectors), IV solution bags, etc. The container can be made of various materials, such as glass or plastic. In one embodiment, the container holds a composition, alone or in combination with another composition that is effective for treating, preventing, and / or diagnosing a condition, and can have a sterile access port (e.g., the container can be a syringe, autoinjector, intravenous solution bag, or a vial with a stopper that can be pierced by a hypodermic needle). At least one active ingredient in the composition is an IL-6 inhibitor as described in the present disclosure, preferably an anti-IL-6 receptor antibody, and more preferably satralizumab.

[0043] In one embodiment, the device as the product of the present invention as described above may be a pre-filled syringe for injection via any administration route, such as intravenous, subcutaneous, etc., containing a fixed dose of an IL-6 inhibitor as described in the present disclosure, preferably an anti-IL-6 receptor antibody, and more preferably satralizumab, in a pharmaceutically acceptable excipient.In another embodiment, the device may be an auto-injector for subcutaneous administration, containing a fixed dose of an IL-6 inhibitor as described in the present disclosure, preferably an anti-IL-6 receptor antibody, and more preferably satralizumab, in a pharmaceutically acceptable excipient.In certain embodiments, devices such as pre-filled syringes and auto-injectors may contain 60 mg, 120 mg, 180 mg, or 240 mg of satralizumab.

[0044] In the present invention, the label or package insert indicates that the pharmaceutical composition or medicament is used to treat a selected condition. In addition, the product may include (a) a first container in which a composition comprising an IL-6 inhibitor, preferably an anti-IL-6 receptor antibody, and more preferably satralizumab, as described above is contained; and (b) a second container in which a composition comprising an additional therapeutic agent is contained. The product in this aspect of the present invention may further include a package insert indicating that the composition can be used to treat a particular condition. Alternatively, or in addition, the product may further include a second (or third) container containing a pharma- ceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0045] Attached document The term "package insert" is used to refer to instructions customarily included in commercial packaging of a therapeutic product, which contain information about the indications, usage, dosage, administration, concomitant therapy, contraindications, and / or warnings regarding the use of such therapeutic product.

[0046] The pharmaceutical composition or medicine of the present invention can be formulated to prepare a lyophilized preparation or a solution preparation by mixing with a suitable pharmaceutically acceptable carrier, vehicle, etc., if necessary. Suitable pharmaceutically acceptable carriers and vehicles include, for example, sterilized water, physiological saline, stabilizers, excipients, antioxidants (such as ascorbic acid), buffers (such as phosphates, citrates, histidine, and other organic acids), preservatives, surfactants (such as PEG and Tween), chelating agents (such as EDTA), and binders. Other low molecular weight polypeptides, proteins, such as serum albumin, gelatin, and immunoglobulins, amino acids, such as glycine, glutamine, asparagine, glutamic acid, aspartic acid, methionine, arginine, and lysine, sugars and carbohydrates, such as polysaccharides and monosaccharides, and sugar alcohols, such as mannitol and sorbitol, may also be included in the formulation. When preparing an injectable aqueous solution, isotonic solutions containing physiological saline, glucose and other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, may be used; and suitable solubilizers, such as alcohol (e.g., ethanol), polyhydric alcohols (such as propylene glycol and PEG), and non-ionic surfactants (such as polysorbate 80, polysorbate 20, poloxamer 188, and HCO-50), may be used in combination. By mixing hyaluronidase into the formulation, a larger amount of liquid can be administered subcutaneously (Expert Opin. Drug Deliv. 2007 July; 4(4): 427-40). In addition, a syringe may be pre-filled with the pharmaceutical composition of the present invention. The solution formulation may be prepared according to the method described in WO2011 / 090088.

[0047] If necessary, the pharmaceutical compositions or medicaments of the present invention may be encapsulated in microcapsules (e.g., those made of hydroxymethylcellulose, gelatin, and poly(methyl methacrylate)) or incorporated into colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) (see, for example, "Remington's Pharmaceutical Science 16th edition", Oslo Ed. (1980)). Methods for formulating drugs as controlled release drugs are also known, and such methods may be applied to the pharmaceutical compositions of the present invention (Langer et al., J. Biomed. Mater. Res. 15: 267-277 (1981); Langer, Chemtech. 12: 98-105 (1982); U.S. Patent No. 3,773,919; European Patent Application Publication No. EP 58,481; Sidman et al., Biopolymers 22: 547-556 (1983); and EP 133,988).

[0048] The anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention can be administered to a patient via any suitable route. For example, it can be administered to a patient intravenously by bolus injection or continuous infusion, intramuscularly, intraperitoneally, intracerebrospinally, transdermally, subcutaneously, intraarticularly, sublingually, intrasynovially, orally, by inhalation, locally, or externally for a certain period of time. Intravenous or subcutaneous administration is preferred. In a certain embodiment of the present invention, the anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention is administered subcutaneously to a subject.

[0049] All prior art references cited herein are hereby incorporated by reference. EXAMPLES

[0050] Hereinafter, the present invention will be specifically described with reference to examples, but should not be construed as being limited thereto.

[0051] Example 1: Preparation of Satralizumab (SA237) An antibody having the generic name satralizumab (and the informal name SA237), which is an IL-6 receptor antibody described in patent document WO 2010 / 035769 as comprising a heavy chain having the amino acid sequence of SEQ ID NO:26 (herein SEQ ID NO:3) and a light chain having the amino acid sequence of SEQ ID NO:29 (herein SEQ ID NO:4), was prepared according to the description in the patent document. The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:1, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:2. Using the prepared antibody, a subcutaneous administration preparation was prepared by the method described in patent document WO 2011 / 090088.

[0052] Example 2: Phase III, randomized, double-blind, placebo-controlled, multicenter study 1. Study Design 1.1 Overall design 1.1.1 Overview of study design This phase III, randomized, double-blind (DB), placebo-controlled, multicenter study is designed to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab compared with placebo as monotherapy or as add-on to baseline / background IST for the prevention of MOGAD relapse.

[0053] The study will include a screening period of up to 28 days, and an event-driven DB treatment period.

[0054] During the screening period, individuals' eligibility for study participation is assessed.

[0055] The study will enroll approximately 152 participants with MOGAD across all locations in the global enrollment phase.

[0056] The study schema is shown in Figure 1.

[0057] 1.1.2 Double-blind treatment period During the DB treatment period, participants will be randomized in a 1:1 ratio to receive either satralizumab (60, 120, or 180 mg based on weight) or placebo as monotherapy or add-on therapy to baseline / background IST used to prevent MOGAD relapse.

[0058] Randomization will be stratified based on: -- Use of baseline / background IST -- region.

[0059] Blinded study medication will be administered subcutaneously to all participants at weeks 0, 2, 4, and then every 4 weeks (Q4W) until the end of the DB treatment period.

[0060] Pharmacokinetic interim analysis An interim analysis of pharmacokinetic (PK) data will be performed during the DB treatment period. The purpose of the interim analysis is to confirm that the achieved exposure (and predicted receptor occupancy [RO]) to satralizumab is within the target range. Based on the results from the interim PK analysis and pre-specified criteria, the dose of study drug may be increased if needed to achieve the target concentration (see Section 1.3).

[0061] Baseline / background immunosuppressive therapy Permitted baseline / background immunosuppressive therapy in this study are AZA, MMF, baseline OCS with study protocol-defined OCS taper, and a combination of AZA or MMF and baseline OCS with study protocol-defined OCS taper. Participants should remain on a stable dose of AZA or MMF throughout the DB treatment period (except for dose reductions or discontinuations for safety reasons, see section 3.2.1.1).

[0062] 1.1.3. Diagnostic criteria for MOGAD recurrence MOGAD relapse, as defined for this study, is the occurrence of new or worsening acute neurological symptoms, as confirmed by the investigator, with objective changes (clinical findings or signs) on clinical (neurological and ophthalmological) examination lasting more than 24 hours. Symptoms must be attributable to MOGAD, i.e. confounding clinical factors (e.g., fever, infection, injury, mood changes, side effects to medication, or other neurological disorders) must be excluded. MOGAD attacks may affect four major areas of the CNS, resulting in corresponding clinical syndromes (symptoms, manifestations, or phenotypes): -- Optic nerve, resulting in optic neuritis -- Spinal cord, resulting in transverse myelitis -- Brain stem and / or cerebellum, resulting in brain stem / cerebellar syndrome --The brain, resulting in acute disseminated encephalomyelitis (ADEM) or other cerebral syndromes with demyelination (swollen lesions, cortical disease with seizures).

[0063] These areas may be affected simultaneously during a seizure (eg, a seizure may consist of simultaneous optic neuritis and transverse myelitis, or optic neuritis and ADEM).

[0064] The diagnosis of MOGAD recurrence in the four involved domains / CNS regions (optic nerve, spinal cord, brainstem and / or cerebellum, brain) (see Table 1) is based on criteria including: -- Description of new or worsening acute neurological symptoms lasting more than 24 hours -- Physical examination (including neurological) and vital signs -- Expanded Disability Status Scale (EDSS) Functional System Score (FSS) as determined by an independent assessor -- Results of an ophthalmologic examination, including high contrast visual acuity (HCVA) and low contrast visual acuity (LCVA), assessment of relative afferent pupillary defect (RAPD), and optic disc appearance (presence of new optic disc swelling), as determined by an independent assessor. --Total neuraxial magnetic resonance imaging (MRI) scan with gadolinium.

[0065] Evidence of at least one corresponding active lesion on MRI of the neuraxis is used for confirmation in cases where clinical findings are equivocal or nonspecific.

[0066] Optic neuritis episodes are based on changes in high-contrast best-corrected visual acuity (BCVA) in combination with additional clinical signs including changes in LCVA, RAPD (specifically new RAPD in the affected eye or loss of RAPD in the fellow eye), or new optic disc swelling in the affected eye. In cases where additional clinical signs are absent or unclear, and in situations where the participant's visual acuity at the pre-recurrence visit is at or worse than index foveal (CF), an MRI is required to demonstrate the presence of active lesions in the anterior visual pathway.

[0067] A transverse myelitis attack is based on changes in the EDSS pyramidal, sensory, or bowel and bladder FSS that would be affected by this type of attack. In milder forms of myelitis, confirmation requires identification of active lesions on an MRI of the spinal cord.

[0068] For strokes involving the brainstem and / or cerebellum (brainstem and / or cerebellar syndrome with demyelination), FSS changes of the brainstem and / or cerebellum are required in conjunction with identification of one or more well-located active MRI lesions in the brainstem and / or cerebellum.

[0069] For seizures involving the brain (cerebral syndrome with demyelination), cerebral, sensory, or pyramidal FSS changes are required in conjunction with identification of one or more well-located active MRI brain lesions or ADEM-specific imaging criteria (Pohl et al. 2016).

[0070] (Table 1) Criteria for MOGAD recurrence TIFF2024543147000002.tif152170 a An acute onset of new symptoms or a worsening of existing symptoms that must last for more than 24 hours. b The diagnosis of bilateral optic neuritis (ON) requires the presence of symptoms in both eyes, major clinical signs, and additional diagnostic criteria.

[0071] New or worsening acute neurological symptoms and clinical signs attributable to MOGAD occurring within 30 days (or within 90 days in the case of ADEM) of the onset of a MOGAD relapse are considered to be the same relapse. The reoccurrence of symptoms after the initiation of salvage therapy and that do not meet the criteria for a new relapse corresponds to a so-called MOGAD relapse episode (Bruijstens et al. 2020b; Bruijstens et al. 2020c).

[0072] Diagnosis of subsequent relapses and MOGAD relapse episodes for an individual participant will be based on the same criteria and involve the same evaluations as the first MOGAD relapse.

[0073] Evaluation for recurrence should be performed before initiating any salvage therapy. For more information, see section 4.1.1.

[0074] 1.2 Rationale for study design 1.2.1 Rationale for Study Population The study will investigate the efficacy and safety of satralizumab in participants with MOGAD. MOG-IgG seropositivity at screening must be determined using a cell-based assay (CBA), as this is the only type of assay that allows for the detection of disease-associated anti-MOG antibodies. Alternative diagnoses with overlapping clinical features, including MS, must be ruled out.

[0075] The study plans to enroll participants who have an EDSS score of 0-6.5 and a BCVA better than 20 / 800 in both eyes at screening, and who have had at least one documented MOGAD relapse within 12 months prior to screening or at least two attacks within the past 24 months. Participants entering the study on stable doses of AZA or MMF must have had MOGAD attacks while receiving background therapy. The selection of participants with MOGAD, with evidence of recent disease activity, is considered appropriate to allow estimation of the treatment effect of satralizumab in a short time frame and small study population.

[0076] 1.2.2 Rationale for including youth participants The inclusion of adolescent participants is supported by several rationales. First, the underlying pathogenesis appears to be identical in pediatric and adult patients with MOGAD, driven by peripherally produced anti-MOG-IgG, which causes demyelination in the context of BBB disruption (Spadaro et al. 2018; Reindl and Waters 2019). Second, the clinical phenotype (type of MOGAD attacks / relapses) and disease course are similar in adolescent and adult patients with MOGAD. ADEM and other types of brain involvement are significantly less frequent in patients over 11 years of age (adolescents and adults) (Hacohen et al. 2018, Baumann et al. 2018). In these patients, optic neuritis and transverse myelitis, alone or in combination, are the most common seizure types. Age-related phenotypic differences have been attributed to changing MOG expression during various stages of brain development and CNS maturation in childhood (Bruijstens et al. 2020a). Third, the main types of treatment, including rescue treatment for attacks / relapses and chronic / maintenance treatment for relapse prevention, are the same in adult and pediatric patients with MOGAD.

[0077] Phase III trials require participants to be reliable witnesses to assessments of disability, pain, and general health. Adolescents are expected to cooperate with the study procedures.

[0078] Satralizumab was tested in nine adolescent patients with NMOSD (mean age 15 years) aged 12 to <18 years at the time of informed consent, of which seven participants were randomized to the DB treatment period of the BN40898 study before the clinical cut-off date (CCOD) for the primary efficacy and safety report. The safety profile of satralizumab in these pediatric patients with NMOSD was generally consistent with that observed in the adult population. All adverse events reported in adolescent participants were of mild or moderate severity and resolved. No adolescent participants discontinued the study due to adverse events. Data obtained in patients with NMOSD aged 12 to <18 years receiving the adult dosing regimen (120 mg Q4W) showed that exposure to satralizumab was not significantly different from that in the adult population when body weight was taken into account.

[0079] 1.2.3 Rationale for Selection of Permitted Baseline / Background Treatments Because the study's goal is to recruit a representative and generalizable population across treatment histories, this Phase III study will enroll participants who are not receiving maintenance (chronic relapse prevention treatment) for MOGAD, are receiving stable doses of AZA or MMF with suboptimal relapse prevention, or are receiving baseline OCS.

[0080] 1.2.4 Rationale for the choice of control treatment In this study, a placebo will be used as a comparator to provide objective evidence of safety and efficacy data from participants exposed to the experimental therapy. No MOGAD treatment has an established safety and efficacy profile in a randomized controlled intervention trial. In addition, retrospective case series strongly suggest that several MS disease-modifying therapies (IFN-γ, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, fingolimod, natalizumab, and alemtuzumab) exacerbate the disease (Cobo-Calvo et al. 2021). In the absence of established effective treatments for the prevention of MOGAD relapses, the use of a placebo with or without baseline / background IST is considered acceptable, especially when the selection of an active comparator means the use of a single unproven agent. The use of baseline / background therapy is permitted to avoid withholding treatments commonly used off-label for the prevention of MOGAD relapses.

[0081] 1.2.5 Rationale for Selection of Primary Endpoint The primary endpoint, time from randomization to onset of first adjudicated relapse, was chosen based on several factors: relapsing disease course, exclusively seizure-driven neurological deficits.

[0082] 1.2.6 Rationale for Selection of Secondary Endpoints Annualized rates of adjudicated MOGAD recurrence, annualized rates of active disease on neuraxial MRI, proportion of participants receiving salvage therapy, and annualized rates of hospitalization (defined as longer than an overnight stay, excluding those for selection procedures) were selected as secondary endpoints for comparing the efficacy of satralizumab versus placebo.

[0083] Prevention of relapse and the associated use of rescue therapy, as well as prevention of hospitalization as a measure of healthcare utilization, are meaningful goals in the chronic treatment of patients with MOGAD.

[0084] The importance of relapse prevention is underscored by the fact that the progression of disability in MOGAD is thought to be exclusively seizure-related and not driven by a progression independent of relapse activity (Akaishi et al. 2021). In addition, MRI of the CNS (total axis) is the most objective available method to study the extent and evolution of MOGAD pathology.

[0085] 1.2.7 Rationale for Recurrence Follow-Up Assessment Visits An RFA visit will be scheduled 12 weeks after the RA visit to assess the outcome of adjudicated MOGAD relapse. The 12-week period was defined based on literature showing that most recovery after attacks / relapses in demyelinating diseases, including MS and idiopathic demyelinating optic neuritis, occurs within the first 3 months (Kantarci et al. 2019, Galetta et al. 2015). Although complete recovery is not expected to occur in all participants within the 12-week period, this interval also allows participants in the placebo group who experience an adjudicated relapse to cross over to open-label satralizumab within a relatively short period from relapse onset. High-dose corticosteroids followed by OCS tapering are routinely used to treat MOGAD attacks and to prevent relapse episodes and rebound recurrence (Jarius et al. 2016; Ramanathan et al. 2018; Brujistens et al. 2020c; Whittam et al. 2020a), therefore continuous use of prednisone / prednisolone up until the RFA visit will allow for consistent assessment of relapse recovery with minimal risk of another relapse or flare-up prior to initiation of open-label satralizumab in all participants.

[0086] 1.2.8 Rationale for Biomarker Evaluation The study will evaluate whether the biomarkers can help characterize the mechanism of action of satralizumab in MOGAD, provide evidence of satralizumab activity in MOGAD, or increase the knowledge and understanding of MOGAD disease biology.Exploratory biomarker samples will be used for research purposes to identify pathways and / or disease biomarkers, including but not limited to those reflecting neuroinflammation, damage to the CNS, disease activity, or a patient's immune phenotype.

[0087] Pharmacodynamic (PD) biomarker samples will be collected for assessment of target engagement (e.g., IL-6 and sIL-6R) in response to satralizumab treatment.

[0088] 1.2.9 Rationale for Pharmacokinetic Sample Collection Schedule Samples to assess serum concentrations of satralizumab will be collected prior to each dose of study drug to explore the pharmacokinetics of satralizumab in the MOGAD population. This evaluation will include the effects of various covariates (e.g., sex, race, age, and weight) on the pharmacokinetics of satralizumab, as well as the relationship between exposure and PD, efficacy, immunogenicity, and safety endpoints to support the recommended dose of satralizumab in the MOGAD population. PK assessment will also be used to inform interim PK analyses to confirm the appropriate dose of satralizumab in the MOGAD population.

[0089] 1.2.10 Rationale for Interim Pharmacokinetic Analysis PK and PD data of satralizumab collected from a Phase I study in patients with rheumatoid arthritis were used to inform dose selection (120 mg Q4W) for a Phase III study in patients with NMOSD, and this regimen was shown to be safe and effective. The PK of satralizumab in patients with MOGAD is assumed to be similar to that in patients with NMOSD, although the sponsors note that there is potential for population differences in satralizumab pharmacokinetics. Thus, the Phase III design in MOGAD allows for interim analyses of PK data to ensure participants are achieving target exposure (based on that associated with near-maximal RO in patients with NMOSD) while the sponsor remains blinded, thereby preserving the integrity of this important study. Simulations using an existing population PK (popPK) model (based on data in healthy volunteers and patients with NMOSD) are used to define alternative doses if the initially proposed dose does not achieve the target exposure. Further details on the interim PK analyses are provided in Sections 1.3 and 5.4.1.

[0090] 1.2.11 Rationale for Immunogenicity Sample Collection Anti-drug antibodies (ADA) were detected in the majority of patients with NMOSD enrolled in Phase III trials. Although an effect of ADA on PK was observed, the benefit of treatment was not affected.

[0091] Serum samples for ADA will be collected in parallel with PK samples for the purpose of evaluating the incidence and titer-time profile of ADA in the MOGAD population and its impact on exposure to satralizumab and on safety and efficacy. ADA data will be included in a blinded review of the PK data at week 8 for the purposes of interpretation of satralizumab concentration data, in addition to subsequent analyses based on the full study dataset.

[0092] 1.2.12 Rationale for the choice of stratification factors Randomization will be stratified for baseline concurrent IST and region. These factors were selected to balance treatment group assignment and are expected to be of prognostic value for the primary endpoint. Use of concurrent IST is included to account for potential differences in efficacy and safety according to treatment. Region is included to account for potential regional differences.

[0093] 1.3 Dose and Schedule Justification As shown in Table 2, weight-graded dosing via SC injection will be used in this study to investigate the efficacy and safety of satralizumab in MOGAD.

[0094] Table 2. Investigational dosing regimens in Phase III trials of satralizumab for the treatment of MOGAD TIFF2024543147000003.tif27170PK=pharmacokinetics; Q4W=every 4 weeks.

[0095] The dosing regimen will be based on a combination of sources of information including PK, PD, and safety data for satralizumab for early development in NMOSD. The 120 mg fixed dosing regimen investigated in Phase III trials in NMOSD was associated with high median trough RO at steady state (RO tr,ss (≥95%) and was shown to be safe and effective across all weight groups. Given the expected similar target expression in MOGAD, exposures similar to those in NMOSD are expected to be efficacious in MOGAD.

[0096] Predicted RO less than 80% tr,ss The few patients with NMOSD who had a baseline weight of >100 kg generally had a baseline weight of >100 kg, and the safety profile was similar across weight groups, although exposure in the lightest participants was near-maximal RO tr,ssTherefore, patients with MOGAD across the expected weight range were able to maintain the same near-maximal RO. tr,ss To estimate the dose required to achieve values, the sponsor performed simulations using an existing popPK model (based on data in healthy volunteers and patients with NMOSD) to maximize the efficacy potential. Considering that the target is the same in both indications (NMOSD and MOGAD) and similar target expression is expected for MOGAD, the use of the existing RO model for this purpose seems appropriate.

[0097] These simulations (see Figure 2) show that the proposed weight-graded dosing regimen is expected to achieve maximum steady-state median plasma drug concentrations and trough concentration values ​​at steady state similar to those observed in NMOSD Phase III trials, which were associated with near-maximal RO throughout the dosing interval. The range of predicted exposures in participants weighing >100 kg receiving 180 mg does not exceed the maximum exposures achieved in Phase III trials in NMOSD, and thus remains within existing exposure-safety envelopes. Conversely, the predicted exposures for the 60 mg regimen in patients weighing <20-40 kg are expected to be sufficient to maintain high target engagement over the dosing interval and avoid unnecessary overexposure.

[0098] As described, the initial dosing assumption of this Phase III study is that the pharmacokinetics of satralizumab in MOGAD are similar to those in NMOSD. However, the sponsor notes that there are potential population differences, as seen in higher total clearance (CL) values ​​in healthy volunteers compared to the NMOSD population (covariate value [95% CI] 95.8% [67.5, 124.1]). Therefore, the proposed study design provides for interim analysis of PK data (see Sections 1.2.10 and 5.4.1).

[0099] Simulations using existing popPK models are used to define alternative doses if the initially proposed dose does not achieve the target exposure. The CL values ​​in MOGAD reflect those in healthy volunteers (higher than the CL values ​​in the NMOSD population), and thus, if the target exposure is not met, the dose adaptation option is to escalate the dose to predefined dosing regimens of 120 mg, 180 mg, and 240 mg for participants <40 kg, ≤100 kg, and >100 kg, respectively.

[0100] In any case, the dosing regimen selected will be associated with exposure that does not significantly exceed existing exposure-safety ranges based on NMOSD clinical trials.

[0101] PK parameters in adolescent patients with NMOSD are similar to those in adult patients, and the predicted exposure resulting from the proposed weight-graded dosing regimen is supported by the existing safety profile established in Phase 3 studies in adult and adolescent patients with NMOSD treated at a fixed dose of 120 mg.

[0102] 1.4 Definition of End of Study Participants were considered to have completed the study if they completed all periods of the study. The end of this study is defined as the later of the last visit of the last participant in the study or the date of receiving the last data point required for SFU from the last participant.The end of the study is expected to occur 2.5 years after the end of the event-driven DB treatment period.In addition, the sponsor may decide to terminate the study at any time.

[0103] 1.5 Duration of Participation Participants are estimated to remain in DB treatment for up to 44 months.

[0104] 2. Study population Approximately 152 participants with MOGAD will be enrolled in this study. The number of participants may be increased depending on the outcome of the interim PK analysis (Section 5.4.1).

[0105] 2.1 Inclusion Criteria Participants were eligible for inclusion in the study only if the following criteria applied: -- Participants who are 12 years of age or older at the time they sign the informed consent form --For adolescent participants: Informed consent form for study participation signed and agreed by parents or legal guardians according to local requirements -- A confirmed diagnosis of MOGAD, meeting the following criteria: - Documented history of 2 or more attacks of MOGAD (initial attack and at least one recurrence) manifested by the following symptoms / syndrome: optic neuritis; transverse myelitis; ADEM; other cerebral, brainstem, or cerebellar syndromes with demyelination; and any combination of the above - A diagnosis of MOGAD attacks based on new or worsening acute neurological symptoms lasting more than 24 hours, with objective changes on neurological and / or ophthalmological examination (clinical signs or MRI findings, or both, in corresponding CNS regions [i.e., optic nerves, spinal cord, brainstem, cerebellum, and / or brain]); and - MOG-IgG seropositivity by CBA, and - Exclude alternative diagnoses, including MS --Confirmation of MOG-IgG seropositivity at screening as assessed by a central laboratory -- Weight ≥ 20 kg at screening -- EDSS score of 0 to 6.5 at screening --BCVA better than 20 / 800 in both eyes at screening. --One or more MOGAD recurrences in the 12 months prior to screening, or a history of two or more attacks (which may include the first attack) in the 24 months prior to screening. A relapse is defined as a new clinical episode (new or worsening acute symptoms and clinical signs, optionally accompanied by MRI evidence of acute demyelination) occurring at least 30 days after the last attack (90 days if the last attack was ADEM). --Any ongoing chronic IST for MOGAD at screening Not received or ongoing treatment with AZA, MMF, OCS, or a combination of AZA or MMF and OCS prior to screening Receiving , participants -- No contraindications to corticosteroids and at least one of two other rescue treatments (IVIg or PLEX) -- No contraindications to MRI (e.g., hypersensitivity to Gd-containing MRI contrast agents, implanted pacemakers, defibrillators, or other metal objects on or within the body that limit the performance of an MRI scan) -- For women of childbearing potential: Participants who agree to remain abstinent (abstain from heterosexual intercourse) or use a reasonable method of contraception during treatment and for at least 3 months after the last dose of satralizumab

[0106] 2.2 Exclusion criteria Exclusion criteria for MOGAD Participants will be excluded from the study if any of the following criteria apply to them: -- Presence of AQP4-IgG in serum -- History of encephalitis unrelated to MOGAD, including anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis defined by the presence of anti-NMDAR antibodies in the CSF -- MRI sequences typical of MS present on the screening brain MRI, as assessed by a central reading center -- Participants who experienced a MOGAD relapse within 12 weeks prior to baseline, unless their EDSS was 0 at screening --Any complication other than MOGAD that may have required treatment with IST or OCS or IV corticosteroids at a dose of prednisone equivalent greater than 20 mg per day for longer than 21 days during the study.

[0107] Exclusion criteria for previous or concurrent treatments Participants who meet any of the following criteria regarding use of previous or concurrent therapies will be excluded from the study: -- IVIg within 4 weeks prior to screening -- PLEX within 4 weeks prior to screening -- OCS, AZA, or MMF within 4 weeks prior to screening (unless continued as baseline / background IST in the study) -- Tacrolimus or cyclosporine within 6 weeks prior to screening -- B-cell depleting agents, including RTX and ocrelizumab, within 6 months prior to baseline -- Methotrexate within 3 months prior to screening -- Neonatal Fc receptor antagonists within 6 months prior to screening -- IV cyclophosphamide within 6 months prior to screening -- Complement inhibitors (e.g., eculizumab) within 6 months prior to screening -- Glatiramer acetate and IFN-β within 1 month prior to screening -- Fumarate (fumaric acid ester) within 2 months prior to screening -- Teriflunomide within 2 years prior to screening, unless teriflunomide serum / plasma concentrations were <0.020 μg / mL (<20 ng / mL) prior to screening as a result of accelerated elimination procedures for teriflunomide with cholestyramine or activated charcoal, per local prescribing information -- Other MS disease-modifying treatments, including natalizumab and S1P receptor modulators (e.g., fingolimod, siponimod, ozanimod) within 6 months prior to screening -- Optional IL-6 blockade (e.g., tocilizumab) -- Total body irradiation, bone marrow transplant, and autologous hematopoietic stem cell transplant -- optionally, a T cell depleting agent, including but not limited to alemtuzumab --Optional anti-B-lymphocyte stimulatory factor monoclonal antibodies (e.g., belimumab) -- Cladribine, mitoxantrone, or oral cyclophosphamide at any time --Treatment with any investigational drug within 24 weeks or 5 drug elimination half-lives of the investigational drug (whichever is longer) prior to screening.

[0108] If retesting is performed, the last retest value before randomization must meet the study criteria.

[0109] 3. Study Treatment and Concomitant Therapy Study treatment is defined as any investigational treatment, marketed product, placebo, or medical device intended to be administered to study participants according to the study protocol.

[0110] The IMP will be supplied by the sponsor as prefilled syringes (PFS) for SC injection corresponding to 120 mg satralizumab. The placebo PFS is identical in composition to the satralizumab PFS but does not contain the satralizumab active ingredient. The appearance and packaging will be identical to satralizumab.

[0111] 3.1 Study treatment to be administered During the DB treatment period, participants will receive satralizumab or placebo (loading doses) at weeks 0, 2, and 4, and maintenance doses Q4W thereafter. Study treatment doses will be based on body weight. Participants will receive 60 mg (<40 kg), 120 mg (40-100 kg), or 180 mg (>100 kg) of satralizumab, depending on their body weight.

[0112] Study medication will be administered by SC injection in the abdomen or thigh after all other study related procedures have been performed at the site visit.

[0113] The dose may be modified based on the results of interim PK analyses (see Section 1.2.10, Section 5.4.1).

[0114] 3.2 Concomitant therapy 3.2.1 Permitted Treatments In general, investigators may manage participants' medical care (including pre-existing conditions) through the use of supportive care, as clinically indicated and in accordance with local standard practice, excluding prohibited therapies and taking into account treatments of caution.

[0115] 3.2.1.1 Baseline / background immunosuppressive treatment Background treatment with any of the medications listed below is permitted: -- AZA -- MMF.

[0116] 4. Test Evaluation and Methodology 4.1 Effectiveness evaluation 4.1.1 Recurrence assessment Prior to the start of the study, participants will be trained on the signs and symptoms that may indicate a potential relapse of optic neuritis, myelitis, or relapse involving any other CNS region, will be instructed to remember the time of onset and duration of such symptoms associated with a potential relapse, and will be asked to contact the study site immediately if they have any such symptoms.

[0117] Reported episodes and corresponding recurrence assessment data will be submitted to the CEC, regardless of the treating investigator's assessment of whether the potential recurrence meets the protocol-defined MOGAD recurrence criteria, including: -- Description of new or worsening neurological symptoms lasting more than 24 hours -- Physical examination (including neurological) and vital signs --FSS of EDSS as determined by an independent assessor -- Results of an ophthalmic examination, including HCVA and LCVA, assessment of RAPD, and optic disc appearance (presence of new optic disc swelling), as determined by an independent assessor. -- Whole neuraxis MRI scan with Gd.

[0118] During DB treatment, an independent CEC will review data obtained at RA visits to determine whether a reported episode meets MOGAD relapse criteria and is a MOGAD relapse contributing to the primary endpoint. The CEC may request additional information to aid in the evaluation of a reported episode, if deemed necessary.

[0119] 4.1.2 Functional System Score and Integrated Disability Scale Assessment The EDSS and its associated FSS provide a system for quantifying disability and for monitoring changes in the level of disability over time. Scores in seven functional systems (FS; visual FS, brainstem FS, pyramidal FS, cerebellar FS, sensory FS, bowel and bladder FS, and cerebral FS) are used to 1) define certain types of MOGAD relapse (see section 1.1.3, Table 1), 2) assess the severity of MOGAD relapse, and 3) assess recovery from / residual disability after relapse. The EDSS is used to assess recovery from / residual disability after relapse.

[0120] FSS / EDSS assessments will be performed by a Neurostatus-certified independent assessor (i.e., not the treating investigator). Whenever possible, the same assessor should perform participants' EDSS / FSS assessments throughout the study.

[0121] 4.1.3 Ophthalmological examination Ophthalmologic evaluation consisted of assessment of HCVA and LCVA, RAPD, and fundus examination to evaluate the appearance of the optic disc.

[0122] Ophthalmic evaluations will be performed by an independent assessor (i.e., not the treating investigator), e.g., an ophthalmologist, optometrist, or another site member with appropriate training and experience. Whenever possible, for each participant, all ophthalmic evaluations should be performed by the same independent assessor throughout the study.

[0123] 4.1.3.1 Assessment of relative afferent pupillary defect For the purposes of this test, RAPD is assessed by the swinging light test, a method that detects differences between the two eyes in how the pupils respond to a light that is shone on one eye at a time.

[0124] RAPD test is used to evaluate unilateral or asymmetric dysfunction of the optic nerve (optic neuropathy). The physiological basis of the test is the consonant pupillary light reflex, i.e., bright light applied to one eye results in equal constriction of both pupils. RAPD is present if the initial consonant pupillary constriction is greater than the initial direct pupillary constriction. RAPD results are reported as the presence or absence of RAPD in either eye.

[0125] 4.1.3.2 Fundus examination for evaluation of optic disc swelling An ophthalmoscopy is performed to assess for the presence of optic disc swelling.

[0126] 4.1.4 Magnetic resonance imaging Brain MRI (without Gd) is required primarily at screening to exclude participants with imaging features that are highly specific for MS.

[0127] 4.2 Pharmacokinetics Serum PK samples will be collected for measurement of serum concentrations of satralizumab.

[0128] If warranted and agreed between the investigator and sponsor, samples may be collected at additional time points during the study.

[0129] Instructions for collection and handling of biological samples will be provided by the sponsor. The actual date and time (24-hour clock) of each sample will be recorded.

[0130] Samples are used to evaluate the pharmacokinetics of satralizumab. Samples collected for analysis of satralizumab (serum) concentrations may also be used to evaluate safety or efficacy aspects related to concerns that arise during or after the study.

[0131] 4.3 Pharmacodynamics For information on PD biomarkers, see Section 4.4.

[0132] 4.4 Biomarker evaluation The following biomarker samples will be collected from participants at all sites, where applicable: -- Serum sample for screening eligibility (autoantibodies (MOG-IgG, AQP4-IgG)) -- Serum samples for measuring MOG-IgG titers over time -- Serum samples for measuring PD biomarkers (IL-6 and sIL-6R) -- Serum, plasma and blood samples for biomarker discovery studies.

[0133] Exploratory biomarker studies may include, but are not limited to: --Changes in immune cells or their receptors in the blood (including, but not limited to, CD19+ B cells and CD3+ T cells, and / or T cell receptors or B cell receptors, or other markers) --Changes in molecular biomarkers related to neuroinflammation in serum and / or plasma -- Changes in RNA in blood related to neuroinflammation, disease activity, or immune cell repertoire --Changes in serum autoantibody titers, including but not limited to MOG-IgG.

[0134] 4.5 Immunogenicity assessment Serum samples collected from all participants will be assessed for antibodies to satralizumab. Additionally, serum samples should be collected from participants who discontinue study treatment or drop out of the study at the final visit. These samples will be tested by the sponsor or its designee.

[0135] Serum samples are screened for antibodies that bind satralizumab and titers of confirmed positive samples are reported. Other analyses may be performed to demonstrate the stability of antibodies to satralizumab and / or to further characterize the immunogenicity of satralizumab.

[0136] Detection and characterization of antibodies to satralizumab will be performed by or under the sponsor's supervision through the use of validated assays.

[0137] All samples collected for detection of antibodies to study treatment will also be evaluated for satralizumab serum concentrations to allow interpretation of the antibody data. Antibodies may be further characterized and / or evaluated for their ability to neutralize the activity of the study treatment. To allow for further analysis of the immune response to satralizumab, samples may be stored at a facility selected by the sponsor for up to 5 years (or in accordance with local regulations) after the last study participant's final visit.

[0138] 4.6 Clinical outcome assessment Participant-reported outcome (PRO) documents will be completed to assess the treatment benefit or pharmacoeconomic evaluation of satralizumab as described in the document.

[0139] PRO data will be collected through the use of the following instruments: NEI VFQ-25, EQ-5D-5L, SF-36v2, and SF-MPQ-2.

[0140] 4.6.1 Data collection methods for clinical outcome assessment PRO documentation will be administered by interviewers at designated times during the study in the clinic. Whenever possible, documentation will be administered in the clinic prior to any other site activities, including safety assessments and other non-PRO assessments, blood draws, and administration of study treatment. Independent assessors should not administer PRO documentation.

[0141] PRO documentation will be translated into the local language as appropriate and completed through the use of an electronic device provided by the sponsor. The device will be pre-programmed to allow the appropriate documentation to be administered at each designated time. During the clinic visit, the PRO documentation should be administered as outlined below: -- The health status of the participant should not be discussed prior to executing the document. -- Sites must execute the official version of each document provided by the sponsor. Documents must not be copied from the protocol. -- Facilities should allow participants adequate time to complete documentation, estimated at 30-40 minutes at each assigned visit. -- Documentation should be completed in a quiet area where distractions and interruptions are minimal. --Participants should be instructed to answer the questions to the best of their ability; there are no right or wrong answers. -- Facility staff should not interpret or explain the questions, but may read the questions verbatim upon request. -- Participants should not obtain advice or assistance from others (e.g., family or friends) in completing the document.

[0142] 4.6.2 Description of clinical outcome measures 4.6.2.1 National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) The NEI VFQ-25 captures participants' perceptions of vision-related function and vision-related quality of life. The core scale includes 25 items with 11 vision-related subscales and one item on general health (Mangione, et al. 2001). Composite and subscale scores range from 0 to 100, with higher scores indicating better vision-related function. Subscale scores include general vision, eye pain, near activity, distance activity, social activity, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. The NEI VFQ-25 was validated in optic neuritis through the Optic Neuritis Treatment Trial (Cole et al. 2000). The NEI VFQ-25 takes approximately 10 minutes on average to administer in an interviewer format. Interviewer-administered forms of the NEI VFQ-25 are available from the National Eye Institute (NEI), e.g., version 2000 is available online at https: / / www.nei.nih.gov / sites / default / files / 2019-06 / vfq_ia.pdf.

[0143] 4.6.2.2 EuroQol EQ-5D-5L The EQ-5D-5L is a validated self-report health status questionnaire used to calculate health status utility scores for use in health economic analyses (EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013). The EQ-5D-5L has two components: a five-item health status profile assessing mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, and a visual analog scale (VAS) to measure health status. The EQ-5D-5L is designed to capture the participant's current health status. A published weighting system allows for the creation of a single composite score of the participant's health status. The EQ-5D-5L takes approximately 3 minutes to complete. It is used in this study to inform the pharmacoeconomic evaluation. User guides for the EQ-5D-5L are available from the EuroQol Group, e.g., version 3.0 is available online at https: / / euroqol.org / wp-content / uploads / 2021 / 01 / EQ-5D-5LUserguide-08-0421.pdf.

[0144] 4.6.2.3 SF-36v2 Health Survey (SF-36v2) The SF-36v2 is a patient-reported outcome measure that assesses participants' health-related quality of life (QoL) (Ware and Sherbourne 1992). This 36-item questionnaire consists of eight domains: physical functioning (10 items), role functioning (physical) (4 items), bodily pain (2 items), general health (5 items), vitality (4 items), social functioning (2 items), role functioning (mental) (3 items), and mental health (5 items), as well as an additional item on reported health transitions. The SF-36v2 has a 1-week recall specification and items are rated on a 3-, 5-, and 6-point Likert scale. Higher scores indicate better health. The SF-36v2 takes approximately 10 minutes to complete. The SF-36v2 is provided by QualityMetric Incorporated.

[0145] 4.6.2.4 Short McGill Pain Questionnaire (SF-MPQ-2) The Short McGill Pain Questionnaire (SF-MPQ-2) is a 22-item PRO scale developed in English (US) by R. Melzack and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide a comprehensive measure of pain symptoms for both neuropathic and non-neuropathic pain conditions (Dworkin et al. 2009). Areas covered in the measure include continuous pain (6 items), intermittent pain (6 items), neuropathic pain (6 items), and emotion descriptors (4 items). The recall period is "during the past week" and each item has response options from 0 to 10, with "none" (next to 0) serving as one anchor and "worst" (next to 10) serving as the other anchor. It can be scored with a global score, scored by domain score, or scored by item. Lower scores correspond to less pain and higher scores correspond to more intense pain. This measurement takes approximately 10-15 minutes to complete.

[0146] 5. Statistical considerations 5.1 Statistical hypotheses This study will compare the efficacy of satralizumab (60 mg, 120 mg, or 180 mg for participants weighing 20 to <40 kg, 40 to 100 kg, or >100 kg, respectively) to placebo in patients with MOGAD. Both satralizumab and placebo may be administered in addition to baseline / background therapy (see section 1.1).

[0147] The primary endpoint was time to first adjudicated recurrence (TFR) during DB.

[0148] Adjudicated times to recurrence and associated hazard ratios (HRs) between the satralizumab and placebo groups will be tested at a two-sided significance level of α=0.05.

[0149] The primary and secondary endpoints will be tested in a hierarchical order to control the study-wide type I error rate at the 5% significance level.

[0150] The following primary hypotheses will be tested for superiority of satralizumab over placebo at a two-sided level of α=0.05 using a two-sided log-rank test: TIFF2024543147000004.tif4170, where S サトラリズマブ and S プラセボ Refer to the survival functions within satralizumab-treated and placebo-treated participants, respectively. The Kaplan-Meier method is used to estimate survival functions and TFR distributions for each treatment group. A visual illustration of the differences between treatment groups is provided in the Kaplan-Meier curves.

[0151] The primary analysis will be based on all randomized participants unless dose adjustment is required. In case of dose adjustment, only participants randomized to the adjusted dose will be included in the primary analysis. For all efficacy analyses, participants will be analyzed as randomized (intention to treat principle). For safety analyses, all enrolled participants who received at least one dose of study treatment will be included.

[0152] 5.2 Determining sample size Approximately 152 participants will be randomly assigned to study treatment.

[0153] The objective of this study is to estimate the effect of satralizumab on TFR during DB treatment compared with placebo treatment. Point and interval estimates of the underlying true HR will be obtained.

[0154] The sample size of this study was determined to be consistent with the primary estimand.

[0155] Randomization will be stratified by: -- Simultaneous IST -- region.

[0156] 5.3 Statistical analysis The Statistical Analysis Plan (SAP) will be finalized prior to database lock for the primary analysis and will contain a more technical and detailed description of the statistical analyses described in this section. This section outlines the planned statistical analyses of the most important endpoints, including the primary and key secondary endpoints.

[0157] 5.3.1 General considerations All analyses and CIs will be performed at a two-sided significance level of 5%. Most analyses will be performed on the DB treatment period and the total Satra treatment period, which is the period from the first dose of satralizumab to the end of the study. For most efficacy analyses, missing data, unless defined differently, will be imputed using reference-based multiple imputation methods. Further details on imputation methods are provided in the SAP.

[0158] 5.3.2 Primary endpoint The primary endpoint is the time from randomization to the first occurrence of MOGAD relapse during the DB treatment period, as determined by a Clinical Evaluation Committee (CEC). Point and interval estimates of the underlying true HR will be obtained. An estimand framework was used to aid in the design of this study (ICH Working Group 2019).

[0159] In addition, estimates of treatment effect are expressed as HR and 95% CI using stratified Cox proportional hazards models. If the survival function is the same between both treatment groups, the estimated HR is 1 and not equal to 1 otherwise.

[0160] In this study, the median TFR is not expected to be reached at the time of the primary analysis; therefore, the distribution of TFR will be described using HR plus recurrence-free rate and its 95% CI every 6 months.

[0161] The elements of the primary estimand are defined below. The primary analysis approach and sample size determination will be consistent with this estimand.

[0162] If a participant drops out of treatment, the reason for dropout will be classified as either related to the study drug or condition (SDCR) or not related to the study drug or condition (NSDCR). More details on this classification will be described in the SAP. The primary comparison will include all participants regardless of reason for dropout, with the assumption that participants who drop out due to NSDCR reasons would have continued to receive their randomized treatment if they had remained in the study.

[0163] Group Participants with MOGAD, as defined by the study inclusion and exclusion criteria (see sections 2.1 and 2.2) Primary efficacy variables : Determined recurrence treatment Satralizumab vs. matching placebo

[0164] Concomitant events : --Treatment with salvage therapy for reported episodes that are not adjudicated recurrences: treatment strategy -- Treatment with salvage therapy before assessing criteria for adjudicated recurrence (BCVA, FSS / EDSS, MRI, or other): Treatment strategy -- Dropouts from study treatment: - SDCR withdrawal from study treatment: Treatment strategy, data from SFU will be used if available - NSDCR dropout from study treatment: Hypothetical, patients are censored at dropout -- Treatment interruption: treatment policy

[0165] Aggregation Scale : TFR during DB treatment (Kaplan-Meier estimates, HR, and 95% CI for treatment comparisons based on Cox proportional hazards models and log-rank tests [p-values]).

[0166] TFR is defined as the time from randomization to the first occurrence of adjudicated relapse during the DB period. Patients who do not experience a relapse are censored at the date of CCOD in the primary analysis or at the time of dropout if dropout is due to NSDCR. For patients who dropout due to SDCR, all observed data from the DB period or from SFU after dropout are considered in the analysis. If these patients also dropout from the study, missing data will be imputed by reference-based multiple imputation methods.

[0167] In addition, subgroup analyses (i.e., by region; by country for China, Japan, and the United States; by baseline / background therapy group) and analyses of supplementary endpoints incorporating various approaches for comorbid events will be performed. In particular, various estimand approaches, such as composite estimand and hypothetical estimand, will be applied to comorbid events related to salvage therapy. These analyses will be performed as supplementary analyses to the primary analysis.

[0168] Further details are provided by SAP.

[0169] 5.3.3 Secondary endpoints 5.3.3.1 Key Secondary Efficacy Endpoints The key secondary efficacy endpoints will be tested in the following hierarchical order to control for a type I error of 0.05: -- Annualized rate of adjudicated MOGAD recurrence -- Annualized rate of active lesions on neuraxis MRI -- Percentage of participants receiving rescue therapy --Annual rates of hospitalizations (defined as longer than an overnight stay, excluding those for selection procedures).

[0170] The following endpoints are primary secondary endpoints and will be described in the estimand attribute. All secondary endpoints will be evaluated during the DB treatment period.

[0171] Annualized rate of adjudicated MOGAD relapse during double-blind treatment period Group Participants with MOGAD, as defined by the study inclusion and exclusion criteria (see Sections 2.1 and 2.2) Key secondary efficacy variables : Annualized recurrence rate (ARR) during DB treatment treatment Satralizumab vs. matching placebo

[0172] Concomitant events : --Treatment with salvage therapy for reported episodes that are not adjudicated recurrences: treatment strategy -- Treatment with salvage therapy before assessing criteria for adjudicated recurrence (BCVA, FSS / EDSS, MRI, or other): Treatment strategy -- Dropouts from study treatment: - SDCR Dropout from Study Treatment: Treatment Strategy - NSDCR Dropout from Study Treatment: Hypothetical -- Treatment interruption: treatment policy

[0173] Aggregation Scale : Adjusted annual relapse rates in each treatment group are compared via rate ratios estimated using a negative binomial model adjusted for stratification factors. Log-transformed censoring or time to event is included as an offset variable in the analysis model. The same censoring rules as for the primary estimand are applied. Missing data due to study dropout are handled in the following manner: if a participant drops out of the study due to lack of efficacy and did not have a relapse before dropout, the relapse is imputed. If a participant drops out of the study for other reasons, no data are imputed. In both cases, observations up to the date of dropout are included in the analysis.

[0174] Annualized rate of active lesions on neuraxis MRI Group Participants with MOGAD, as defined by the study inclusion and exclusion criteria (see Sections 2.1 and 2.2) Key secondary efficacy variables: Annualized rate of active lesions on MRI of the neuraxis. Median readings are used to identify these lesions. treatment Satralizumab vs. matching placebo

[0175] Proportion of Participants Receiving Rescue Therapy During the Double-Blind Treatment Period Group Participants with MOGAD, as defined by the study inclusion and exclusion criteria (see Sections 2.1 and 2.2) Key secondary efficacy variables : Proportion of participants receiving rescue therapy during DB treatment treatment Satralizumab vs. matching placebo

[0176] Concomitant events : -- Treatment with salvage therapy: The composite was used because the use of salvage therapy was included as an endpoint. -- Dropouts from study treatment: - SDCR Dropout from Study Treatment: Treatment Strategy - NSDCR Dropout from Study Treatment: Hypothetical -- Treatment interruption: treatment policy

[0177] Aggregation Scale : The proportion of participants receiving salvage therapy is based on the number of participants who received salvage therapy for episodes with adjudicated MOGAD recurrence. Every participant is counted once in this analysis. If a participant received salvage therapy at least once, the participant is considered a responder in this analysis. Proportions between treatment groups and associated odds ratios are estimated using logistic regression models adjusted for stratification factors.

[0178] Annualized rate of hospitalizations, defined as stays longer than one night, excluding those for selection procedures Group Participants with MOGAD, as defined by the study inclusion and exclusion criteria (see Sections 2.1 and 2.2) Key secondary efficacy variables: Annualized rate of hospitalizations (defined as longer than an overnight stay, excluding those for selection procedures) treatment Satralizumab vs. matching placebo

[0179] Concomitant events : --Treatment of defined relapses with salvage therapy within 4 days of symptom onset can prevent severe disability requiring inpatient management (Stiebel-Kalish et al. 2019): treatment strategy. In addition, the timing between symptom onset and rescue medication will be investigated. -- Dropouts from study treatment: - SDCR Dropout from Study Treatment: Treatment Strategy - NSDCR Dropout from Study Treatment: Hypothetical -- Treatment interruption: treatment policy

[0180] Aggregation Scale : Annualized rates of hospitalization in each treatment group are compared via rate ratios estimated using negative binomial models adjusted for stratification factors. Log-transformed censoring or time to event is included as an offset variable in the analysis model. All hospitalizations longer than an overnight stay and not due to selection procedures are counted as hospitalizations in this analysis.

[0181] 5.3.3.2 Supplementary Secondary Endpoints A supplementary secondary efficacy outcome measure was the proportion of participants free of relapse at 6-month intervals. These proportions and corresponding 95% CIs were based on Kaplan-Meier curves estimated for TFR for adjudicated relapse (primary outcome measure). Concomitant events were treated as defined for the primary outcome measure.

[0182] Further details will be provided by SAP.

[0183] 5.3.3.3 Secondary Safety Endpoints Safety will be assessed through a summary of exposure to study treatment, adverse events, changes from baseline in targeted clinical laboratory test results, targeted vital signs, weight, height (adolescents only), ECG, and suicidality (based on C-SSRS). Due to potentially different lengths of observation in the treatment arms, all adverse event analyses will be performed as rates and proportions per 100 patient-years (100 PY).

[0184] Study treatment exposure (including treatment duration, total dose received, and number of cycles and dose modifications, total patient-years of exposure) will be summarized with descriptive statistics.

[0185] All verbatim adverse event terms will be matched to MedDRA thesaurus terms and the severity of the adverse events will be graded according to NCI CTCAE v5.0. All adverse events, serious adverse events, adverse events resulting in death, adverse events of special interest, and adverse events resulting in discontinuation of study treatment that occurred at or after the first dose of study treatment (i.e., treatment-emergent adverse events) will be summarized by matched term, appropriate thesaurus level, and severity grade. For events of different severity, the highest grade will be used in the summary. Deaths and causes of death will be summarized.

[0186] Relevant laboratory, vital signs (pulse rate, respiratory rate, blood pressure, pulse oximetry, and temperature), weight, and ECG data will be displayed by time and graded where appropriate. Additionally, baseline and maximum post-baseline severity grades will be summarized using shift tables of selected laboratory tests. Changes in vital signs, weight, and ECG will be summarized.

[0187] Further details will be provided by SAP.

[0188] 5.3.4 Other Analyses 5.3.4.1 Pharmacokinetic Analysis The PK analysis population consists of all participants in the safety analysis set with at least one valid post-dose concentration result with dosing records and sampling times. The study will evaluate the PK properties of satralizumab treatment by summary statistics and nonlinear mixed-effects analysis (popPK).

[0189] Both satralizumab concentration data and the results of the popPK analysis will be reported separately from the CSR.

[0190] 5.3.4.2 Immunogenicity analysis The immunogenicity analysis population will consist of all participants with at least one ADA assessment. Participants will be grouped according to treatment received or, if they had not received any treatment prior to study discontinuation, according to treatment assigned.

[0191] The number and percentage of ADA-positive and ADA-negative participants at baseline (baseline prevalence) and after drug administration (post-baseline incidence) are summarized by treatment group. When determining post-baseline incidence, participants are considered ADA-positive if they show a treatment-induced or treatment-enhanced ADA response. Participants who are ADA-negative or have missing data at baseline, but develop an ADA response after exposure to study drug, have a treatment-induced ADA response. Participants who are ADA-positive at baseline and have one or more post-baseline sample titers at least 4-fold (0.60 titer units) higher than the titer of the baseline sample have a treatment-enhanced ADA response. Participants are considered to be any ADA-negative if they are ADA-negative or have missing data at baseline and all post-baseline samples are negative, or if they are ADA-positive at baseline but do not have any post-baseline samples with titers at least 4-fold (0.60 titer units) higher than the titer of the baseline sample (not affected by treatment).

[0192] The percentage of participants with positive or negative ADA results for satralizumab are summarized in the Table. PK, PD, efficacy parameters, and safety are summarized by anti-satralizumab antibody (i.e., satralizumab ADA) status.

[0193] 5.3.4.3 Pharmacodynamic analysis Serum IL-6 and sIL-6R levels will be summarized graphically and descriptively by treatment group and time point, as appropriate.

[0194] 5.4 Interim Analysis 5.4.1 Planned Interim Pharmacokinetic Analyses An interim PK analysis will be performed during the DB treatment period. The purpose of the interim analysis is to confirm that the achieved exposure (and predicted RO) for satralizumab is within the expected target range. If the achieved exposure (and predicted RO) is not within the expected target range, the dose may be increased to 120 mg, 180 mg, and 240 mg for participants 20-<40 kg, 40-<100 kg (inclusive), and >100 kg, respectively. The dosing regimen selected is associated with an exposure that does not significantly exceed the existing exposure-safety range.

[0195] The iDMC will make a recommendation as to whether 1) the trial can continue at the initial dose, 2) dose should be adapted to a pre-specified higher dose, or 3) further enrollment in the trial should be halted until further consideration.

[0196] 5.4.2 Optional Interim Analyses To accommodate information that may become evident during the course of the study, the sponsor may choose to perform one interim efficacy analysis. This interim analysis may be performed, for example, after results from clinical trials of competing molecules become available. The following are appropriate specifications to ensure that the study continues to meet the highest standards of integrity when any interim analysis is performed:

[0197] If interim analyses are performed, the sponsor will remain blinded. Interim analyses will be performed by an external statistical group and reviewed by the iDMC. Dialogue between the iDMC and the sponsor will be conducted as specified in the iDMC Charter.

[0198] The decision to conduct any interim analysis will be documented in the SAP along with the rationale, timing, and statistical details of the analysis, and the SAP will be submitted to the relevant health authorities at least two months prior to conducting the interim analysis. The iDMC Charter will be updated to document any potential recommendations the iDMC may make to the sponsor as a result of the analysis (e.g., stopping the study due to futility), and the iDMC Charter will also be made available to the relevant health authorities. The study will not be stopped due to positive efficacy as a result of an interim analysis.

[0199] When a trial may be stopped for futility as a result of an interim analysis, the threshold for denoting futility includes an assessment of the predicted probability that a specified endpoint will achieve statistical significance. Additional criteria for recommending that a trial be stopped for futility may be added to the iDMC charter. Interim analyses that may result in stopping a trial for futility will not be performed before at least 50% of the information (i.e., 50% of participants) has been accumulated. [Industrial Applicability]

[0200] The present invention provides a means for treating a demyelinating disease of the central nervous system (CNS) characterized by the presence of an anti-myelin oligodendrocyte glycoprotein (MOG) antibody, comprising an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, and also for reducing the risk of recurrence of the demyelinating disease. The present invention also provides a pharmaceutical product or pharmaceutical composition for treating said demyelinating disease or reducing the risk of recurrence by administering an anti-IL-6 receptor antibody or an antigen-binding fragment thereof to a subject in need thereof. The present invention further provides a method for treating said demyelinating disease or reducing the risk of recurrence by administering an anti-IL-6 receptor antibody or an antigen-binding fragment thereof to a subject in need thereof.

[0201] References Akaishi T, Misu T, Takahashi T, et al. Progression pattern of neurological disability with respect to clinical attacks in anti-MOG antibody-associated disorders. J Neuroimmunol. 2021;351:577467. Baumann M, Grams A, Djurdjevic T, et al. MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein. Journal of Neurology 2018;265:845-855. Brooks R. EuroQol: the current state of play. Health Policy 1996;37:53-72. Bruijstens AL, Lechner C, Flet-Berliac L, et al. E.U. paediatric MOG consortium consensus: Part 1 - Classification of clinical phenotypes of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders. Eur J Paediatr Neurol. 2020a;29:2-13. Bruijstens AL, Breu M, Wendel E-M, et al. E.U. paediatric MOG consortium consensus: Part 4 - Outcome of paediatric myelin oligodendrocyte glycoprotein antibody- associated disorders. Eur J Paediatr Neurol 2020b;29:32-40. Bruijstens AL, Wendel EM, Lechner C, et al. E.U. paediatric MOG consortium consensus: Part 5 - Treatment of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders. Eur J Paediatr Neurol. 2020c;29:41-53. Burnham JA, Wright RR, Dreisbach J, Murray RS. The effect of high-dose steroids on MRI gadolinium enhancement in acute demyelinating lesions. Neurology. 1991;41(9):1349-54. Chen JJ, Flanagan EP, Bhatti MT, et al. Steroid-sparing maintenance immunotherapy for MOG-IgG associated disorder. Neurology. 2020;95(2):e111-e120. Chen JJ and Bhatti MT. Clinical phenotype, radiological features, and treatment of myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) optic neuritis. Curr Opin Neurol. 2020;33(1):47-54. Cobo-Calvo A, Ruiz A, Rollot F, et al. Clinical Features and Risk of Relapse in Children and Adults with Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease. Ann Neurol. 2021;89(1):30-41. Cole SR, Beck RW, Moke PS, et al. The National Eye Institute Visual Function Questionnaire: experience of the ONTT. Optic Neuritis Treatment Trial. Invest Ophthalmol Vis Sci. 2000;41(5):1017-1021. Durozard P, Rico A, Boutiere C, et al. Comparison of the Response to Rituximab between Myelin Oligodendrocyte Glycoprotein and Aquaporin-4 Antibody Diseases. Ann Neurol. 2020;87(2):256-266. Dworkin RH, Turk DC, Revicki DA, et al. Development and initial validation of an expanded and revised version of the Short-form McGill Pain Questionnaire (SF- MPQ-2). Pain. 2009;144(1-2):35-42 EuroQol Group. EuroQol: a new facility for the measurement of health-related quality of life. Health Policy 1990;16:199-208. Galetta SL, Villoslada P, Levin N, et al. Acute optic neuritis: Unmet clinical needs and model for new therapies. Neurol Neuroimmunol Neuroinflamm. 2015;2(4):e135. Hacohen Y, Wong YY, Lechner C, et al. Disease Course and Treatment Responses in Children With Relapsing Myelin Oligodendrocyte Glycoprotein Antibody- Associated Disease. JAMA Neurol. 2018;75(4):478-487. Hegen H, Reindl M. Recent developments in MOG-IgG associated neurological disorders. Ther Adv Neurol Disord. 2020;13:1756286420945135. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:1727-36. Hofer LS, Mariotto S, Wurth S, et al. Distinct serum and cerebrospinal fluid cytokine and chemokine profiles in autoantibody-associated demyelinating diseases. Mult Scler J Exp Transl Clin. 2019;5(2):2055217319848463. Hyun JW, Woodhall MR, Kim SH, et al. Longitudinal analysis of myelin oligodendrocyte glycoprotein antibodies in CNS inflammatory diseases. J Neurol Neurosurg Psychiatry. 2017;88(10):811-817. ICH Working Group. E9(R1) Addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clincial trials. 2019. Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life Res 2013;22:1717-27. Jarius S, Ruprecht K, Kleiter I, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflammation. 2016;13(1):280. Kantarci OH, Zeydan B, Atkinson EJ, et al. Relapse recovery: The forgotten variable in multiple sclerosis clinical trials. Neurol Neuroimmunol Neuroinflamm. 2019;7(2):e653. Lopez-Chiriboga AS, Majed M, Fryer J, et al. Association of MOG-IgG Serostatus With Relapse After Acute Disseminated Encephalomyelitis and Proposed Diagnostic Criteria for MOG-IgG-Associated Disorders. JAMA Neurol. 2018 Nov 1;75(11):1355-1363. Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD; National Eye Institute Visual Function Questionnaire Field Test Investigators. Development of the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol. 2001;119(7):1050-8. Pohl D, Alper G, Van Haren K, et al. Acute disseminated encephalomyelitis: Updates on an inflammatory CNS syndrome. Neurology. 2016;87(9 Suppl 2):S38-45. Ramanathan S, Mohammad S, Tantsis E, et al. Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination. J Neurol Neurosurg Psychiatry. 2018;89(2):127-137. Reindl M, Waters P. Myelin oligodendrocyte glycoprotein antibodies in neurological disease. Nat Rev Neurol. 2019;15(2):89-102. Salama S, Pardo S, Levy M. Clinical characteristics of myelin oligodendrocyte glycoprotein antibody neuromyelitis optica spectrum disorder. Mult Scler Relat Disord. 2019;30:231-235. Spadaro M, Winklmeier S, Beltran E, et al. Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein. Ann Neurol. 2018;84(2):315-328. Stiebel-Kalish H, Hellmann MA, Mimouni M, et al. Does time equal vision in the acute treatment of a cohort of AQP4 and MOG optic neuritis? Neurol Neuroimmunol Neuroinflamm. 2019;6(4):e572. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30(6):473-83. PMID: 1593914. Whittam DH, Karthikeayan V, Gibbons E, et al. Treatment of MOG antibody associated disorders: results of an international survey. J Neurol. 2020a;267(12):3565-3577. Whittam DH, Cobo-Calvo A, Lopez-Chiriboga AS, et al. Treatment of MOG-IgG- associated disorder with rituximab: An international study of 121 patients. Mult Scler Relat Disord. 2020b;44:102251. Wildemann B, Jarius S, Schwarz A, et al. Failure of alemtuzumab therapy to control MOG encephalomyelitis. Neurology. 2017;89(2):207-209. Wynford-Thomas R, Jacob A, et al. Neurological update: MOG antibody disease. J Neurol. 2019;266(5):1280-1286.

Claims

1. A pharmaceutical for treating myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) in a subject who is anti-MOG antibody-positive, comprising an anti-IL-6 receptor antibody or its antigen-binding fragment, the antibody comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:

10.

2. The pharmaceutical product according to claim 1, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO:

2.

3. The pharmaceutical product according to claim 1, wherein the anti-IL-6 receptor antibody is an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain comprising the amino acid sequence of SEQ ID NO:

4.

4. The pharmaceutical product according to claim 1, wherein the anti-IL-6 receptor antibody is satralizumab.

5. 5. The pharmaceutical product of any one of claims 1 to 4 for delaying relapse of MOGAD, reducing the frequency of relapse, reducing the severity of relapse, or reducing the risk of relapse in patients with MOGAD.

6. 5. The pharmaceutical product of any one of claims 1-4, wherein MOGAD is characterized by (i) seropositivity for MOG-IgG by a cell-based assay; and (ii) two or more attacks of one or more of the following: optic neuritis (ON), transverse myelitis (TM), acute disseminated encephalomyelitis (ADEM), brainstem encephalitis, cortical encephalitis, demyelinating brainstem syndrome, demyelinating cerebellar syndrome, and demyelinating cerebral syndrome.

7. The pharmaceutical product according to any one of claims 1 to 4, wherein the subject is anti-aquaporin-4 (AQP4) antibody negative.

8. The pharmaceutical product according to any one of claims 1 to 4, wherein the pharmaceutical product is used so that 60 mg or 120 mg, 120 mg or 180 mg, and 180 mg or 240 mg of the anti-IL-6 receptor antibody or antigen-binding fragment thereof are administered to a subject weighing less than 40 kg, 40 to 100 kg, and more than 100 kg, respectively.

9. The pharmaceutical product according to any one of claims 1 to 4, wherein the pharmaceutical product is used so that the anti-IL-6 receptor antibody or its antigen-binding fragment is administered subcutaneously to the subject.

10. The pharmaceutical product according to any one of claims 1 to 4, wherein the pharmaceutical product is used so that the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered to a subject three times at two-week intervals (Q2W) and then four weeks at four-week intervals (Q4W).

11. The pharmaceutical product according to any one of claims 1 to 4, characterized in that the pharmaceutical product is used in combination with immunosuppressive therapy (IST).

12. 12. The pharmaceutical product of claim 11, wherein the IST is a treatment with one or more of an immunosuppressant selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and oral corticosteroids (OCS).

13. 13. The pharmaceutical product of claim 12, wherein the immunosuppressant comprises prednisone or prednisolone.

14. A subcutaneous administration device containing a fixed dose of 60 mg satralizumab in a pharmaceutically acceptable excipient.

15. A subcutaneous administration device containing a fixed dose of 180 mg satralizumab in a pharmaceutically acceptable excipient.

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