Use of anti-CD19 antibodies to treat autoimmune diseases

Abstract

Disclosed herein are methods for treating autoimmune diseases using anti-CD19 antibodies, specifically the treatment of neuromyelitis optica spectrum disorder using VIB551, an affinity-optimized, humanized, defucosylated IgG1κ monoclonal antibody. TIFF2022529743000026.tif137153

Description

[Background technology]

[0001] Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune inflammatory central nervous system disease with a prevalence of 0.5-4.4 cases per 100,000 people. 1 In NMOSD, optic neuritis and transverse myelitis 1 and, less frequently, diencephalic, brainstem, and hemispheric seizures. Recovery from seizures is usually incomplete, and patients are at risk of death from respiratory failure. 2 .

[0002] NMOSD was once thought to be a variant of multiple sclerosis but is now recognized as a separate disease. 2 , characterized by astroglial injury, demyelination, and severe neuronal loss; most injury occurs during acute attacks 3 60-80% of patients have astrocyte water channel aquaporin-4 (AQP4)-immunoglobulin G (IgG) 4 Highly specific serum autoantibodies against 5~7 In the presence of complement or inflammatory T cell responses, AQP4-IgG induces disease-specific central nervous system injury. 5 Multiple lines of evidence suggest that NMOSD is primarily a B-cell-mediated disorder driven by pathological autoantibody production, proinflammatory cytokine secretion, and B-cell antigen presentation. 8 .

[0003] Currently, there are no approved treatments for NMOSD, and randomized controlled trials have only recently begun. Immunosuppressant and B-cell depleting drugs, such as rituximab, 9 , azathioprine 9 , corticosteroid drugs 9 , and mycophenolate mofetil 9 These drugs, including steroids, are only being used experimentally to prevent seizures.

[0004] There is a clear, unmet need for effective, evidence-based treatments to delay or prevent attacks in NMOSD. 12 .

[0005] VIB551 is an affinity-optimized, humanized, defucosylated IgG1κ monoclonal antibody that binds to the B cell surface antigen CD19. In contrast to anti-CD20 monoclonal antibodies, which recognize and deplete a subset of CD20-expressing T lymphocytes (in addition to B lymphocytes), 13 , anti-CD19 antibodies recognize and deplete only lymphocytes of the B cell lineage.

[0006] Now, in the N-MOmentum clinical trial, VIB551 has been found to be an effective B-cell-depleting monotherapy for preventing relapse and disability in NMOSD. VIB551 has been shown to be superior to placebo in reducing a) the risk of NMOSD attacks, b) the risk of worsening disability, c) MRI lesion activity, and d) disease-related hospitalizations in a globally representative population of NMOSD patients recruited at 99 centers in 24 countries. Summary of the Invention

[0007] Provided herein is a method for treating NMOSD. The method includes administering VIB551 to a patient in need thereof, and treating the NMOSD. VIB551 is administered intravenously at a dose of 300 mg every 6 months or every 26 weeks.

[0008] Also provided herein is a method for reducing active magnetic resonance imaging (MRI) lesions in a patient diagnosed with NMOSD. The method includes administering VIB551 to a patient in need of treatment for NMOSD, and reducing the MRI lesions in the patient. VIB551 is administered intravenously at a dose of 300 mg every 6 months or every 26 weeks.

[0009] The present disclosure further provides a method for treating NMOSD with AQP4-IgG. +A method for reducing AQP4-IgG titers in a patient is provided. The method includes administering VIB551 to a patient in need of treatment for NMOSD, and reducing the patient's AQP4-IgG titer. VIB551 is administered intravenously at a dose of 300 mg every 6 months or every 26 weeks.

[0010] Provided herein is an additional method of treating a patient diagnosed with NMOSD, comprising administering VIB551 to a patient in need of treatment for NMOSD and treating the NMOSD. VIB551 is (i) depleting at least 90% of circulating CD20+ B cells for at least 6 months; and (ii) not increase the patient's risk of infection The dose is administered.

[0011] Further provided herein is a method for reducing disability in a patient diagnosed with NMOSD, comprising administering VIB551 to a patient in need of treatment for NMOSD and reducing the patient's disability. VIB551 is administered intravenously at a dose of 300 mg every 6 months or every 26 weeks.

[0012] Further provided herein is a method for reducing NMOSD-associated seizures in a patient in need of treatment for NMOSD, comprising administering VIB551 to a patient in need of treatment for NMOSD and reducing NMOSD-associated seizures in the patient. VIB551 is administered intravenously at a dose of 300 mg every 6 months or every 26 weeks.

[0013] The present disclosure further provides a method for monitoring the progression of NMOSD in a patient diagnosed with NMOSD, the method comprising determining first and second MRI lesion counts for the patient. The patient's NMOSD is identified as progressive if the second MRI lesion count exceeds the first MRI lesion count. The patient's NMOSD is identified as non-progressive if the second MRI lesion count does not exceed the first MRI lesion count.

[0014] Additionally provided herein are methods for identifying a test agent suitable for treating NMOSD in a patient diagnosed with NMOSD. A first MRI lesion count is determined in the patient at least one month prior to treatment with the test agent. A second MRI lesion count is determined in the patient 3 to 24 months after treatment with the test agent. The test agent is identified as suitable for treating NMOSD if the second MRI lesion count is equal to or less than the first MRI lesion count. The test agent is identified as not suitable for treating NMOSD if the second MRI lesion count exceeds the first MRI lesion count. [The present invention 1001] Methods of treating neuromyelitis optica spectrum disorder (NMOSD), including: administering VIB551 to a patient in need of treatment for NMOSD, wherein said VIB551 is administered intravenously at a dose of 300 mg every six months; and Treating said NMOSD. [The present invention 1002] 1002. The method of claim 1001, wherein said treating is a reduction in the worsening of the Kurtzke Expanded Disability Status Scale (EDSS) in said patient. [The present invention 1003] said reducing EDSS worsening in said patient a worsening of EDSS score of less than 2 points when the patient's baseline score is 0; a worsening of less than 1 point if the patient has a baseline score of 1 to 5; or A worsening of less than 0.5 points if the patient has a baseline score of 5.5 or greater The method of the present invention 1002. [The present invention 1004] 1001. The method of claim 1001, wherein said treatment is a reduction in the number of active magnetic resonance imaging (MRI) lesions. [The present invention 1005] 1005. The method of claim 1004, wherein said active MRI lesion is an enlarging T2 MRI lesion. [The present invention 1006] 1001. The method of claim 1001, wherein said treatment is a reduction in the number of new MRI lesions. [The present invention 1007] 1001. The method of claim 1001, wherein said treatment is a reduction in the deterioration of the modified Rankin score in said patient. [The present invention 1008] 1001. The method of claim 1001, wherein said treatment is a reduction in the frequency of hospitalization of said patient associated with NMOSD. [The present invention 1009] 1001. The method of claim 1001, wherein said treatment is a reduction in said patient's risk of NMOSD-associated seizures. [The present invention 1010] 1009. The method of claim 1009, wherein said NMOSD-associated seizure is characterized by the appearance of a new symptom associated with NMOSD or a worsening of an existing symptom associated with NMOSD. [The present invention 1011] The method of claim 1010, wherein the condition is an ocular condition. [The present invention 1012] The method of claim 1011, wherein said ocular symptom is eye pain, blurred vision, loss of vision, or the appearance of optic nerve lesions detected by MRI. [The present invention 1013] The method of claim 1010, wherein the condition is a spinal condition. [The present invention 1014] 1013. The method of claim 1013, wherein said spinal symptom is deep or radicular pain, paresthesias in the limbs, weakness, sphincter dysfunction, Lhermitte's sign, or a spinal lesion detectable by MRI. [The present invention 1015] The method of claim 1010, wherein the symptom is a brain or brainstem symptom. [The present invention 1016] 1015. The method of claim 1015, wherein said brain or brainstem symptom is nausea, diplopia, oculomotor palsy, dizziness, intractable vomiting, intractable hiccups, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, or a brain or brainstem lesion detectable by MRI. [The present invention 1017] 1009. The method of claim 10, wherein said reduction in risk of NMOSD-associated seizures is 60-85%. [The present invention 1018] 1017. The method of claim 1017, wherein said reduction in risk of NMOSD-associated seizures is 65-75%. [The present invention 1019] 1018. The method of claim 1018, wherein said reduction in risk of NMOSD-associated seizures is 70%. [The present invention 1020] 1017. The method of claim 1017, wherein said reduction in risk of NMOSD-associated seizures is 80%. [The present invention 1021] 1009. The method of claim 1009, wherein said reduction in risk of NMOSD-associated seizures is greater than a 75% chance that said patient will be seizure-free within at least 6 months after said administration. [The present invention 1022] 1021. The method of claim 1021, wherein said reduction in risk of NMOSD-associated seizures is greater than an 80% probability that said patient will be seizure-free within at least 6 months after said administration. [The present invention 1023] 1023. The method of claim 1022, wherein said reduction in risk of NMOSD-associated seizures is greater than an 85% chance that said patient will be seizure-free within at least 6 months after said administration. [The present invention 1024] 1009. The method of claim 1009, wherein said reducing the risk of NMOSD-associated seizures is reducing the annualized risk of NMOSD-associated seizures in said patient to between 0.18 and 0.07. [The present invention 1025] 1025. The method of claim 1024, wherein said reducing the risk of NMOSD-associated seizures is reducing the annualized risk of NMOSD-associated seizures in said patient to between 0.15 and 0.08. [The present invention 1026] 1025. The method of claim 1025, wherein said patient is AQP4-IgG seropositive and said reduction in annualized risk of NMOSD-associated seizures is 0.15 to 0.11. [The present invention 1027] 1025. The method of claim 1024, wherein said patient is AQP4-IgG seronegative and said reduction in annualized risk of NMOSD-associated seizures is 0.07 to 0.09. [The present invention 1028] 1001. The method of claim 1001, wherein said treatment is a reduction in optic neuritis. [The present invention 1029] 1001. The method of claim 1001, wherein said treatment is a reduction in the severity of NMOSD-associated seizures. [The present invention 1030] 1029. The method of claim 1029, wherein said reduction in the severity of NMOSD-associated seizures is a reduction in NMOSD-associated seizures graded as grand mal seizures. [The present invention 1031] 1029. The method of claim 1029, wherein said reduction in the severity of NMOSD-associated attacks is a reduction in NMOSD attacks requiring inpatient admission. [The present invention 1032] 1001. The method of claim 1001, wherein said treatment is a reduction in NMOSD-associated pain in said patient. [The present invention 1033] The method of claim 1032, wherein said reduction in NMOSD-associated pain is determined by measuring leg pain in said patient. [The present invention 1034] 1001. The method of claim 1001, wherein said subject is administered an initial 300 mg dose of VIB551 two weeks prior to said administration of 300 mg VIB551 every six months. [This invention 1035] The method of claim 1034, wherein an oral corticosteroid is co-administered to said patient along with said initial 300 mg VIB551 dose. [The present invention 1036] 1001. The method of claim 1001, wherein said patient is AQP4-IgG seropositive. [This invention 1037] The method of claim 1036, wherein said patient is screened for AQP4-IgG prior to said administration of VIB551. [The present invention 1038] Methods for reducing active MRI lesions in patients diagnosed with NMOSD, including: administering VIB551 to a patient in need of treatment for NMOSD, wherein said VIB551 is administered intravenously at a dose of 300 mg every six months; and Reducing said MRI lesions in said patient. [This invention 1039] 1038. The method of claim 1038, wherein said active MRI lesion is an enlarging T2 MRI lesion. [The present invention 1040] The method of claim 1038, wherein said active MRI lesion comprises a new MRI lesion. [This invention 1041] The method of claim 1038, wherein said subject is administered an initial 300 mg dose of VIB551 two weeks prior to said administration of 300 mg VIB551 every six months. [The present invention 1042] The method of claim 1041, wherein an oral corticosteroid is co-administered to said patient along with said initial 300 mg VIB551 dose. [This invention 1043] The method of claim 1042, wherein said oral corticosteroid is administered daily for at least two weeks. [This invention 1044] The method of claim 1038, wherein said patient is AQP4-IgG seropositive. [This invention 1045] 1038. The method of claim 1038, wherein said reducing active MRI lesions in the patient is a reduction in the number of new MRI lesions in said patient. [The present invention 1046] AQP4-IgG in need of treatment for NMOSD, including: + Methods to reduce a patient's AQP4-IgG titer: administering VIB551 to a patient in need of treatment for NMOSD, wherein said VIB551 is administered intravenously at a dose of 300 mg every six months; and Reducing the AQP4-IgG titer in the patient. [This invention 1047] Methods of treating patients diagnosed with NMOSD, including: Administering VIB551 to a patient in need of treatment for NMOSD, wherein said VIB551: (i) depleting at least 90% of circulating CD20+ B cells for at least 6 months; and (ii) does not increase the patient's risk of infection administered in doses; and Treating said NMOSD. [This invention 1048] The VIB551 increases peripheral blood CD20 within 8 days after the administration. - The method of claim 1047, further depleting plasmablasts and plasma cells. [This invention 1049] 1047. The method of claim 10, wherein the dose is 300 mg. [The present invention 1050] The method of claim 1048, wherein said dose is administered intravenously. [This invention 1051] Methods of reducing NMOSD-related disability in patients diagnosed with NMOSD, including: administering VIB551 to a patient in need of treatment for NMOSD, wherein said VIB551 is administered intravenously at a dose of 300 mg every six months; and Reducing the NMOSD-related disability in the patient. [This invention 1052] 1051. The method of claim 1051, wherein said reducing said NMOSD-related disability in said patient is a reduction in the rate of deterioration of NMOSD-related disability in said patient. [This invention 1053] 1051. The method of claim 1051, wherein said reducing said NMOSD-related disability in said patient is an alleviation of NMOSD-related disability in said patient. [This invention 1054] Any of the methods of claims 1051 to 1053, wherein the NMOSD-related disability is a neurological disability. [This invention 1055] 1054. The method of any one of claims 1051 to 1053, wherein said reducing said NMOSD-related disability is determined using EDSS. [The present invention 1056] 1054. The method of claim 1054, wherein said reducing said NMOSD-related disability is determined using the modified Rankin Scale (mRS). [This invention 1057] 1054. The method of any one of claims 1051 to 1053, wherein said reducing said NMOSD-related disability is determined using mRS and EDSS. [This invention 1058] The method of any of claims 1051 to 1053, wherein said subject is administered an initial 300 mg dose of VIB551 two weeks prior to said every six months administration of 300 mg VIB551. [This invention 1059] The method of claim 1058, wherein an oral corticosteroid is co-administered to said patient along with said initial 300 mg VIB551 dose. [The present invention 1060] 1059. The method of claim 1059, wherein said oral corticosteroid is administered daily for at least two weeks. [This invention 1061] 1051. The method of claim 1051, wherein said reducing said NMOSD-related disability in said patient is detectable within 6 to 12 months after administering an initial dose of 300 mg of said VIB551. [This invention 1062] 1061. The method of claim 1061, wherein said reducing said NMOSD-related disability in said patient is detectable within 6 to 8 months after administering said initial dose of 300 mg of said VIB551. [This invention 1063] 1062. The method of claim 1062, wherein said reducing said NMOSD-related disability in said patient is detectable within 6 to 7 months after administering said initial dose of 300 mg of said VIB551. [This invention 1064] 1001. The method of claim 1001, wherein said treatment is a reduction in NMOSD-associated damage in said patient. [This invention 1065] 1064. The method of claim 1064, wherein said NMOSD-associated lesions are clinically asymptomatic new MRI lesions. [The present invention 1066] The method of claim 1065, wherein said clinically asymptomatic new MRI lesions occur in said patient without symptoms of NMOSD attacks. [This invention 1067] the NMOSD-associated damage is associated with an NMOSD-associated seizure, and the patient experiences symptoms of the NMOSD-associated seizure; and the NMOSD-associated lesions include clinically asymptomatic new MRI lesions in areas other than those in which the patient experiences symptoms of the NMOSD-associated attacks; The method of the present invention 1064. [The present invention 1068] 1068. The method of claim 1067, wherein said NMOSD-associated lesions further comprise new MRI lesions in areas where said patient experiences symptoms of said NMOSD attack. [The present invention 1069] 104. The method of claim 100, wherein at least one of said new MRI lesions is an asymptomatic MRI lesion. [The present invention 1070] Methods for monitoring the progression of NMOSD in patients diagnosed with NMOSD, including: determining first and second MRI lesion counts for the patient; and Identifying the patient's NMOSD as progressive if the second MRI lesion count exceeds the first MRI lesion count, or identifying the patient's NMOSD as non-progressive if the second MRI lesion count does not exceed the first MRI lesion count. [This invention 1071] the first and second MRI lesion counts are determined at a time interval of 6 to 24 months; and the patient is clinically asymptomatic throughout the time interval; The method of the present invention 1070. [This invention 1072] 1071. The method of claim 1071, wherein the time interval is 6 to 12 months. [This invention 1073] 1072. The method of claim 1072, wherein said time interval is about 6 months. [This invention 1074] The method of claim 1071, wherein the patient's NMOSD is identified as progressive and the patient is diagnosed as having had an NMOSD attack. [This invention 1075] 1072. The method of claim 1070 or 1071, wherein said NMOSD is identified as progressive and said method further comprises the step of treating said patient. [This invention 1076] 1075. The method of claim 1075, wherein said treating said patient comprises administering to said patient intravenously VIB551 at a dose of 300 mg every six months. [This invention 1077] 1070. The method of claim 1070, wherein said first MRI lesion count is determined prior to the first administration of treatment. [This invention 1078] 1077. The method of claim 1077, wherein said first MRI lesion count is determined prior to a first administration of a treatment, and said second MRI lesion count is determined 6 to 24 months after said first administration of said treatment. [This invention 1079] 1078. The method of claim 1078, wherein said patient is clinically asymptomatic from said first administration of said treatment until said 6 to 24 months after said first administration of said treatment. [The present invention 1080] 1079. The method of claim 1078 or 1079, wherein said NMOSD is identified as non-progressive and said patient is identified as a responder to said treatment. [This invention 1081] 1079. The method of claim 1078 or 1079, wherein said NMOSD is identified as progressive and said patient is identified as a non-responder to said treatment. [This invention 1082] The method of claim 1081, wherein the patient is diagnosed as having had an NMOSD attack. [This invention 1083] A method for identifying a test agent as suitable for treating NMOSD in a patient diagnosed with NMOSD, comprising: determining the patient's first MRI lesion count at least one month prior to treatment with the study agent; determining a second MRI lesion count in the patient 3 to 24 months after treatment with the study agent; and Identifying the test agent as suitable for treating NMOSD if the second MRI lesion count is equal to or less than the first MRI lesion count, or identifying the test agent as unsuitable for treating NMOSD if the second MRI lesion count is greater than the first MRI lesion count. [This invention 1084] 1084. The method of claim 1083, wherein said first MRI lesion count is determined in said patient at least two weeks prior to said treatment with said test agent. [This invention 1085] 1085. The method of any one of claims 1083 to 1084, wherein said second MRI lesion count is determined in said patient 6 to 12 months after treatment with said test agent. [This invention 1086] 1085. The method of claim 1085, wherein said second MRI lesion count is determined in said patient about 6 months after treatment with said test agent. [This invention 1087] A method for reducing NMOSD-associated seizures in a patient in need of treatment for NMOSD, including: administering VIB551 to a patient in need of treatment for NMOSD, wherein said VIB551 is administered intravenously at a dose of 300 mg every six months; and Reducing said NMOSD-associated seizures in said patient. [This invention 1088] 1087. The method of claim 1087, wherein said patient is administered an initial 300 mg dose of VIB551 two weeks prior to said administration of 300 mg VIB551 every six months. [This invention 1089] The method of claim 1088, wherein an oral corticosteroid is co-administered to said patient along with said initial 300 mg VIB551 dose. [The present invention 1090] 1089. The method of claim 1089, wherein said oral corticosteroid is administered daily for at least two weeks. [This invention 1091] said reducing said NMOSD-associated seizures in said patient comprises reducing the number of NMOSD-associated seizures occurring in said patient during a first period of time compared to a second period of time; the first period occurs after administration of an initial VIB551 dose; the second period of time occurs before administration of the first dose of VIB551; and The first period and the second period are of equal length. The method of the present invention 1087. [This invention 1092] said reducing said NMOSD-associated seizures in said patient comprises reducing the number of NMOSD-associated seizures occurring in said patient during a first period of time compared to a second period of time; the first period of time occurs after administration of the initial VIB551 dose; the second period of time occurs before the initial VIB551 dose; and The first period and the second period are of equal length. The method of the present invention 1088. [This invention 1093] 13. The method of claim 1091 or 1092, wherein said first and second periods are 6 months. [This invention 1094] 13. The method of claim 1091 or 1092, wherein said first and second periods are 12 months. [This invention 1095] 13. The method of claim 1091 or 1092, wherein said first and second periods are 18 months. [This invention 1096] 13. The method of claim 1091 or 1092, wherein said first and second periods are 24 months. [This invention 1097] The method of claim 1091 or 1092, wherein the NMOSD-related seizures occurring in the patient during the first and second time periods include any one or more of optic neuritis, myelitis, or brainstem seizures. [This invention 1098] 1097. The method of claim 1097, wherein one or more of said NMOSD-associated attacks occurring in said patient are asymptomatic. [Brief explanation of the drawings]

[0015] [Figure 1] Flowchart of the multiplicity adjustment strategy for the N-MOmentum clinical trial.

[0016] [Figure 2] Study design flow diagram of the N-MOmentum clinical trial (AC, adjudication committee; FU, follow-up; iv, intravenous; max, maximum; min, minimum; NMO / NMOSD, neuromyelitis optica / neuromyelitis optica spectrum disorder; OLP, open-label period; RCP, randomized controlled period; Q26, every 26 weeks; SFP, safety follow-up period).

[0017] [Figure 3] Flow diagram of seizure assessment and adjudication in N-MOmentum (general). *MRI reports / scans will be reviewed only if required by the assessment criteria. †Lifesaving treatment may be initiated at any time at the investigator's discretion (AC, Adjudication Committee; AE, Adverse Event; EDSS, Expanded Disability Status Scale; FSS, Functional Disability Scale; MRI, Magnetic Resonance Imaging; OLP, Open Label Period; RCP, Randomized Control Period).

[0018] [Figure 4]Flow diagram of seizure assessment and adjudication related to NMOSD ocular symptoms (AE, adverse event; MRI, magnetic resonance imaging; NMO / NMOSD, neuromyelitis optica / neuromyelitis optica spectrum disorder; RAPD, relative afferent pupillary defect; RCP, randomized controlled period).

[0019] [Figure 5] Flow diagram of NMO / NMOSD seizure assessment and adjudication related to spinal symptoms (AE, adverse event; EDSS, Expanded Disability Status Scale; FSS, Functional Disability Scale; MRI, magnetic resonance imaging; NMO / NMOSD, neuromyelitis optica / neuromyelitis optica spectrum disorder; RCP, randomized controlled period).

[0020] [Figure 6] Flow diagram of NMO / NMOSD seizure assessment and adjudication related to brain / brainstem symptoms (AE, adverse event; EDSS, Expanded Disability Status Scale; FSS, Functional Disability Status Scale; MRI, magnetic resonance imaging; NMO / NMOSD, neuromyelitis optica / neuromyelitis optica spectrum disorder; RCP, randomized controlled period).

[0021] [Figure 7]N-MOmentum Clinical Trial CONSORT flow diagram. (*Efficacy endpoints were assessed in the intent-to-treat population (defined as participants who were randomized to receive any study drug, regardless of whether they received any other planned intervention, and were analyzed based on their randomized treatment group). †Safety endpoints were assessed in the as-treated population (defined as participants who received any study drug; however, participants randomized to VIB551 who received all placebo were included in the placebo group). Conversely, participants randomized to placebo who received at least one dose of VIB551 were included in the active treatment group. ‡Others included one case each of need for treatment with prohibited medication, incorrect randomization of an ineligible participant, and pre-dose dropout due to seizure occurrence on the day of randomization (VIB551 arm), and patient decision (placebo arm). CONSORT, Consolidated Standards of Reporting Trials; iv, intravenous; RCP, randomized controlled period).

[0022] [Figure 8] Figures 8A and 8B. Primary endpoint: time to adjudicated NMOSD seizure. (A) Kaplan-Meier plot of time to adjudicated NMOSD seizure in the entire intent-to-treat population. (B) Kaplan-Meier plot of time to adjudicated NMOSD seizure in the AQP4-IgG seropositive population. Seizures were analyzed using Cox proportional hazards regression with placebo as the reference group and treatment and serotype as explanatory factors (AQP4-IgG, aquaporin-4-immunoglobulin G; CI, confidence interval; NMOSD, neuromyelitis optica spectrum disorder).

[0023] [Figure 9]Figures 9A and 9B. Effect of VIB551 and placebo on CD20+ B cells at 28 weeks in (A) the AQP4-IgG seropositive population and (B) the overall intent-to-treat population. Data are shown as mean + standard deviation. Differences between treatment groups were significant from 4 weeks, p<0.0001. AQP4-IgG, aquaporin-4 immunoglobulin G; +ve, seropositive.

[0024] [Figure 10] VH (SEQ ID NO: 1) and VL (SEQ ID NO: 2) amino acid sequences of VIB551 antibody.

[0025] [Figure 11] Figures 11A and B. Median plasma cell-specific gene expression signature as fold change from baseline over time, randomized control period (intent-to-treat population). Figure 11A: Median fold change from baseline in inebilizumab- and placebo-treated subjects plotted on a linear scale. Figure 11B: Median fold change from baseline in inebilizumab- and placebo-treated subjects plotted on a logarithmic scale. Error bars represent the 25% and 75% percentiles for each treatment group. ITT = intent-to-treat.

[0026] [Figure 12] Median percent change from baseline in total immunoglobulin levels, randomized controlled period (intent-to-treat population). Ig = immunoglobulin; Ineb = inebilizumab / VIB551; PBO = placebo.

[0027] [Figure 13] Median percentage change from baseline in IgA levels, randomized controlled period (intent-to-treat population). IgA = immunoglobulin A; Ineb = inebilizumab / VIB551; PBO = placebo.

[0028] [Figure 14]Median percentage change from baseline in IgE levels, randomized controlled period (intent-to-treat population). IgE = immunoglobulin E; Ineb = inebilizumab / VIB551; PBO = placebo.

[0029] [Figure 15] Median percentage change from baseline in IgG levels, randomized control period (intent-to-treat population). IgG = immunoglobulin G; Ineb = inebilizumab / VIB551; PBO = placebo.

[0030] [Figure 16] Median percentage change from baseline in IgM levels, randomized controlled period (intent-to-treat population). IgM = immunoglobulin M; Ineb = inebilizumab / VIB551; PBO = placebo.

[0031] [Figure 17] Median percent change from baseline in IgG levels, open-label period (open-label population). IgG = immunoglobulin G; Ineb = inebilizumab / VIB551; PBO = placebo. DETAILED DESCRIPTION OF THE INVENTION

[0032] Described herein is VIB551 (also known as MEDI551 or inebilizumab), as well as methods for treating NMOSD, reducing active MRI lesions in patients diagnosed with NMOSD, and administering AQP4-IgG to patients in need of treatment for NMOSD. + Its utility in methods for reducing AQP4-IgG titers in patients, methods for reducing NMOSD-related disability in patients diagnosed with NMOSD, and methods for reducing NMOSD-related seizures in patients in need of treatment for NMOSD is described.

[0033] When VIB551 is used to treat NMOSD, it may treat NMOSD by reducing the worsening of the patient's Kurtzke Expanded Disability Status Scale (EDSS), or reducing the patient's active magnetic resonance imaging (MRI) lesion count, or reducing the patient's worsening of the patient's modified Rankin score, or reducing the patient's frequency of hospitalizations associated with NMOSD, or reducing the patient's risk of NMOSD-related seizures, or reducing optic neuritis, or reducing the severity of NMOSD-related seizures in the patient, or reducing the patient's pain, or reducing NMOSD-related damage in the patient, or reducing NMOSD-related seizures in the patient.

[0034] VIB551 treats a patient's NMOSD by reducing the patient's EDSS score worsening, and if the patient's baseline EDSS score is 0, then the patient's EDSS score may be worsened by less than 2 points, or by less than 1 point, or by less than 0.5 points. This reduction in EDSS score worsening for patients with a baseline score of 0 may extend over a period of at least 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. VIB551 treats a patient's NMOSD by reducing the patient's EDSS score worsening, and if the patient's baseline score is 1 to 5, then the patient's EDSS score may be worsened by less than 1 point, or by less than 0.5 points. This reduction in worsening for patients with a baseline EDSS score of 1 to 5 may extend over a period of more than 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. VIB551 treats NMOSD in a patient by reducing the worsening of the patient's EDSS score, and if the patient has a baseline EDSS score of 5.5 or greater, then the patient's EDSS score can be less than 0.5 points worse, or less than 0.25 points worse. For patients with a baseline score of 5.5 or greater, this reduction in worsening can be a reduction in worsening EDSS score over a period of more than 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years.

[0035] When VIB551 treats NMOSD in a patient by reducing the number of active MRI lesions, treating can be a reduction in the number of enlarged T2 MRI lesions, or a reduction in the number of new MRI lesions, or a reduction in both the number of enlarged T2 MRI lesions and the number of new MRI lesions. The reduction in lesions can be a reduction in brain lesions, a reduction in brainstem lesions, a reduction in spinal cord lesions, a reduction in optic nerve lesions, or a reduction in lesions in any two or more of the brain, brainstem, spinal cord, and optic nerve. The new MRI lesions can be clinically asymptomatic.

[0036] Where VIB551 treats NMOSD in a patient by reducing a worsening in the patient's modified Rankin score, the reduced worsening can be such that the patient's modified Rankin score worsens by less than 2 points, or less than 1 point, over a period of at least 6 months, or at least 9 months, or at least 1 year, or at least 2 years, or at least 3 years, or at least 4 years, or at least 5 years, or at least 7.5 years, or at least 10 years.

[0037] When VIB551 treats a patient for NMOSD by reducing the risk of NMOSD-associated seizures, the patient's seizure risk may be reduced by 60% to 85%, or by 65% ​​to 75%, or by 70% to 80%. The patient's seizure risk may be reduced by at least 70%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, or at least 80%. The patient's seizure risk may be reduced by 70%, 75%, 76%, 77%, 78%, 79%, or 80%.

[0038] If VIB551 treats NMOSD in a patient by reducing the risk of NMOSD-associated seizures, then as a result of the reduced risk of NMOSD-associated seizures, the probability that a treated patient will be free of NMOSD-associated seizures can be greater than 70% for at least 6 months after treatment with VIB551, or greater than 70% for at least 12 months after treatment with VIB551, or greater than 70% for at least 18 months after treatment with VIB551. As a result of the reduced risk of NMOSD-associated seizures, the probability that a treated patient will be free of NMOSD-associated seizures can be greater than 75% for at least 6 months after treatment with VIB551, or greater than 75% for at least 12 months after treatment with VIB551, or greater than 75% for at least 18 months after treatment with VIB551. Additionally, as a result of the reduced risk of NMOSD-associated seizures, the probability that a treated patient will be NMOSD-associated seizure-free may be greater than 80% for at least 6 months after treatment with VIB551, or greater than 80% for at least 12 months after treatment with VIB551, or greater than 80% for at least 18 months after treatment with VIB551. Also, as a result of the reduced risk of NMOSD-associated seizures, the probability that a treated patient will be NMOSD-associated seizure-free may be greater than 85% for at least 6 months after treatment with VIB551, or greater than 85% for at least 12 months after treatment with VIB551, or greater than 85% for at least 18 months after treatment with VIB551.

[0039] Furthermore, if VIB551 treats a patient for NMOSD by reducing the risk of NMOSD-related seizures, then as a result of the risk reduction, the patient's annualized risk of NMOSD-related seizures under treatment may be reduced to 0.18 to 0.08, or it may be reduced to 0.15 to 0.08, or it may be reduced to 0.14, or 0.13, or 0.12, or 0.11, or 0.10, or 0.09, or 0.08, or 0.07. If a patient being treated for NMOSD is AQP4-IgG seropositive, then the patient's annualized risk of NMOSD-related seizures may be reduced to 0.15 to 0.11, or it may be reduced to 0.14 to 0.12, or it may be reduced to 0.14, 0.13, 0.12, or 0.11. If a patient being treated for NMOSD is AQP4-IgG seronegative, then the patient's annualized risk of NMOSD-related seizures may be reduced to 0.09 to 0.07, or it may be reduced to 0.09, 0.08, or 0.07.

[0040] An NMOSD-related seizure, the risk of which may be reduced as seen with treatment of an NMOSD patient, may be a seizure characterized by the appearance of a new NMOSD symptom or a worsening of an existing NMOSD symptom. The new or existing symptom may be an ocular symptom. If the new or existing symptom is an ocular symptom, it may be eye pain, a new optic nerve lesion, an enlarged optic nerve lesion, blurred vision, vision loss, or a decrease of 5 or more letters on a low-contrast Landolt C Broken Rings Chart. The new or existing symptom may be a spinal symptom. If the new or existing symptom is a spinal symptom, it may be deep or radicular pain, paresthesias in the extremities, weakness, sphincter dysfunction, Lhermitte's sign, a new spinal cord lesion, or an enlarged spinal cord lesion. The new or existing symptom may be a cerebral or brainstem symptom. If the new or existing symptom is a brain or brainstem symptom, it can be nausea, diplopia, oculomotor palsy, dizziness, intractable vomiting, intractable hiccups, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, a new brain or brainstem lesion, or an enlarging brain or brainstem lesion. The new or worsening symptom can be a combination of any two or more of the eye, spinal cord, or brain / brainstem symptoms. It can be a combination of any two, three, or four of these symptoms.

[0041] When VIB551 treats NMOSD in a patient by reducing optic neuritis, the patient may then experience reduced eye pain, reduced vision loss, reduced visual field loss, reduced loss of color vision, or reduced flashing or flickering lights with eye movement. Reduction of optic neuritis may result in improved vision and / or relief of eye pain.

[0042] When VIB551 treats NMOSD in a patient by reducing the severity of the patient's NMOSD-associated seizures, the severity of any NMOSD-associated seizures the patient experiences can be graded as mild or moderate, as opposed to being graded as severe. A mild seizure can be a transient seizure, a seizure that requires minimal treatment or therapeutic intervention, and / or a seizure that does not interfere with normal activities of daily living. A moderate seizure can be a seizure that can be alleviated by specific additional therapeutic intervention. Any moderate seizure can interfere with normal activities of daily living and / or cause discomfort, but pose no significant or permanent risk of harm to the patient. A reduction in the severity of a patient's NMOSD-associated seizures can be a reduction in the number of seizures the patient experiences, as graded as grand mal seizures. Such grand mal seizures can be seizures that require intensive therapeutic intervention, that interfere with normal activities of daily living, or that have a significant impact on the patient's clinical status. Such grand mal seizures can require hospitalization.

[0043] Where VIB551 treats a patient's NMOSD by reducing the patient's pain, the reduction may be determined by a reduction in pain in the patient's eyes, legs, arms, upper back, and / or lower back. The reduction in pain may be in any one, any two, any three, any four, or all five of these areas. The reduction in pain may be measured by a pain numerical rating scale (PRS). The reduction in pain may be monitored relative to a baseline PRS level on a scale of 1 to 10. The reduction in pain may be a reduction in pain of at least 1 scale, at least 2 scales, at least 3 scales, at least 4 scales, or at least 5 scales. The reduction in pain may be a reduction in pain on a scale of 1 to 5, or a reduction in pain on a scale of 1 to 3, or a reduction in pain on a scale of 1 to 2.

[0044] When VIB551 treats NMOSD in a patient by reducing NMOSD-related damage, then the NMOSD-related damage can be the occurrence of new clinically asymptomatic MRI lesions in the patient. When the NMOSD-related damage is the occurrence of new clinically asymptomatic MRI lesions, it can occur in patients who have never experienced symptoms of NMOSD-related seizures or in patients who have experienced symptoms of NMOSD-related seizures.

[0045] When new clinically asymptomatic MRI lesions occur in patients who have never experienced symptoms of NMOSD-related seizures, VIB551 may reduce the occurrence, or likelihood of occurrence, of new clinically asymptomatic MRI lesions in any one or more regions of the patient, such as the brain / brainstem, optic nerve, or spinal cord. The occurrence, or reduction in likelihood of occurrence, of new clinically asymptomatic MRI lesions may be prevention of the occurrence of new clinically asymptomatic MRI lesions. Patients who have never experienced symptoms of NMOSD-related seizures and whose NMOSD-related damage is reduced by VIB551 may be those who have not experienced symptoms of NMOSD-related seizures for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 24 months. Administration of VIB551 to patients who have never experienced symptoms of NMOSD-related seizures may reduce the occurrence, or likelihood of occurrence, of new clinically asymptomatic MRI lesions over the duration of the patient's treatment with VIB551. Administration of VIB551 to patients who have not experienced symptoms of NMOSD-associated seizures may result in the development, or reduction in the likelihood of development, of new MRI lesions starting within 1 month, 2 months, or 3 months after administration of the first dose of VIB551, and may continue for at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, or at least 60 months after administration of the first dose of VIB551.

[0046] If new clinically asymptomatic MRI lesions occur in a patient who has experienced symptoms of an NMOSD-related seizure, then VIB551 may reduce the occurrence, or likelihood of occurrence, of new clinically asymptomatic MRI lesions in areas other than the area where the patient experienced symptoms of an NMOSD-related seizure. For example, in the case of a patient who experienced symptoms of an NMOSD-related seizure in the spinal cord, VIB551 may reduce the occurrence, or likelihood of occurrence, of new MRI lesions in the optic nerve or brain / brainstem, or both. If VIB551 reduces the occurrence, or likelihood, of new clinically asymptomatic MRI lesions associated with NMOSD-related seizures, it may completely reduce, i.e., prevent, the occurrence of new clinically asymptomatic MRI lesions in the patient. Furthermore, VIB551 may not only reduce, or reduce the likelihood, of new clinically asymptomatic MRI lesions in a patient experiencing symptoms of an NMOSD-related seizure, but it may also reduce, or reduce the likelihood, of new MRI lesions in the area where the patient experienced symptoms of an NMOSD-related seizure.

[0047] VIB551 may also be used in methods for reducing active MRI lesions in patients diagnosed with NMOSD. When VIB551 is used in methods for reducing active MRI lesions in a patient, VIB551 may reduce the cumulative total number of new and enlarging lesions in the patient. When VIB551 is used in methods for reducing active MRI lesions in a patient diagnosed with NMOSD, VIB551 may reduce the cumulative total number of new gadolinium [Gd]-enhancing lesions, new T2 lesions, and enlarging T2 lesions in the patient. When VIB551 is used in methods for reducing active MRI lesions in a patient diagnosed with NMOSD, VIB551 may reduce the number of new T2 lesions in the patient and the number of enlarging T2 lesions in the patient. When VIB551 is used in methods for reducing active MRI lesions in a patient diagnosed with NMOSD, VIB551 may reduce the number of new T2 lesions in the patient or the number of enlarging T2 lesions in the patient. The active MRI lesions reduced in a patient may be cumulative lesions in the brain / brainstem, spinal cord, and optic nerve, or may be lesions in one or two of the brain / brainstem, spinal cord, or optic nerve. The active MRI lesions reduced in a patient may be clinically symptomatic or clinically asymptomatic MRI lesions. If the MRI lesion is clinically asymptomatic, it may be a new MRI lesion that occurs in a patient who has never experienced symptoms of an NMOSD-related seizure. If the MRI lesion is clinically asymptomatic, it may be a new MRI lesion that occurs in a patient in association with an NMOSD-related seizure, but not in the same region where the patient experiences symptoms of an NMOSD-related seizure.

[0048] VIB551 is also an AQP4-IgG inhibitor in the treatment of NMOSD. + VIB551 may be used in a method for reducing AQP4-IgG titers in a patient in need of treatment for NMOSD. +When used in a method for reducing AQP4-IgG titers in a patient, VIB551 may reduce AQP4-IgG titers by 75% to 100%, or 75% to 90%, or 75% to 85%, or 80% to 100%, or 85% to 100%, or 90% to 95%, or 75%, 80%, 85%, 90%, 95, or 100%. VIB551 may reduce AQP4-IgG titers for a duration of at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months after administration of a VIB551 dose.

[0049] VIB551 may also be used in a method for reducing NMOSD-related disability in a patient diagnosed with NMOSD. Reducing NMOSD-related disability in a patient can be a reduction in the worsening of the patient's NMOSD-related disability, or it can be a relief of the patient's NMOSD-related disability. The NMOSD-related disability can be a neurological disability or a manifestation of a neurological disability. The NMOSD-related disability can be characterized by one or more of eye pain, loss of color vision, total vision loss, blurred vision, double vision, general weakness or complete paralysis, weakness or complete paralysis of the arms or legs, radicular pain, uncontrollable hiccups, uncontrollable nausea or vomiting, loss of bladder or bowel control, complete paralysis, and / or fatigue.

[0050] The reduction in NMOSD-related disability may be determined using the EDSS, or the modified Rankin Scale (mRS), or the EDSS and the mRS. The reduction in NMOSD-related disability may be detectable within 6 to 12 months, 6 to 8 months, or 6 to 7 months of administration of a dose of VIB551 or the first dose of VIB551.

[0051] When reducing NMOSD-related disability is determined using the EDSS, reducing NMOSD-related disability can be either a reduction in worsening of the patient's EDSS score or a decline in the patient's EDSS score.

[0052] When reducing NMOSD-related disability is a reduction in the worsening of a patient's EDSS score, and the patient's baseline EDSS score is 0, then the reduction in worsening can be such that the patient's EDSS score, if worsened, worsens to a score of 0.5, or a score of 1 or less, or a score of 1.5 or less, or a score of 2 or less in a given period of time. The period during which a patient with a baseline score of 0 worsens to a score of 0.5, 1 or less, 1.5 or less, or 2 or less can be a period of at least 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. When reducing NMOSD-related disability is a reduction in the worsening of a patient's EDSS score, and the patient's baseline EDSS score is 1 to 5, then the reduction in worsening can be a worsening of the patient's EDSS score of 0.5 points or 1 point or less in a given period of time. The time period during which a patient with a baseline score of 1 to 5 worsens by 0.5 points or 1 point or less can be at least 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. When reducing NMOSD-related disability is a reduction in worsening of the patient's EDSS score, and the patient's baseline EDSS score is 5.5 or higher, then the reduction in worsening can be a worsening of the patient's EDSS score by 0.5 points or less. The time period during which a patient with a baseline score of 5.5 worsens by 0.5 points or less can be at least 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. The patient's baseline EDSS score can be determined within about 1 month, 2 weeks, 1 week, 3 days, 2 days, or 1 day of administration of the first VIB551 dose. The patient's baseline EDSS score may be determined simultaneously with administration of the first VIB551 dose, or it may be determined within 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month of administration of the first VIB551 dose.

[0053] When reducing NMOSD-related disability is a decrease in the patient's EDSS score, the patient's EDSS score may be decreased by at least 0.5 points, or at least 1 point, or at least 1.5 points, or at least 2 points. A decrease or decline in the patient's EDSS score of at least 0.5, at least 1, at least 1.5, or at least 2 points may occur over a period of about 2 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, or about 18 months. The period during which the patient's EDSS score is decreased or declined may begin within 1 month, 2 weeks, 1 week, 3 days, 2 days, or 1 day after administration of the first VIB551 dose; or it may begin simultaneously with administration of the first VIB551 dose; or it may begin within 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month after administration of the first VIB551 dose. The period of decline or decrease in the patient's EDSS score may begin at the time of the NMOSD attack or may begin within 1, 2, 3, 4, 5, 6, or 7 days from the time of the NMOSD attack.

[0054] When reducing NMOSD-related disability is determined using the mRS, then reducing NMOSD-related disability can be either a reduction in worsening of the patient's mRS score or a decrease in the patient's mRS score.

[0055] When reducing NMOSD-related disability is a reduction in worsening of the patient's mRS score, the reduction in worsening of the mRS score can be a worsening of the patient's baseline mRS score of 0.5 points or less, or 1 point or less, or 1.5 points or less, or 2 points or less in a given period of time. The period during which the patient's baseline mRS score worsens by 0.5 points or less, 1 point or less, 1.5 points or less, or 2 points or less can be a period of at least 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. The patient's baseline mRS score from which the reduction in worsening is determined can be the patient's mRS score about 1 month, about 2 weeks, about 1 week, about 3 days, about 2 days, or about 1 day before administration of the first VIB551 dose. The patient's baseline mRS score can be the patient's mRS score at the time of administration of the first VIB551 dose, or it can be the patient's mRS score within 1 day, within 2 days, within 3 days, within 1 week, within 2 weeks, or within 1 month of administration of the first VIB551 dose.

[0056] When reducing NMOSD-related disability is a decrease in the patient's mRS score, the patient's mRS score may be decreased or reduced by at least 0.5 points, or at least 1 point, or at least 1.5 points, or at least 2 points. A decrease or reduction of at least 0.5, at least 1, at least 1.5, or at least 2 points in the patient's mRS score may occur over a period of about 2 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, or about 18 months. The period during which the patient's mRS score is decreased may begin within 1 month, 2 weeks, 1 week, 3 days, 2 days, or 1 day after administration of the first VIB551 dose; or it may be simultaneous with administration of the first VIB551 dose; or it may occur within 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month after administration of the first VIB551 dose. The period of decline in the patient's mRS score may begin at the time of the NMOSD attack, or may begin within 1, 2, 3, 4, 5, 6, or 7 days from the time of the NMOSD attack.

[0057] VIB551 may also be used in a method for reducing NMOSD-associated seizures in a patient in need of treatment for NMOSD. Reducing NMOSD-associated seizures in a patient can be a reduction in the number of NMOSD-associated seizures the patient experiences in a first time period compared to a second time period. The first time period can occur after administration of a first VIB551 dose, and the second time period can occur before administration of the first VIB551 dose. The first time period can begin immediately after administration of the first VIB551 dose, and the second time period can end immediately before administration of the first VIB551 dose. The first and second time periods can be of equal length of time. For example, the first and second periods can both be at least 6 months, or 6 months, or at least 12 months, or 12 months, or at least 18 months, or 18 months, or at least 24 months, or 24 months, or at least 30 months, or 30 months, or at least 36 months, or 36 months, or at least 42 months, or 42 months, or at least 48 months, or 48 months, or at least 54 months, or 54 months, or at least 60 months.

[0058] The reduction in the number of NMOSD-related seizures experienced by the patient during the first time period compared to the second time period can be such that the patient experiences at least one fewer seizure, or one fewer seizure, or at least two fewer seizures, or two fewer seizures, or at least three fewer seizures, or three fewer seizures, or at least four fewer seizures, or four fewer seizures, or at least five fewer seizures, or five fewer seizures during the first time period compared to the second time period. The NMOSD-related seizures experienced by the patient during the first and / or second time periods can be NMOSD-related seizures that are optic neuritis seizures, myelitis seizures, or brainstem seizures. If the patient experiences NMOSD-related seizures during the first time period, the NMOSD-related seizures may or may not be in the same region, e.g., the optic nerve, spinal cord, or brain / brainstem, as the NMOSD-related seizures experienced by the patient during the second time period.

[0059] NMOSD-related seizures occurring in patients whose frequency can be reduced in patients in need of treatment for NMOSD can be NMOSD-related seizures characterized by the appearance of new NMOSD symptoms, or worsening of existing NMOSD symptoms, or the appearance of new MRI lesions, which may or may not be symptomatic.

[0060] When an NMOSD-related attack is characterized by new symptoms or worsening of existing symptoms, the new or worsening symptom can be an ocular symptom. If the new or worsening symptom is an ocular symptom, it can be eye pain, new optic nerve lesion, enlarged optic nerve lesion, blurred vision, loss of vision, or a decline of 5 or more letters on a low-contrast Landolt chart.NMOSD-related attacks characterized by new ocular symptoms or worsening of pre-existing ocular symptoms may also / or meet any one or more of the following criteria: a decline of more than 15 letters in the high-contrast Landolt ring chart since the most recent clinical visit when measured in the previously affected eye and no other ophthalmological explanation; a decline of 2 or more lines in CF to NLP since the most recent clinical visit when measured in the previously affected eye and no other ophthalmological explanation; a decline of 7 or more letters in the low-contrast Landolt ring chart since the most recent clinical visit when measured in either eye alone (monocular) and a new RAPD in the affected eye; a decline of 7 or more letters in the low-contrast Landolt ring chart since the most recent clinical visit when measured in either eye alone (monocular) and a loss of a previously recorded RAPD in the fellow eye; A loss of 5 or more letters on a high-contrast Landolt ring chart since the most recent clinical visit when measured monocularly and a new RAPD in the affected eye; a loss of 5 or more letters on a high-contrast Landolt ring chart since the most recent clinical visit when measured monocularly and a loss of a previously recorded RAPD in the fellow eye; a loss of 1 or more steps on CF to NLP since the most recent clinical visit when measured monocularly in the previous affected eye§ and a new RAPD in the affected eye; a loss of 1 or more steps on CF to NLP since the most recent clinical visit when measured monocularly in the previous affected eye§ and a loss of a previously recorded RAPD in the fellow eye; a loss of 7 or more letters on a low-contrast Landolt ring chart since the most recent clinical visit when measured monocularly and a new Gd enhancement or new / enlarging T2 in the corresponding optic nerve MRI lesions, a decrease of ≥5 letters on the high-contrast Landolt chart since the most recent clinical visit when measured in either eye alone (monocular) and new Gd-enhancement or new / enlarging T2 MRI lesion in the corresponding optic nerve, a decrease of ≥1 grade in CF to NLP since the most recent clinical visit when measured in the previously affected eye§ and new Gd-enhancement or new / enlarging T2 MRI lesion in the corresponding optic nerve.

[0061] When an NMOSD-related attack is characterized by a new symptom or a worsening of an existing symptom, the new or worsening symptom can be a spinal symptom. If the new or worsening symptom is a spinal symptom, it can be deep or radicular pain, paresthesias in the extremities, weakness, sphincter dysfunction, Lhermitte's sign, a new spinal lesion, or an enlarging spinal lesion. NMOSD-related attacks characterized by new or worsening of existing spinal symptoms may also / or meet any one or more of the following criteria: a worsening of at least one relevant (pyramidal, bladder / bowel, sensory) FSS score of 2 or more points compared to the most recent clinical visit; a worsening of the EDSS score of 1 or more points compared to the most recent clinical visit when the previous EDSS score was 5.5 or greater; a worsening of at least two relevant (pyramidal, bladder / bowel, sensory) FSS scores of 1 or more points compared to the most recent clinical visit when the score at the most recent clinical visit was 1 or greater and new Gd enhancement or new / enlarging T2 MRI lesions in the spinal cord; a worsening of the EDSS score of 0.5 or more points compared to the most recent clinical visit and new Gd enhancement or new / enlarging T2 MRI lesions in the spinal cord when the previous EDSS score was 5.5 or greater.

[0062] When an NMOSD-related attack is characterized by a new symptom or a worsening of an existing symptom, the new or worsening symptom can be a brain or brainstem symptom. When the new or existing symptom is a brain or brainstem symptom, it can be nausea, diplopia, oculomotor palsy, dizziness, intractable vomiting, intractable hiccups, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, a new brain or brainstem lesion, or an enlarging brain or brainstem lesion. NMOSD-related attacks characterized by new brain / brainstem symptoms or worsening of existing brain / brainstem symptoms may also / alternatively meet any one or more of the following criteria: isolated (no findings at most recent clinical visit) refractory nausea, vomiting, and / or hiccups lasting more than 48 hours AND new Gd-enhancing or new / enlarging T2 MRI lesions in the brainstem; worsening of at least one relevant (brainstem, cerebellar) FSS by 2 or more points compared to most recent clinical visit AND new Gd-enhancing or new / enlarging T2 MRI lesions in the brainstem; or worsening of at least one relevant (cerebral, sensory, pyramidal) FSS (score 3 or greater at the current visit) by 2 or more points compared to most recent clinical visit AND new Gd-enhancing or new / enlarging T2 MRI lesions in the brain consistent with clinical findings.

[0063] An NMOSD-associated attack can be a attack characterized by any combination of one, two, or more new and / or worsening symptoms of the eye, spinal cord, or brain / brainstem. An NMOSD-associated attack can be a attack characterized by any combination of two, three, or four specific symptoms or other criteria of one or more of the eye, spinal cord, or brain / brainstem.

[0064] Additionally, NMOSD-related attacks can be attacks characterized by the appearance of new MRI lesions in the patient, which can be, but are not necessarily, symptomatic.

[0065] Methods for treating NMOSD, methods for reducing active MRI lesions in NMOSD patients, AQP4-IgG +In the methods for reducing AQP4-IgG titers in patients with NMOSD, for reducing disability in patients diagnosed with NMOSD, and for reducing NMOSD-related seizures in patients in need of treatment for NMOSD, VIB551 may be administered at intervals of approximately 6 months and may be administered intravenously. Approximately 6 months may be administered every 6 months, every 180 days, every 170-190 days, every 175-185 days, every 175-190 days, or every 170-185 days. Approximately 6 months may be administered every 26 weeks, every 25 weeks, every 27 weeks, every 25-27 weeks, every 25-26 weeks, or every 26-27 weeks. An initial VIB551 dose may be administered to the NMOSD patient before the approximately 6-monthly administration of VIB551 in the methods. The initial VIB551 dose may be administered about 2 weeks before the approximately 6-monthly administration of VIB551. Administration of the initial VIB551 dose about two weeks before administration of VIB551 about every six months can be administration of the initial VIB551 dose 12 days, 13 days, 14 days, 15 days, or 16 days before administration of VIB551 about every six months. The initial VIB551 dose may or may not be co-administered with an oral corticosteroid.

[0066] Methods for treating NMOSD, methods for reducing active MRI lesions in NMOSD patients, AQP4-IgG + The dose of VIB551 administered in the methods for reducing AQP4-IgG titers in patients with NMOSD and for reducing disability in patients diagnosed with NMOSD can be about 300 mg. About 300 mg can be a dose of 250 mg to 350 mg, a dose of 275 mg to 325 mg, a dose of 290 mg to 310 mg, a dose of 205 mg to 305 mg, or a dose of 300 mg.

[0067] Methods for treating NMOSD, methods for reducing active MRI lesions in NMOSD patients, AQP4-IgG +The VIB551 administered in the methods for reducing AQP4-IgG titers in NMOSD patients and for reducing disability in patients diagnosed with NMOSD may have the VH and VL amino acid sequences as shown in Figure 10. The VIB551 administered in the methods may have the VH and VL amino acid sequences as shown in Figure 10, but with one or more amino acid residue changes that do not alter the function of the VIB551 amino acid sequence. The number of amino acid changes may be one, two, three, four, or five amino acid residue changes. The VIB551 administered in the methods may have the CDR amino acid sequences of the VH and VL sequences as shown in Figure 10, but with one or more modifications in the framework regions of the VH and VL sequences shown in Figure 10.

[0068] Methods for treating NMOSD, methods for reducing active MRI lesions in NMOSD patients, AQP4-IgG + VIB551 administered in the methods for reducing AQP4-IgG titers in patients with NMOSD and for reducing disability in patients diagnosed with NMOSD contains 20 mM histidine / histidine hydrochloride, 70 mM NaCl, 106 mM (4% [w / v] to Rehalose dihydrate and 0.01% (w / v) polysorbate 80, pH 6.0.

[0069] The NMOSD patients to whom VIB551 is administered in the methods of treating NMOSD, reducing active MRI lesions in NMOSD patients, and reducing NMOSD-related disability in patients diagnosed with NMOSD may or may not be AQP4-IgG seropositive. NMOSD patients can be screened for AQP4-IgG prior to administration of VIB551.

[0070] VIB551 may also be used in a method of treating a patient in need of treatment for NMOSD, wherein VIB551 is (i) depleting at least 90% of circulating CD20+ B cells for at least 6 months; and (ii) not increase the patient's risk of infection The dose that depletes at least 90% of circulating CD20+ B cells for at least 6 months also depletes peripheral blood CD20 - It may also deplete plasmablasts and plasma cells. A dose that depletes at least 90% of circulating CD20+ B cells for at least 6 months may also reduce the plasma cell gene signature of a patient in need of treatment for NMOSD, or it may eliminate the plasma cell gene signature of a patient in need of treatment for NMOSD. A dose that depletes at least 90% of circulating CD20+ B cells may deplete circulating CD20+ B cells for longer than 6 months. It may deplete at least 90% of circulating CD20+ B cells for at least 9 months or at least 1 year.

[0071] In a method of treatment, a dose of VIB551 that depletes at least 90% of circulating CD20+ B cells for at least 6 months also does not increase the risk of infection in an NMOSD patient. The risk of infection may not be increased in an NMOSD patient compared to their risk of infection before administration of VIB551. The risk of infection may not be increased in an NMOSD patient compared to an NMOSD patient not treated with VIB551. The risk of infection can be a risk of infection due to or resulting in typical pneumonia, beta-hemolytic streptococcus infection, bronchitis, conjunctivitis, viral conjunctivitis, fungal skin infection, viral gastroenteritis, gastrointestinal infection, gingivitis, cystitis, shingles, influenza, laryngitis, viral meningitis, muscle abscess, oral herpes, otitis externa, periodontitis, pneumonia, rhinitis, retinitis, pyelocystitis, retinitis, sinusitis, urinary tract infection, tinea cururis, septic shock, or upper respiratory tract infection.

[0072] 0072 A dose of VIB551 that can be used in a method of treating a patient in need of treatment for NMOSD (wherein the VIB551 dose depletes at least 90% of circulating CD20+ B cells for at least 6 months and does not increase the patient's risk of infection) can be about 300 mg. About 300 mg can be a dose of 250 mg to 350 mg, it can be a dose of 275 to 325 mg, it can be a dose of 290 to 310 mg, it can be a dose of 205 to 305 mg, or it can be a dose of 300 mg.

[0073] Doses of VIB551 that may be used in methods of treating a patient in need of treatment for NMOSD, where the VIB551 dose depletes at least 90% of circulating CD20+ B cells for at least 6 months and does not increase the patient's risk of infection, may be doses administered intravenously at intervals of about every 6 months, or every 7 months, or every 8 months, or every 9 months, or every 10 months, or every 11 months, or yearly.

[0074] In addition to this specification providing VIB551 and its utility in methods for treating patients diagnosed with NMOSD, e.g., by treating NMOSD, or by reducing active MRI lesions, or by reducing AP4-IgG titers, or by reducing NMOSD-related disability in patients, this specification also provides methods for monitoring the progression of NMOSD and for identifying test agents as suitable for treating NMOSD in patients.

[0075] In a method for monitoring the progression of NMOSD, NMOSD is monitored in a patient diagnosed with NMOSD. Monitoring the progression of NMOSD may be performed by determining first and second MRI lesion counts in the patient. The first and second MRI lesion counts in the patient may be determined at time intervals of 6 to 24 months, 6 to 18 months, 6 to 12 months, 12 to 24 months, or 18 to 24 months apart. The first and second MRI lesion counts in the patient may be determined at time intervals of about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 24 months, about 30 months, or about 36 months apart. The first and second MRI lesions may include clinically asymptomatic MRI lesions.

[0076] The first MRI lesion count may or may not be determined before the first administration of the treatment. If the first MRI lesion count is determined before the first administration of the treatment, the first MRI lesion count may be determined about 1 month, 3 weeks, 2 weeks, 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before the first administration of the treatment. A second MRI lesion count may then be determined 6 to 24 months, 6 to 18 months, 6 to 12 months, 12 to 24 months, or 18 to 24 months after the first administration of the treatment. The second MRI lesion count may be determined 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 30 months, or 36 months after the first administration of the treatment.

[0077] Once the first and second MRI lesion counts have been determined, the patient may be identified as a progressor if the second MRI lesion count exceeds the first MRI lesion count, or alternatively, the patient may be identified as a non-progressor if the second MRI lesion count does not exceed the first MRI lesion count.

[0078] If the first MRI lesion count is determined before the first administration of the treatment and the second MRI lesion count exceeds the first MRI lesion count, then the patient may further be identified as a non-responder to the treatment. Alternatively, if the first MRI lesion count is determined before the first administration of the treatment and the second MRI lesion count does not exceed the first MRI lesion count, then the patient may be identified as a responder to the treatment.

[0079] A patient whose NMOSD progression is monitored may or may not experience clinical symptoms of an NMOSD attack throughout the time interval between the determination of the first and second MRI lesion counts, i.e., may be clinically asymptomatic. If the patient is clinically asymptomatic throughout the time interval and the second MRI lesion count exceeds the first MRI lesion count, the patient may be identified as a progressor without clinical symptoms of an NMOSD attack. Furthermore, even if the patient is clinically asymptomatic, if the patient's second MRI lesion count exceeds the first MRI lesion count, the patient may be identified as having had an NMOSD attack. For example, if the patient is determined to have one or more, two or more, three or more, four or more, or five or more second MRI lesions compared to the first MRI lesions, the patient may be identified as a progressor and / or as having had at least one NMOSD attack.

[0080] If a patient is identified as progressive and / or has had at least one NMOSD attack, i.e., has more second MRI lesions than the first, the patient may be treated. If the patient is treated, the patient may be administered a therapeutic agent. The therapeutic agent may be, for example, a steroid, eculizumab, satralizumab, or VIB551. If the therapeutic agent is VIB551, the VIB551 may be administered intravenously to the patient at a dose of 300 mg every six months, or according to any other VIB551 dose / dose schedule described herein. If a patient is identified as progressive and / or has had at least one NMOSD attack, and the patient is further identified as a non-responder to a treatment, the patient may discontinue treatment and an initial dose of a second treatment may be administered, or an initial dose of a second treatment may be administered in combination with the first treatment.

[0081] In a method for identifying a test agent suitable for treating NMOSD in a patient diagnosed with NMOSD, a first MRI lesion count and a second MRI lesion count are determined in the patient. The first MRI lesion count is determined prior to treating the patient with the test agent. The first MRI lesion count may be determined as early as one month prior to treating the patient with the test agent. The first MRI lesion count may be determined as early as three weeks, two weeks, one week, six days, five days, four days, three days, two days, or one day prior to treating the patient with the test agent. After treatment with the test agent, a second MRI lesion count is determined. The patient's second MRI lesion count may be determined 3 to 24 months after treatment with the test agent. The patient's second MRI lesion count may be determined 6 to 24 months, or 9 to 24 months, or 12 to 24 months, or 15 to 24 months, or 18 to 24 months, or 21 to 24 months, or 3 to 21 months, or 3 to 18 months, or 3 to 15 months, or 3 to 12 months, or 3 to 9 months, or 3 to 6 months after treatment with the study agent. The patient's second MRI lesion count may be determined 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months after treatment with the study agent.

[0082] The test agent may be identified as suitable for treating NMOSD if the second MRI lesion count is the same as or less than the first MRI lesion count. The test agent may not be identified as suitable for treating NMOSD if the second MRI lesion count exceeds the first MRI lesion count. The first and / or second MRI lesions may include clinically asymptomatic MRI lesions.

[0083] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein which equivalents are intended to be encompassed by the claims appended hereto.

[0084] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference herein. [Example]

[0085] Example 1 - Rationale for each element of clinical trial design Overview: The N-MOmentum NMOSD clinical trial was designed as a randomized, placebo-controlled, double-blind, 197-day phase 2 / 3 study with an open-label extension period to evaluate the efficacy and safety of VIB551 (also known as VIB551 or Medi551), an anti-CD19 B-cell-depleting antibody, in patients with NMOSD recruited from 99 centers in 24 countries. Participants were randomized (3:1) using an interactive voice response system / web-based interactive response system to receive intravenous VIB551 300 mg or placebo on days 1 and 15, respectively. Efficacy endpoints were assessed in the intent-to-treat population, and safety endpoints were assessed in the as-treated population. The primary endpoint was time to first clinically-reported seizure; secondary endpoints included disability deterioration, magnetic resonance imaging (MRI) lesion activity, and hospitalization.

[0086] Arm Selection: Currently, there are no approved medications for the treatment of neuromyelitis optica spectrum disorder, so a placebo-controlled treatment arm was chosen. The use of a placebo arm allowed for a clear and robust evaluation of VIB551 by avoiding the confounding effects of other treatments, providing the highest sensitivity and robustness for detecting efficacy, and helping to derive clinically meaningful outcomes for the study.

[0087] Randomization. The 3:1 randomization ratio used in this study was an effective and efficient method for building a pooled safety database for VIB551 while minimizing the number of events or patients required in the placebo arm to an acceptable level. This randomization ratio also addressed, to some extent, investigator and patient ethical concerns regarding enrolling patients in the placebo arm. In addition to limiting the number of patients receiving placebo, the study was designed to limit the duration of active placebo exposure to a maximum of 197 days or time to seizure onset, whichever occurred first, after which all patients were given the option to proceed to the open-label period and receive VIB551.

[0088] Before randomization, patients were stratified based on AQP4-IgG serostatus (determined at screening) and region (Japan or non-Japan). Within each stratum, patients were randomized in a 3:1 ratio using an interactive voice response system / web-based interactive response system (IVRS / IWRS) with a permuted block randomization scheme to treatment groups and blinded allocation of investigational drug kit numbers. Patients were considered randomized into the study once the investigator notified the IVRS / IWRS that the patient met the eligibility criteria and the IVRS / IWRS assigned the patient a masked investigational drug kit number.

[0089] Blinding. This was a double-blind study. VIB551 and placebo were identically labeled and indistinguishable in appearance; both were supplied as clear to milky white, colorless to yellow liquids, and were free or substantially free of particulate contamination. VIB551 doses were indistinguishable from placebo doses during dose preparation, handling, and injection.

[0090] Neither the patient / proxy nor any investigator or sponsor staff involved in the patient's treatment or clinical evaluation knew about the treatment to be received. If the patient's treatment allocation was not disclosed, the sponsor was notified immediately.

[0091] To ensure that patients previously randomized to placebo received the correct loading dose of VIB551 600 mg iv, or that patients previously randomized to VIB551 did not receive an excess treatment dose, it was necessary to administer the blinded dose of VIB551 or placebo on Day 15 during the open-label period. This blinding mechanism was performed by the IVRS, ensuring that the sites were not exposed to the details of the randomized treatment.

[0092] VIB551 is known to deplete CD19+ B cells; therefore, flow cytometry results counting B cells were potentially unblinded. After randomization, these data were not available to the investigational sites for the remainder of the study.

[0093] Early development data in a non-cancer patient population receiving VIB551 suggested that treatment may be associated with potential, unspecified, mild decreases in total immunoglobulins in individual patients. Because these decreases were potentially open-label, these data were not made available to the investigational sites after randomization and throughout the remainder of the study.

[0094] It is hypothesized that VIB551 reduces AQP4-IgG titers. AQP4-IgG titers from the central laboratory were not made available to the investigational sites at any time during the study.

[0095] VIB551 is known to reduce the plasma cell gene signature. Because the results could potentially be unblinded, plasma cell gene signature assay samples were not tested prior to unblinding of the study.

[0096] VIB551 may also reduce tetanus vaccine titers; therefore, vaccine potency assay results were not made available to the facility at any time during the study.

[0097] Any potentially unmasked data from this study was not made available to the sponsor until the database was locked and the study was unblinded after the completion of the randomized controlled period.

[0098] The study design included an unblinded interim analysis. The interim analysis to determine futility was performed by a data monitoring committee; the sponsor and sites remained blinded to treatment assignment after the interim analysis.

[0099] Built-in Safety Mechanisms. Due to the potential severity and debilitating nature of neuromyelitis optica spectrum disorder attacks, the study was further designed to ensure safety in this patient population through careful monitoring and early evaluation of signs and symptoms of neuromyelitis optica spectrum disorder attacks; regular study visits and study assessments; biweekly follow-up phone calls to study patients by study site staff; a "waiver clause" (i.e., immediate access to life-saving treatment after identification of a neuromyelitis optica spectrum disorder attack); and monitoring by an independent data monitoring committee.

[0100] Comparator: Placebo was the comparator chosen with comprehensive ethical considerations in mind; no approved treatments or controlled trials had been conducted to establish the risk / benefit profile of off-label medications. 1、18 .

[0101] Discontinuation. Treatment was discontinued if the participant withdrew consent or if the investigator determined an adverse event precluded further dosing, including elevated hepatic aminotransferase levels, severe anaphylaxis, hypersensitivity reactions, infusion reactions, neutropenia, and pregnancy. Specifically, subjects did not receive further study drug if any of the following occurred in the patient in question: withdrawal of consent for further treatment with study drug or the patient was lost to follow-up; an adverse event that, in the opinion of the investigator or sponsor, contraindicated further administration; the patient met one or more of the exclusion criteria or was determined not to have met all inclusion criteria for study participation and there were potential safety risks associated with continuation identified in consultation with the medical monitor; any of the following liver function abnormalities: (a) ALT or AST >8 x ULN, (b) ALT or AST >5 x ULN for more than 2 weeks (in the absence of elevated bilirubin and / or other symptoms listed in item "d"), (c) ALT or AST >3 x ULN and total bilirubin >2 x ULN or international normalized ratio >1.5 (i.e., an example of High's law), (d) ALT or AST >3 x ULN and , accompanied by the occurrence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and / or eosinophilia (>5%); any life-threatening (Grade 4) clinical event related to the investigational product, including anaphylaxis, as agreed in consultation with the medical monitor; recurrent severe (Grade 3) hypersensitivity reactions related to the investigational product, as agreed in consultation with the medical monitor; recurrent severe (Grade 3) infusion reactions related to the investigational product, as agreed in consultation with the medical monitor; Grade 3 or greater neutropenia that has not improved to at least Grade 2 within 5 days, as agreed in consultation with the medical monitor; administration of prohibited medication before Day 15 during the randomized controlled period or during the open-label period, as determined by the medical monitor; non-compliance with the study protocol, as determined by the investigator and / or sponsor.

[0102] Example 2 - Clinical Trial Subject Recruitment and Admission Criteria Summary. The main inclusion criteria were: diagnosis of NMOSD2、17 and adults with an EDSS score of 8.0 or less who had either a history of at least one attack requiring life-saving treatment (intravenous corticosteroids, intravenous immunoglobulin, and / or plasma exchange) within the year prior to screening or at least two attacks requiring life-saving treatment within the two years prior to screening. AQP4-IgG seropositive and seronegative patients were eligible; seronegative participants met the Wingerchuk 2006 criteria. 17 There were no preplanned recruitment targets regarding AQP4-IgG serostatus. It was assumed that recruitment would reflect the known demographics of the patient population, with approximately 80% seropositive and 20% seronegative. 17 All participants provided written informed consent.

[0103] Sample size. An initial sample size calculation concluded that 212 patients would need to be recruited to observe the required 67 attacks. This number was calculated by assuming 1-year hazard ratios of 1.5 and 1.0 for attacks in the placebo arm for the seropositive and seronegative groups, respectively. These hazard ratios were based on observed seizure rates in four open-label cohort studies (Bedi, et al. "Impact of rituximab on relapse rate and disability in neuromyelitis optica." MultiScler 2011;17:1225-30; Costanzi, et al. "Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica." Neurology 2011;77:659-66; Jacob, et al. "Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients." Muscle Nerve 2008;39:87-90; Kim, et al. "Repeated treatment with rituximab based on the assessment of peripheral circulating memory B cells in patients with relapsing neuromyelitis optica over 2 years"). "Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study". Lancet Neurol 2013;12:554-62).

[0104] This study faced challenges in recruitment and in achieving the required number of neuromyelitis optica spectrum disorder attacks planned to achieve statistical significance. Most participating centers contributed one to three patients to the study, and additional centers were activated over the three-year period during recruitment. These challenges were expected given the rarity of the disease worldwide and the lack of established diagnostic tools. A patient attrition effect was observed, in which centers screened and enrolled existing eligible patients immediately after center activation, followed by a drop in recruitment. Because attack rates were lower than expected and varied during the study, it was necessary to increase the target number of patients from 212 to 252 based on a projected number of patients needed to achieve the required number of attacks.

[0105] An interim sample size reassessment was planned to be performed prior to the planned futility analysis. Because neuromyelitis optica spectrum disorder attack rates have not been established in the literature, this reassessment was important to prevent a loss of statistical power in the seropositive cohort and the overall population due to a failure to reach the required number of events. Given the lower-than-expected attack rate and the possibility that the initial sample size assessment could subsequently change and eliminate opportunities for further sample size increases, the protocol was amended on December 15, 2016, in collaboration with the U.S. Food and Drug Administration. The preplanned sample size reassessment was canceled, and the enrollment target was revised to 252 patients. This was determined by analyzing the actual attack rate based on masked data from the first 78 patients who completed the randomized controlled period of the study. These 78 patients were randomly assigned seizure status (seizure present / seizure absent) at various attack rates, thereby providing an estimate of the number of attacks for the total sample size. This simulation process was repeated 10,000 times to determine the distribution of attack rates for the total sample size, from which the probability of observing at least 67 attacks could be estimated. Based on 78 completed patients, this procedure demonstrated a 50% probability of reaching the required 67 committee-determined seizures with a sample size of 227, and a 90% probability of reaching the required 67 committee-determined seizures with 252 patients. Thus, a sample size of 252 patients was selected to provide a high degree of confidence that 67 seizures would be observed in this study.

[0106] Statistical Analysis—Number Needed to Treat and Multiplicity Adjustment Strategy. The primary endpoint was assessed by survival analysis using Cox proportional hazards regression with placebo as the reference group and treatment and serotype as explanatory factors. The proportional hazards model assumption was confirmed by visual inspection of survival curves and by a test of the hypothesis (p=0.1790); both were confirmed, suggesting that the proportional hazards model assumption held. Due to the fact that the primary endpoint was a time-to-event outcome, the number needed to treat was estimated from the survival probabilities in the VIB551 and placebo groups and the hazard ratio comparing these two groups, as discussed in Altman DG, Anderson PK. "Calculating the number needed to treat for trials where the outcome is time to an event." BMJ 1999;319:1492-5. The time-to-event nature of the primary endpoint also meant that informative censoring was possible. Of the total 230 participants, only 7 did not complete the randomized controlled period (2 placebo and 5 VIB551). Given this and the magnitude of the treatment effect observed in 43 seizures during the randomized controlled period, the impact of potentially informative censoring was considered minimal.

[0107] For key secondary outcomes, odds ratios for worsening EDSS scores were assessed using logistic regression models and nonresponder imputation, with treatment, serostatus, and baseline scores as explanatory variables. The least-squares mean difference in change in low-contrast binocular visual acuity scores was assessed using an analysis of covariance model with treatment, serostatus, and baseline Landolt binocular scores as explanatory variables, and the most recent nonmissing low-contrast visual acuity score. Rate ratios for cumulative active MRI lesion counts and disease-related hospitalizations were assessed using negative binomial regression with treatment and serostatus as explanatory variables. Whole blood samples for B-cell quantification were collected according to the assessment schedule; B-cell counts and immunophenotyping of various B-cell subsets were performed by flow cytometry at a central laboratory, and data were reported descriptively. Treatment-emergent adverse events were summarized by system organ class and preferred term using the Medical Dictionary for Regulatory Activities, version 21.0, and reported descriptively.

[0108] The primary endpoint and four secondary endpoints were considered to ensure control of type 1 error.

[0109] Primary endpoint: Time (in days) from Day 1 to occurrence of a neuromyelitis optica spectrum disorder seizure as determined by an adjudication committee on or before Day 197. A seizure was defined as the presence of a new neuromyelitis optica-related symptom or a worsening of a pre-existing neuromyelitis optica-related symptom that met at least one of the protocol-defined criteria for a neuromyelitis optica spectrum disorder seizure.

[0110] The four key secondary endpoints were: 1. Worsening of EDSS score from baseline at the final visit during the randomized controlled period. EDSS assessments in this study were performed by independent, blinded raters at each site using an electronic data capture system developed by the University of Basel and Neurostatus GmbH that incorporates an internal algorithm to provide raters with feedback on discrepancies in EDSS assessments; 2. Change from baseline in low-contrast visual acuity binocular score measured with a low-contrast Landolt ring chart at the final visit during the randomized controlled period; 3. Cumulative total number of active MRI lesions (new gadolinium-enhancing or new / enlarging T2 lesions) during the randomized controlled period; and 4. Number of neuromyelitis optica-related hospital admissions, where hospital admission is defined as a stay of more than one night.

[0111] This resulted in testing 10 null hypotheses of treatment ineffectiveness based on the two target populations (seropositive and ITT). Neither the pre-specified futility analysis nor the ongoing evaluation by the Data Monitoring Committee was required to take into account the control of type I error. Both were independent of and had no effect on the primary and key secondary endpoints.

[0112] The multiplicity adjustment strategy was based on a Bonferroni-based chaining procedure. In Figure 1, each hypothesis is represented by a rectangular box. The connections between hypotheses are shown using arrows. Solid arrows are used to define the decision path after a hypothesis is rejected (e.g., hypothesis O1 is tested if and only if hypothesis S1 is rejected).

[0113] Bonferroni-based chaining procedures are characterized by two rules: 1. The α allocation rule specifies the initial distribution of the type I error rate among the null hypotheses based on their relative importance; 2. The α propagation rule defines the process of redistributing the available type I error rate among the non-rejected null hypotheses after each rejection.

[0114] For the assignment of α, the null hypothesis S1 is given an initial weight of 1 (i.e., it is tested entirely at α = 0.05), and the other null hypotheses are given weights of 0. The propagation of α states that if the null hypothesis O1 is rejected, the available type I error rate is divided equally among the null hypotheses S2, S3, S4, and S5 (one-quarter of the available type I error rate is assigned to each null hypothesis). The α assignment and α propagation uniquely define a Bonferroni-based chaining procedure, and the associated multiplicity-adjusted p-values ​​can be calculated using Algorithm 2 in Bretz, et al., 2009.

[0115] In N-MOmentum, the primary endpoint was validated hierarchically at α = 0.05, first in the AQP4-IgG seropositive cohort and, if significant, in the entire intention-to-treat population. The reason for this approach was that, despite the use of Wingerchuck 2006 criteria and the role of an independent eligibility committee, uncertainty remained regarding the exact nature of the AQP4-IgG seronegative cohort and how it might respond to B cell depletion. Because AQP4-IgG seropositive patients represent the majority of people with neuromyelitis optica and the direct relationship between AQP4 and B cell-related mechanisms of action is clear, we decided to statistically test the primary endpoint first in AQP4-IgG seropositive participants and then in the entire cohort. In this way, the intention was to collect the maximum amount of clinically relevant data while ensuring that any potential differential effect of AQP4-IgG seronegative participants was mitigated.

[0116] If the primary endpoint was met in the ITT population, then all major secondary hypotheses were tested in the same way, with each secondary hypothesis initially tested based on a chaining procedure with α = 0.0125. If the null hypothesis of a secondary endpoint was rejected in both the seropositive and total populations, the remaining type I error was propagated evenly to the set of other non-rejected secondary null hypotheses. p-values ​​are provided in the text after multiplicity adjustment as described above with α = 0.05.

[0117] Inclusion Criteria. To be included in the study, subjects had to meet all of the following criteria: (1) 18 years of age or older at the time of screening; (2) written informed consent and any local authorization required (e.g., Health Insurance Portability and Accountability Act (HIPAA) in the United States (USA), Data Privacy Directive in the EU) obtained from the subject / legal representative before any protocol-related procedures, including screening assessments; (3) one of the following: (a) a positive serum anti-AQP4-IgG result at screening (confirmed by an assigned central laboratory) and a documented history of one or more acute NMO / NMOSD relapses requiring life-saving treatment within the past year, or two or more acute NMO / NMOSD relapses requiring life-saving treatment within the two years prior to screening; or (b) consistent with MS and consistent with Wingerchuk et al. (3) Negative serum anti-AQP4-IgG result at screening (confirmed by the assigned central laboratory) without evidence of brain lesions meeting clinical criteria for NMO according to [the original text]. et al., 2006, and a documented history of at least one acute relapse of NMO requiring life-saving treatment within the last year, or at least two acute relapses of NMO requiring life-saving treatment within the two years prior to screening. Note that data from AQP4-IgG seronegative subjects will be reviewed by an independent eligibility committee to confirm eligibility (see Section 4.2.1.1). (If a subject does not receive life-saving treatment for a relapse due to misdiagnosis or mismanagement of symptoms in a clinic or medical facility outside the investigator's control, the subject may still be eligible for the study if, after review of the relapse data, the medical monitor and investigator are satisfied that the subject truly experienced a relapse; (4) Subjects who experienced a relapse immediately prior to screening must have had at least 4 weeks for their relapse to stabilize or improve before randomization; (5) A comprehensive disability status scale score at randomization of 7.5 or less.A score of 8.0 may be eligible if the investigator and medical monitor assess that the subject is sufficiently able to participate in the study; (6) Women of childbearing potential who are sexually active with an unsterilized male partner must use highly effective contraception from screening onwards (and one additional method of contraception for subjects in the Czech Republic only) and agree to continue using such protection for 6 months after the last dose of study drug; discontinuation of contraception after that 6-month period should be discussed with the treating physician. Periodic abstinence, rhythm methods, and withdrawal are not acceptable methods of contraception. (a) Women of childbearing potential are defined as those who are not surgically sterilized (i.e., bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or postmenopausal (according to International Council for Harmonization (ICH) M3(R2)11.2: defined as the absence of menstruation for 12 months without another medical cause). (b) Highly effective contraceptive methods are defined as those with a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Acceptable highly effective contraceptive methods are listed in Table 4. (7) Non-sterilized men who are sexually active with a female partner of childbearing potential must use male condoms plus spermicide from Day 1 onwards for 3 months after receiving the last dose of study drug (for subjects in the Czech Republic only, one additional method of contraception must be used) (see Table 4). Because male condoms and spermicides are not highly effective methods of contraception, it is strongly recommended that female partners of male subjects also use highly effective methods of contraception throughout this period; (8) Surgically sterilized men who do not have adequate post-vasectomy documentation of the absence of sperm in the ejaculate and who are sexually active with a female partner of childbearing potential must use condoms and spermicides after Day 1 and for 3 months after receiving the last dose of study drug.

[0118] Exclusion Criteria. Any of the following will exclude a subject from participation in this study: (1) any condition that, in the opinion of the investigator, could interfere with the evaluation or administration of the investigational drug or with the subject's safety or interpretation of the study results; (2) history of concurrent / previous enrollment in another clinical trial involving the investigational treatment within 4 weeks prior to randomization or within 5 published half-lives of that investigational treatment, whichever is longer; (3) an estimated glomerular filtration rate (GFR) less than 60 mL / min; (4) lactating or pregnant women or women intending to become pregnant at any time from signing the ICF, throughout the study, and up to 6 months after the last dose of investigational drug; (5) a known history of allergy or reaction to any component of the investigational drug formulation or anaphylaxis after any biologic therapy; (6) evidence of alcohol, drug, or chemical abuse, or a recent history of such abuse less than 1 year prior to randomization; (7) major surgery within 8 weeks prior to signing the ICF, or a planned waiting period throughout the study's RCP since screening. (8) spontaneous or induced abortion, stillbirth or live birth, or pregnancy within 4 weeks prior to signing the ICF; (9) subjects who cannot undergo MRI scans (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); (10) at screening (one repeat test may be performed before randomization within the same screening period to confirm the results), including: (a) aspartate transaminase (AST) greater than 2.5 × upper limit of normal (ULN); (b) alanine transaminase (ALT) greater than 2.5 × ULN; (c) total bilirubin (excluding that due to Gilbert syndrome) greater than 1.5 × ULN; (d) platelet count less than 75,000 / μL (or less than 75 × 109 / L); (e) hemoglobin less than 8 g / dL (or less than 80 g / L); (f) glycosylated hemoglobin (I IbAlc) greater than 8% at screening (only for subjects with diabetes); or (g) CD19 B-cell count below the lower limit of normal (LLN) by central laboratory.Any of the following related to concomitant medications will exclude a subject from participation in this study: (11) receipt of the following at any time before randomization: (a) alemtuzumab; (b) total lymph node irradiation; (c) bone marrow transplant; (d) T-cell vaccine therapy; (12) receipt of rituximab or any experimental B-cell depleting agent within 6 months prior to screening, unless the subject's B-cell count exceeds the LLN by central laboratory; (13) receipt of IVIG within 1 month prior to randomization; (14) receipt of IVIG within 3 months prior to randomization Administration of any of the following within the last 12 months: (a) natalizumab (Tysabri®), (b) cyclosporine, (c) methotrexate, (d) mitoxantrone, (e) cyclophosphamide, (f) tocilizumab, (g) eculizumab; or (15) a history of severe drug allergies or anaphylaxis to two or more foods or medications (including known hypersensitivity to acetaminophen / paracetamol, diphenhydramine or equivalent antihistamines, and methylprednisolone or equivalent glucocorticoids). Any of the following criteria related to NMO and other diseases will exclude a subject from participating in the study: (16) AQP4-IgG seronegative subject with brain MRI abnormalities that meet the diagnostic criteria for MS (MRIs taken at screening will be centrally reviewed); (17) uncontrolled hypertension as noted by the treating physician and / or investigator; (18) any comorbidity other than NMO that required treatment with oral or intravenous steroids at a dose greater than 20 mg / day for more than 21 days within 6 months prior to screening; (19) any subject diagnosed with a concomitant autoimmune disease that is either uncontrolled or requires the use of disease-modifying or immunosuppressive agents. Any of the following criteria related to infection and malignancy risk factors will exclude a subject from participating in the study: (20) Administration of any of the following - (a) any live or attenuated vaccine within 3 weeks prior to Day 1 (administration of killed vaccines is permitted).The sponsor advises the investigator to ensure that all subjects are up to date on required vaccinations prior to study enrollment), (b) Bacillus Calmette-Guerin (BCG) vaccine within 1 year of signing the ICF, (c) blood transfusion within 4 weeks prior to signing the ICF; (21) clinically significant severe active or chronic viral infection within 60 days prior to randomization that required anti-infective treatment, hospitalization, or that, in the investigator's opinion, represents an additional risk to the subject. or bacterial infection; (22) known history of primary immunodeficiency (congenital or acquired) or history of underlying condition that predisposes the subject to infection, such as human immunodeficiency virus (HIV) infection or splenectomy; (23) any of the following at screening (one repeat test may be performed before randomization within the same screening period to confirm the result): (a) total Ig less than 600 mg / dL, (b) absolute neutrophil count less than 1200 cells / μL, or (c) CD4 T lymphocyte count less than 300 cells / μL; (24) confirmed hepatitis B / hepatitis C serology positive at screening: (a) hepatitis B surface antigen positive, (b) hepatitis B core antibody positive and hepatitis B surface antibody negative, or (c) hepatitis C antibody positive; (25) subject with a positive QuantiFERON®-TB Gold test, unless there is documentation of an adequate course of anti-tuberculosis (TB) treatment. Subjects with an indeterminate outcome may be eligible if their chest x-ray shows no evidence of TB and they have no evidence of latent TB; (26) A history of cancer treatment for more than 3 months prior to randomization, apart from squamous or basal cell carcinoma of the skin with documented successful curative therapy.

[0119] Example 3 - Clinical Trial Protocol Screening Period. Subjects with a diagnosis of NMO / NMOSD were screened over a 28-day period to establish their eligibility for participation in the study based on the inclusion and exclusion criteria. All subjects who met the eligibility criteria were randomized into the study.

[0120] Randomization. Subjects were randomized into the study in a 3:1 ratio to receive intravenous VIB551 (30 mg) or placebo, as described in Table 1. Randomization occurred on Day 1 and was stratified by AQP4-IgG serostatus (approximately 80:20 ratio of seropositive and seronegative subjects, respectively) and region (Japan vs. outside Japan). [Table 1]

[0121] Randomized-Controlled Period (Days 1-197). After randomization on Day 1, subjects were treated with VIB551 or placebo on Days 1 and 15. An oral corticosteroid course was initiated on Day 1 (prednisone 20 mg / day or equivalent oral glucocorticoid) and continued through Day 14. A tapering of oral corticosteroids was performed from Days 15 to 21 (for prednisone: 15 mg prednisone on Day 15, 10 mg prednisone on Day 16, 7.5 mg prednisone on Day 17, 5 mg prednisone on Days 18 and 19, and 2.5 mg prednisone on Days 20 and 21). By Day 21, tapering was complete. The rationale for using oral corticosteroids (prednisone 20 mg / day or equivalent oral glucocorticoid) for the first 14 days (with a 1-week taper) was to provide prophylaxis of neuromyelitis optica spectrum disorder attacks during this period when the pharmacodynamic effects of VIB551 are not expected (maximal B-cell depletion requires a period of approximately 2 to 4 weeks).

[0122] During the randomized-controlled period, subjects were followed at scheduled study visits and by telephone interview. The duration of each subject's randomized-controlled period was planned to be 197 days. All subjects who completed the randomized-controlled period without experiencing an NMO / NMOSD attack were given the option to proceed to the open-label period.

[0123] Open-label Period. Subjects were given the option to proceed to the open-label period if they (1) completed the 197-day randomized-controlled period; (2) experienced an adjudication committee-determined NMO / NMOSD seizure during the randomized-controlled period; (3) were in the randomized-controlled period at the time of the occurrence of 67 adjudication committee-determined NMO / NMOSD seizures; or (4) were in the randomized-controlled period when enrollment was halted following a DMC recommendation based on efficacy and safety evidence.

[0124] Patients who discontinued the randomized-controlled period for reasons other than adjudicated seizures or the occurrence of 67 adjudicated seizures were ineligible for the open-label period. The reason for patients not proceeding to the open-label period was determined. These patients were then followed for safety during the safety follow-up period.

[0125] If patients entered the open-label period for one of the four reasons outlined above, they received 300 mg of VIB551 every 26 weeks; however, patients randomized to placebo during the randomized-controlled period received an additional 300 mg dose on day 15 of the open-label period to maintain their initial total dose of 600 mg. Table 2 provides the open-label period treatment regimen. [Table 2]

[0126] During the open-label period, patients were followed at scheduled study visits and continued to receive VIB551 therapy for up to 3 years (after the last patient progressed) until regulatory approval of VIB551 in each participating country or discontinuation of VIB551 in this indication by the sponsor, whichever occurred first. Patients were followed identically to the randomized-controlled period for seizures, and events were centrally adjudicated.

[0127] Patients could choose to terminate the open-label period at any time for any reason, including seeking alternative treatment options, at which point they proceeded to the safety follow-up period (unless consent was withdrawn).

[0128] Safety Follow-Up Period. The safety follow-up period began when a patient prematurely discontinued from the randomized-controlled or open-label period. The length of the safety follow-up period was determined by the time elapsed between the last dose and the time of premature discontinuation, completing a total of 52 weeks. During the safety follow-up period, patients were monitored for adverse / serious adverse events, B-cell levels, anti-drug antibodies, and immunoglobulin levels. Patients could receive standard of care for their condition at the investigator's discretion.

[0129] The overall study design flow diagram is provided in Figure 2 .

[0130] Example 4 - Patient monitoring during clinical trial treatment Randomized Controlled Treatment Period. After a screening period (≤56 days), eligible participants were randomized 3:1 (permuted block randomization scheme) via a central voice / web automated response system to receive intravenous VIB551 300 mg or placebo, respectively, on days 1 and 15. Participants, investigators, sponsors, adjudication committees, and staff involved in patient care or clinical evaluation, including EDSS assessors, were masked / blinded as to the treatment received, and VIB551 was visually indistinguishable from placebo.

[0131] Table 3 shows all procedures that had to be performed during the randomized controlled treatment period. Patient-reported outcomes were performed first, followed by all other assessments / procedures in an order determined by the site. If a subject elected to enroll in the open-label period, the subject followed the open-label period enrollment procedures in Table 4. [Table 3] TIFF0007779738000004.tif216170TIFF0007779738000005.tif93170

[0132] Open-Label Period. All procedures performed during the open-label period are listed in Table 4. Patient-reported outcomes were performed first, followed by all other assessments / procedures in an order determined by the site. For subjects who completed Day 197 of the randomized-controlled period, Day 1 of the open-label period must be the same day; however, this may be delayed for up to 14 days (procedures do not need to be repeated). After 14 days, subjects will not be allowed to proceed to the open-label period unless there is a compelling reason to do so in consultation with and with the consent of the medical monitor, in which case a short-term extension may be granted.

[0133] Subjects who experienced an adjudication committee-determined NMO / NMOSD seizure during the randomized-controlled period had to proceed to the open-label period within 28 days of the site receiving confirmation of the seizure from the adjudication committee. Day 1 of the open-label period could use procedures performed during the final visit if it occurred within 14 days of the assessment visit. Otherwise, the required procedures must be performed on Day 1 of the open-label period.

[0134] Subjects who were in the randomized-controlled period when the 67th committee-determined seizure occurred or when enrollment was stopped following an independent DMC recommendation based on efficacy and safety evidence and who wanted to enroll in the open-label period were required to do so as soon as possible, preferably within 14 days. If transition to the open-label period was not completed within 14 days, consultation with a medical examiner was encouraged.

[0135] VIB551 administration began on day 1 of the open-label period.

[0136] The open-label period had to continue for a minimum of 1 year and a maximum of 3 years (after the last subject was initiated), or until regulatory approval of VIB551 in the participating country, or until development of VIB551 in NMO / NMOSD was discontinued. [Table 4] TIFF0007779738000007.tif245170TIFF0007779738000008.tif108170

[0137] Evaluation visits were conducted for subjects experiencing new or worsening symptoms potentially related to NMO / NMOSD. Evaluation visits should be scheduled as soon as possible, within 72 hours of symptom onset. Table 5 lists all study procedures to be performed at the evaluation visit. Procedures to determine whether symptoms are related to NMO / NMOSD should be performed first, followed by procedures to determine NMO / NMOSD seizures. Table 6 lists the criteria used for NMO / NMOSD seizures, along with the severity based on the criteria. All clinical evaluations had to be documented with the date and time, and the order of evaluations was determined by the nature of the suspected seizures (e.g., EDSS before independent ophthalmology in the case of spinal cord inflammation symptoms). MRI of all regions had to be performed as part of the evaluation visit and could be performed at any time during the evaluation visit. The order of MRI regions performed could be determined by the nature of the suspected seizures. MRI images / study reports were not to be reviewed by the investigator, unless specific seizure criteria required MRI review. In such cases, MRI review had to be performed after review of all relevant clinical evaluation data (e.g., EDSS in the case of myelitis / brainstem / cerebral symptoms, or ophthalmology in the case of optic neuritis symptoms) was completed. Evaluation had to occur as soon as possible but should not extend beyond 4 days from day 1 of the evaluation visit.

[0138] If the investigator determined that the new or worsening symptoms were not related to NMO / NMOSD, then an independent evaluation (EDSS, independent ophthalmology, and MRI) was not required. [Table 5] [Table 6] TIFF0007779738000011.tif141170

[0139] Evaluation Visit for Subjects Who Experienced an NMO / NMOSD Seizure. Regardless of the outcome of the adjudication committee review, subjects who met the protocol-defined criteria and experienced an NMO / NMOSD seizure requiring life-saving treatment were to undergo a seizure follow-up visit. Table 7 shows the procedures that were to occur at the seizure follow-up visit. Patient-reported outcomes were to be performed first, followed by all other assessments / procedures in an order determined by the site. The seizure follow-up visit was to occur on days 1 through 28 of the evaluation visit. This visit could overlap with the open-label period or safety follow-up visit, or could be scheduled separately. [Table 7]

[0140] Safety Follow-Up Period. The safety follow-up period begins when a subject prematurely discontinues the randomized-controlled or open-label period. Procedures to be performed during the safety follow-up period are provided in Table 8. The length of the safety follow-up period will be determined by the time elapsed between the last dose of VIB551 and the time of early discontinuation, completing a total of 52 weeks. Subjects who prematurely discontinue during the randomized-controlled period will continue to receive study evaluations through Day 197, unless they specifically withdraw consent for further study evaluations. [Table 8]

[0141] Example 5 - Seizure Assessment Neuromyelitis Optica Spectrum Disorder Seizure Adjudication Process. To ensure uniform application of defined seizure diagnostic criteria, a detailed process for seizure diagnosis and real-time adjudication was developed and followed. See Table 6. Patients were monitored for new or worsening symptoms associated with neuromyelitis optica spectrum disorder seizures between scheduled study visits and with follow-up phone calls every 2 weeks between study visits (or if they missed a scheduled visit).

[0142] Patients were required to notify the facility if they experienced new or worsening symptoms potentially related to neuromyelitis optica spectrum disorder. If an evaluation visit was required, it was scheduled as soon as possible, but within 72 hours of symptom onset. At the evaluation visit, patients were assessed to determine whether their symptoms were related to neuromyelitis optica spectrum disorder. If so, patients underwent further evaluation to determine whether their symptoms met at least one of the protocol-defined neuromyelitis optica spectrum disorder seizure criteria.

[0143] Patients continued in the randomized control period if the new or worsening symptom did not meet at least one of the protocol-specified neuromyelitis optica spectrum disorder attack criteria. Data related to the assessment of symptoms determined by the investigator not to be related to neuromyelitis optica spectrum disorder were sent to an adjudication committee for review.

[0144] Assessment of new symptoms or worsening of existing symptoms had to be completed within 5 days to determine whether a seizure had occurred. After the seizure assessment was completed and it was determined that the protocol seizure criteria had been met, seizure treatment was initiated as appropriate; however, the investigator could initiate rescue therapy at any time earlier if necessary. Rescue therapy was provided as directed by the investigator. This could have included intravenous corticosteroids, intravenous immunoglobulin, and / or plasma exchange.

[0145] After completion of the evaluation visit, the complete data set generated by the evaluation was sent to the evaluation committee, regardless of whether a neuromyelitis optica spectrum disorder (NMSD) seizure was diagnosed by the investigator per protocol criteria. Data sent included: (1) a description of any new or worsening symptoms; (2) physical and neurologic examination findings; (3) relevant laboratory test results; (4) relevant radiographic studies, if performed in connection with the evaluation; (5) Expanded Disability Status Scale (EDSS) score as determined by an independent assessor; (6) ophthalmologic examination results performed by an independent ophthalmologist; (7) MRI scans, as appropriate, depending on the suspected per-protocol seizure criteria; and (8) a short narrative written by the investigator summarizing the evaluation without disclosing whether a NMSD seizure was diagnosed (a narrative template was provided by the sponsor).

[0146] The investigator's opinion regarding whether a neuromyelitis optica spectrum disorder seizure occurred was not provided to the adjudication committee, nor was information sent to the adjudication committee regarding which protocol seizure criteria were met or whether rescue medication was provided.

[0147] The adjudication process was completed within 14 days (+3 days) of initiation by an independent blinded adjudication committee of three experts (discussed above). The adjudication committee's decisions were communicated to the investigator. Only seizures adjudicated by the adjudication committee were used in the primary analysis. Adjudication decisions were made independently by each reviewer, and conclusions were based on majority vote.

[0148] To minimize bias, both the Kurtzke EDSS assessor and the ophthalmologist who performed the assessments used to determine seizures were blinded to study treatment and other patient information and were not part of the patient's treatment team. To ensure the predominance of clinical findings in determining seizures, investigators were not permitted to review MRI scans at the time of the seizure unless specific seizure diagnostic criteria required review of MRI scans of relevant areas. Flowcharts illustrating the seizure assessment process, including symptoms affecting the eyes, spinal cord, or brain / brainstem, are shown in Figures 3–6.

[0149] Patients without a diagnosis of neuromyelitis optica spectrum disorder seizures determined by the adjudication committee had the option to continue in the randomized controlled period until day 197. Patients with a diagnosis of neuromyelitis optica spectrum disorder seizures determined by the adjudication committee had the option to proceed to the open-label period.

[0150] In addition, regardless of the outcome of the adjudication committee review, patients who experienced a neuromyelitis optica spectrum disorder seizure that required life-saving treatment and met protocol-defined criteria had a seizure follow-up visit on Day 28 following the evaluation visit. This visit could overlap with or be scheduled separately from the open-label or safety follow-up visits.

[0151] If a patient did not wish to proceed to the open-label period or decided to leave the randomized controlled period at any time, the patient would continue in the safety follow-up period (unless consent was withdrawn).

[0152] Example 6 - Summary of study outcomes Primary endpoint: Time (in days) from Day 1 to onset of a neuromyelitis optica spectrum disorder seizure as determined by an adjudication committee on or before Day 197. A seizure was defined as the presence of a new neuromyelitis optica-related symptom or a worsening of a pre-existing neuromyelitis optica-related symptom that met at least one of the protocol-defined criteria for a neuromyelitis optica spectrum disorder seizure.

[0153] Secondary Outcomes. To control for type I error throughout the study, four key secondary outcomes were considered: (1) worsening of EDSS scores from baseline at the final visit during the randomized controlled period. EDSS assessments in this study were performed by independent, blinded raters at each site using an electronic data collection system developed by the University of Basel and Neurostatus GmbH, which incorporates an internal algorithm that provides raters with feedback on discrepancies in EDSS assessments; (2) change from baseline in low-contrast visual acuity binocular scores measured with a low-contrast Landolt ring chart at the final visit during the randomized controlled period; (3) cumulative total number of active MRI lesions (new gadolinium-enhancing or new / enlarging T2 lesions) during the randomized controlled period; and (4) number of neuromyelitis optica-related hospitalizations, where hospitalization is defined as a stay of more than one night.

[0154] The remaining secondary endpoints were: (1) annualized seizure rate during any exposure to VIB551 (total number of adjudicated seizures, normalized by person-years); (2) treatment-emergent adverse events, including treatment-emergent serious adverse events; (3) clinical laboratory measurements and their changes or shifts from baseline over time; (4) the pharmacokinetic profile of VIB551; and (5) the incidence of anti-drug antibodies to VIB551 during the study, both pre- and post-dose, for each patient.

[0155] Exploratory endpoints: (1) Change from baseline in the 4-week retrospective 36-item Short Form Health Survey, 2nd Edition, physical component score and mental component score at the final visit during the randomized controlled period; (2) Change from baseline in the pain numeric rating scale at five sites at the final visit during the randomized controlled period; (3) B cell counts (total and subsets); (4) Change from baseline in plasma cell gene signature; and (5) serum AQP4-IgG titer.

[0156] Example 7 - Characteristics of Study Participants Between January 2015 and October 2018, 467 participants were screened at 99 participating sites in 24 countries. Of these, 231 enrolled, and 175 were randomized to VIB551 (AQP4-IgG seropositive, n = 161) and 56 to placebo (AQP4-IgG seropositive, n = 52; Figure 1). On September 7, 2018, the Data Monitoring Committee recommended halting enrollment before the target number of seizures (252 participants / 67 adjudicated cases) was achieved, due to clear evidence of efficacy and conditional power of 99% or greater. On September 21, 2018, the sponsor halted enrollment and locked the database while remaining blinded to treatment assignment.

[0157] Of those assigned to VIB551, 174 (99.4%) were included in the analysis population (one participant [0.6%] did not receive the study drug); 169 (97.1%) participants completed the randomized-controlled period, and 6 either discontinued due to adverse events (n = 2), withdrew consent (n = 1), or were assigned "other" (n = 3). Of the 56 participants assigned to placebo, 54 (96.4%) completed the randomized-controlled period; 2 participants discontinued (n = 1 withdrew consent, n = 1 was assigned "other"; Figure 7). Most participants were female (n = 209, 90.9%; Table 9) and white (n = 120, 52.2%; Table 9). Participant characteristics were broadly similar between the overall treatment group and the AQP4-IgG seropositive population (Table 9). The open-label period is ongoing, with 213 participants receiving VIB551 (originally randomized: VIB551, n=162; placebo, n=51). [Table 9] TIFF0007779738000015.tif139170

[0158] Example 8 - VIB551 is effective in reducing NMOSD attack risk The study achieved its primary endpoint, with a significant difference in time to NMOSD seizures favoring VIB551 compared with placebo. Overall, 21 of 174 participants (12.1%) receiving VIB551 experienced a seizure compared with 22 of 56 participants (39.3%) receiving placebo; relative risk reduction, 72.8%; hazard ratio, 0.272 (95% confidence interval [CI], 0.150–0.496; p<0.0001); and number needed to treat, 3.73 (95% CI, 3.06–5.66) (Figure 8A). In the AQP4-IgG seropositive subgroup, the relative risk reduction was 77.3%; hazard ratio 0.227 (95% CI, 0.121–0.423; p<0.0001); and number needed to treat 3.23 (95% CI, 2.72–4.54) (Figure 8B). After 1 year of continuous VIB551 treatment, 85% of patients were NMOSD attack-free. In the combined safety analysis of RCP and OLP, the median duration of VIB551 treatment was 1.5 years (range, 0.2–3.7).

[0159] A breakdown of seizure types is provided in Table 10. Of the 43 seizures determined by the AC, 27 were myelitis, 20 were ON, and 2 were brainstem seizures, with 6 affecting more than one region. Of the 43 events, the AC considered the criteria requiring MRI to be met 16 times. Of the 22 seizures in the placebo group, 10 (45%) were graded as grand mal and 12 (55%) as petit mal, compared with 6 of 21 (29%) grand mal and 15 of 21 (71%) petit mal in the VIB551-treated group. [Table 10]

[0160] Seizure recovery was graded as shown in Table 11. Seizure recovery was assessed using a predefined exploratory scale (large, small, no recovery) according to the degree of domain-specific neurological recovery at the seizure follow-up visit (within 35 days of the seizure) compared to the seizure visit. Of 17 seizures with follow-up data in the placebo group, 9 (53%) did not recover, and 8 (47%) had at least partial recovery. In the VIB551 group, 6 of 13 seizures (46%) did not recover, and 7 of 13 (54%) had at least partial recovery. [Table 11]

[0161] The annualized attack rate (the total number of AC-determined NMOSD seizures normalized by person-years) during any exposure to VIB551 was also determined. Of note, because subjects were removed from the placebo-controlled portion of the study after an AC-determined seizure, annualized attack rates could not be calculated for the placebo treatment period. Therefore, any such calculations during the placebo period would likely have been biased and would have overestimated the attack rate. However, subjects in the VIB551-treated group remained in the study and received VIB551 after the seizure; therefore, an estimate of the annualized attack rate could be calculated for this period during which subjects were treated with VIB551.

[0162] The AC-determined annualized NMOSD attack rate in any subject treated with VIB551 was low at 0.126 (see Table 12). When calculated separately for AQP4-IgG seropositive and AQP4-IgG seronegative subjects, the annualized attack rates were 0.13 and 0.088, respectively. [Table 12]

[0163] The study was stopped early following the recommendation of an independent data monitoring committee because efficacy was clearly demonstrated.

[0164] Example 9 - VIB551 achieved key secondary endpoints of reducing EDSS score deterioration from baseline, reducing the number of active MRI lesions, and reducing disease-related hospitalizations. Key secondary endpoints for the overall intent-to-treat population and the AQP4-IgG seropositive population are presented in Table 13. The proportion of subjects experiencing a worsening of EDSS scores from baseline to the final RCP visit was lower in the VIB551 group than in the placebo group among AQP4-IgG seropositive subjects. This difference was statistically significant, with an odds ratio for the VIB551 group compared with the placebo group of 0.371 (95% CI: 0.1807, 0.7633; p=0.0070). Similarly, in the overall ITT population, a lower proportion of subjects in all VIB551 groups compared with all placebo groups experienced a worsening of EDSS scores. The odds ratio for the VIB551 group compared with the placebo group was 0.370 (95% CI: 0.1850, 0.7389; p=0.0049). Subjects were considered to have experienced a worsening of the overall EDSS score if they met one of the following criteria: a worsening of the EDSS score of 2 or more points for subjects with a baseline score of 0; a worsening of the EDSS score of 1 or more points for subjects with a baseline score of 1 to 5; or a worsening of the EDSS score of 0.5 or more points for subjects with a baseline score of 5.5 or greater.

[0165] There was no difference between treatment groups in the change from baseline in low-contrast visual acuity binocular scores; however, VIB551-treated participants appeared to experience less optic neuritis; overall intent-to-treat population: hazard ratio 0.288 (95% CI, 0.120 to 0.694); AQP4-IgG seropositive population: hazard ratio 0.222 (95% CI, 0.088 to 0.565).

[0166] Treatment with VIB551 significantly reduced the cumulative number of active MRI lesions compared with treatment with placebo. The between-group rate ratio was 0.568 (95% CI: 0.3851, 0.8363; p-0.0042) among AQP4-IgG seropositive subjects (Table 13). For subjects with active MRI lesions, the mean cumulative number of active MRI lesions was lower in the VIB551 group (1.7 lesions) compared with the placebo group (2.3 lesions) among AQP4-IgG seropositive subjects. Similar results were observed across the ITT population. Note that the mean lesion counts were calculated based on all subjects in each population.

[0167] Treatment with VIB551 significantly reduced hospital admissions compared with placebo. Among AQP4-IgG seropositive subjects, the between-group rate ratio was 0.258 (95% CI: 0.0904, 0.7384; p=0.0115) (Table 13). For subjects with hospitalizations, the mean number of NMOSD-related hospital admissions was lower in the inebilizumab group compared with the placebo group among AQP4-IgG seropositive subjects. A similar significant difference was observed in the overall ITT population. [Table 13]

[0168] Example 10 - Change at baseline in mRS for Neurological Disability showed significant benefit for VIB551-treated NMOSD subjects The treatment effect based on the mRS score during RCP was assessed using the Wilcoxon-Mann-Whitney odds method. The mRS is a commonly used scale to measure the degree of disability or dependency on care for daily activities in people who have suffered a stroke or other neurological disability. The mRS ranges from 0 to 6, ranging from complete health without symptoms to death: 0 - no symptoms; 1 - some symptoms but no significant disability, able to perform all usual activities; 2 - mild disability, able to care for oneself without assistance but unable to perform all previous activities; 3 - moderate disability, able to walk independently but with some assistance; 4 - moderate to severe disability, unable to manage one's own physiological needs without assistance and with difficulty walking independently; 5 - severe disability, requiring full-time care, bedridden, and incontinent; and 6 - death.

[0169] AQP4-IgG seropositive subjects receiving VIB551 were 74.2% more likely to report milder disability compared with placebo subjects. In 52.8% of possible pairs of VIB551 and placebo subjects, the VIB551-treated subject had a better outcome than the placebo subject at the final visit. In 25.7% of pairs, the placebo subject had a better outcome, and in 21.5% of pairs, the VIB551 subject tied with the placebo subject. This leads to a Wilcoxon-Mann-Whitney odds of 1.742 (p=0.0014).

[0170] In the overall ITT population, in 51.5% of pairs, VIB551 subjects had a better outcome than placebo subjects; in 26.6% of pairs, placebo subjects had a better outcome; and in 21.9% of pairs, the mRS was tied. Subjects receiving VIB551 were 66.3% more likely to report milder disability compared with placebo subjects.

[0171] After just six and a half months, VIB551-treated subjects had a reduced risk of worsening disability as measured by the mRS. Not only did VIB551-treated subjects have a reduced risk of worsening disability as measured by the mRS, they also had a reduced risk of worsening disability as measured by the EDSS.

[0172] Example 11 - VIB551-Treated NMOSD Subjects Experienced Decreased Limb Pain Overall, the mean changes from baseline to week 28 in mean pain NRS scores for all body regions were similar between the placebo and VIB551 groups. However, among AQP4-IgG seropositive subjects and in the overall intent-to-treat population, the VIB551 group tended to show smaller mean increases in leg pain than the placebo group. See Table 14. [Table 14] TIFF0007779738000021.tif246170TIFF0007779738000022.tif27170

[0173] It is also noted that limb pain was less common in the VIB551 group compared to the placebo group (0.6% vs. 7.1% during the randomized controlled period; 4.9% in the any VIB551 population). This difference may reflect lower NMOSD activity and is consistent with the findings of better outcomes for leg pain as measured by NRS, shown in Table 14 and discussed above.

[0174] Example 12 - VIB551 depletes CD20+ B cells and reduces immunoglobulin levels in NMOSD subjects Peripheral blood mononuclear cell subsets, including B cells (CD20+, transitional, naive, memory B cells, plasmablasts, and plasma cells), T cells (CD4+ and CD8+), and NK cells, were assayed by flow cytometry (FACS) throughout the 28-week randomized controlled period (RCP). Peripheral blood B cell- and plasma cell-specific gene expression signatures were also assessed by reverse transcriptase qPCR (rt-qPCR).

[0175] For both AQP4-IgG serum populations, a pharmacodynamic effect of VIB551 on CD20+ B cells was observed within 4 weeks, with significant and robust depletion of circulating B cells compared with placebo. B cell counts in the VIB551 group fell to below 10% of baseline and remained below this threshold throughout the randomized control period. See Figures 9A and 9B. No such effect was observed with placebo.

[0176] CD20+ B cell counts were significantly reduced in 94% of patients during the randomized control period and remained below the lower limit of normal (LLN; 74.4 CD20+ B cells / uL). T cell counts were unchanged; NK cells showed a transient decline on day 15. Peripheral blood CD20- plasmablasts and plasma cells were rapidly depleted by day 8 and remained depleted throughout the randomized control period.

[0177] Plasma cell depletion was confirmed by plasma cell gene expression signature analysis. The plasma cell signature was based on expression analysis of four genes (IGHA1, IGJ, IGKV4-1, and TNFRSF17) primarily expressed in blood plasma cells. Plasma cell-specific gene expression signatures were determined by reverse transcriptase quantitative PCR (rt-qPCR) of blood cell RNA samples collected on days 1, 15, 29, 85, 113, 155, and 197 of the randomized control period. Signatures were calculated as the mean expression levels of these four plasma cell-specific genes minus the mean expression levels of five control genes (B2M, GAPDH, TFRC, GUSB, and UBC) at each time point. The fold change in plasma cell gene expression signature relative to the day 1 pretreatment level was calculated at each time point and interpreted as the change in plasma cell abundance. The plasma cell-specific gene expression signature was significantly reduced in VIB551-treated subjects by day 15, and this declined by more than 10-fold during the 28-week randomized controlled period. In the placebo group, there were no significant differences in the plasma cell-specific gene signature between any of the time points. See Figures 11A and 11B.

[0178] Subjects with complete FACS data were stratified by the depth and duration of B cell depletion. "Stable depletion [SD]" (74% of treated subjects) consistently maintained B cell counts below 5 cells / uL throughout RCP. "Partial depletion [PD]" (9% of treated subjects) maintained B cell counts below LLN >5 cells / uL throughout RCP. "Early reconstitution [ER]" (17% of treated subjects) demonstrated initial B cell depletion but replenished to >5 cells / uL before their final RCP visit. Early B cell replenishment was attributed to the emergence of transitional and naive B cells. There was no association between NMOSD attack frequency and CD20+ B cell depletion in VIB551-treated subjects (SD: 12 / 118 (10%), PD: 2 / 15 (13%), ER: 4 / 28 (14%)). Plasma cell gene signatures were not significantly elevated in relapsed VIB551-treated subjects.

[0179] Consistent with the known class effect of B cell-depleting agents, serum immunoglobulin levels also decreased with the use of VIB551. For subjects receiving VIB551 from the start of the randomized controlled period, the median percent change in total Ig levels was -12.42% at open-label week 0, -19.48% at open-label week 52, -28.59% at open-label week 104, and -40.12% at open-label week 143. For subjects receiving VIB551 from the start of RCP, the median percent change in IgG levels was -8.88% at open-label week 0, -16.69% at open-label week 52, -25.33% at open-label week 104, and -36.12% at open-label week 143. See Figures 12-17.

[0180] Example 13 - VIB551 is safe for treating NMOSD Adverse events occurred in 71.8% of participants receiving VIB551 and 73.2% of participants receiving placebo (Table 15). Most adverse events were more common with placebo than with VIB551, including infusion-related reactions (placebo, 10.7%; VIB551, 9.2%). Urinary tract infections, arthralgia, back pain, headache, falls, hypoesthesia, cystitis, and eye pain were nominally more frequent with VIB551. Serious adverse events occurred in 4.6% of participants receiving VIB551 and 8.9% receiving placebo VIB551; none were reported in more than two participants, and no deaths occurred throughout the randomized-controlled period. Safety endpoints in the AQP4-IgG seropositive population were similar to those reported above. [Table 15] TIFF0007779738000024.tif131170

[0181] B-cell depletion therapy is associated with increased risk of cancer and infections, including PML. 20、23VIB551 did not result in any malignancies, and infection rates were lower than with placebo. No deaths occurred during the randomized-controlled period; however, two deaths were reported during the open-label phase. The first occurred in a participant who had a serious adverse event of pneumonia shortly after randomization, followed by an adjudicated seizure before enrollment in the open-label phase. This participant died 9 days later at home, presumably from respiratory failure. The second participant developed new-onset weakness, aphasia, neuropathy, and seizures during the open-label phase. Brain MRI demonstrated large new lesions affecting both white and gray matter structures. The patient suffered respiratory arrest and died from cardiopulmonary complications. No brain biopsy or autopsy was performed. Polymerase chain reaction testing of cerebrospinal fluid for John Cunningham virus (JCV) was negative by two independent, certified laboratories, but a positive result was reported by another, unidentified laboratory. Although there was no confirmatory MRI or JCV information, the differential diagnosis included progressive multifocal leukoencephalopathy (PML), acute disseminated encephalomyelitis, and atypical NMOSD attacks.

[0182] Example 14 - Subclinical MRI lesion activity is a hallmark of NMOSD disease As part of the clinical trial, longitudinal MRI was systematically performed in patients with NMOSD. Each patient underwent MRI of the brain, optic nerve, and spinal cord at baseline, within 8 days of an NMOSD attack (if the patient had an NMOSD attack), and at the end of the RCP (6.5 months). MRIs were centrally read for new gadolinium-enhancing T1 (new Gad-T1) lesions by two independent neuroradiologists blinded to treatment. Seizures were adjudicated by an expert committee.

[0183] Complete MRI data were available for 192 of 230 participants (83%), of whom 42 had adjudicated seizures (22 myelitis, 14 optic neuritis, 6 multiregional). Interrater agreement between the two neuroradiologists for gadolinium-enhancing lesions was 98% for the brain, 95% for the spinal cord, and 90% for the optic nerve.

[0184] Among 42 participants with adjudicated NMOSD attacks, 19 / 22 (86%) with myelitis and 11 / 14 (79%) with optic neuritis attacks had novel Gad-T1 MRI lesions corresponding to the clinically affected area. During the optic neuritis attack, asymptomatic novel Gad-T1 lesions were simultaneously observed on spinal cord MRI in 4 / 14 (29%) and brain MRI in 1 / 14 (7%). During the myelitis attack, asymptomatic novel Gad-T1 lesions were simultaneously observed on optic nerve MRI in 6 / 22 (27%) and brain MRI in 3 / 22 (14%). Thus, asymptomatic Gad-T1 lesions were detected outside the symptomatic attack area in approximately one-third of these participants.

[0185] Among 150 participants without adjudicated seizures, new Gad-T1 MRI lesions were observed in the brain (3%), spinal cord (18%), and optic nerve (51%) of these participants at the end of the randomized controlled period.

[0186] These data demonstrate that subclinical MRI lesions occur outside the symptomatic area during NMOSD attacks and that de novo MRI lesions were detected in some patients without NMOSD attacks. These data suggest that, contrary to current understanding of NMOSD, subclinical radiographic disease activity is not uncommon in NMOSD. Analysis of complete neuraxial MRI scans in clinical trials will provide information about the potential role of MRI in NMOSD disease management and treatment.

[0187] References 1.Cree BA, Bennett JL, Sheehan M, et al.Placebo-controlled study in neuromyelitis optica-ethical and design considerations.Mult Scler 2016;22:862-72. 2.Wingerchuk DM,Lennon VA,Lucchinetti CF,Pittock SJ,Weinshenker BG.The spectrum of neuromyelitis optica.Lancet Neurol 2007;6:805-15. 3.Fujihara K,Misu T,Nakashima I,et al.Neuromyelitis optica should be classified as an astrocytopathic disease rather than a demyelinating disease.Clin Exp Neuroimmunol 2012;3:58-73. 4.Weinshenker BG,Wingerchuk DM,Vukusic S,et al.Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis.Ann Neurol 2006;59:566-9. 5.Bennett JL,Lam C,Kalluri SR,et al.Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica.Ann Neurol 2009;66:617-29. 6.Jarius S,Frederikson J,Waters P,et al.Frequency and prognostic impact of antibodies to aquaporin-4 in patients with optic neuritis.J Neurol Sci 2010;298:158-62. 7.Saadoun S,Waters P,Bell BA,Vincent A,Verkman AS,Papadopoulos MC.Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice.Brain 2010;133:349-61. 8.Bennett JL,O’Connor KC,Bar-Or A,et al.B lymphocytes in neuromyelitis optica.Neurol Neuroimmunol Neuroinflamm 2015;2:e104. 9.Trebst C,Jarius S,Berthele A,et al.Update on the diagnosis and treatment of neuromyelitis optica:recommendations of the Neuromyelitis Optica Study Group(NEMOS).J Neurol 2014;261:1-16. 10.Damato V,Evoli A,Iorio R.Efficacy and Safety of Rituximab Therapy in Neuromyelitis Optica Spectrum Disorders:A Systematic Review and Meta-analysis.JAMA Neurol 2016;73:1342-8. 11.Ciron J,Audoin B,Bourre B,et al.Recommendations for the use of Rituximab in neuromyelitis optica spectrum disorders.Rev Neurol(Paris)2018;174:255-64. 12.Cree BA,Lamb S,Morgan K,Chen A,Waubant E,Genain C.An open label study of the effects of rituximab in neuromyelitis optica.Neurology 2005;64:1270-2. 13.Palanichamy A,Jahn S,Nickles D,et al.Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients.J Immunol 2014;193:580-6. 14.Millen B,Dmitrienko A.Chain procedures:a class of flexible closed testing procedures with clinical trial applications.Stat Biopharm Res 2012;3:14-30. 15.Patra K,Cree BAC,Katz E,Pulkstenis E,Dmitrienko A,Cutter G.Statistical considerations for an adaptive design for a serious rare disease.Ther Innov Regul Sci 2016;50:375-84. 16.Schiopu E,Chatterjee S,Hsu V,et al.Safety and tolerability of an anti-CD19 monoclonal antibody,MEDI-551,in subjects with systemic sclerosis:a phase I,randomized,placebo-controlled,escalating single-dose study.Arthritis Res Ther 2016;18:131. 17.Wingerchuk DM,Lennon VA,Pittock SJ,Lucchinetti CF,Weinshenker BG.Revised diagnostic criteria for neuromyelitis optica.Neurology 2006;66:1485-9.. 18.Cree BA.Placebo controlled trials in neuromyelitis optica are needed and ethical.Mult Scler Relat Disord 2015;4:536-45. 19.Bretz F,Maurer W,Brannath W,Posch M.A graphical approach to sequentially rejective multiple test procedures.Stat Med 2009;28:586-604.. 20.Genentech.Ocrevus prescribing information.2017.Https: / / www.gene.com / download / pdf / ocrevus_prescribing.pdf(accessed February 28 2019). 21.Hauser SL,Bar-Or A,Comi G,et al.Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.N Engl J Med 2017;376:221-34. 22.Montalban X,Hauser SL,Kappos L,et al.Ocrelizumab versus placebo in primary progressive multiple sclerosis.N Engl J Med 2017;376:209-20.. 23.Genentech.Rituxan prescribing information.1997.Https: / / www.gene.com / download / pdf / rituxan_prescribing.pdf(accessed February 28 2019) 24.ClinicalTrials.gov.Efficacy and safety study as monotherapy of SA237 to treat NMO and NMOSD.2014.Https: / / clinicaltrials.gov / ct2 / show / NCT02073279(accessed January 25 2019). 25.ClinicalTrials.gov.Efficacy and safety study as add-on therapy of SA237 to treat NMO and NMOSD.2014.Https: / / clinicaltrials.gov / ct2 / show / NCT02028884(accessed January 25 2019).. 26.ClinicalTrials.gov.A double blind trial to evaluate the safety and efficacy of eculizumab In relapsing NMO Patients(PREVENT study).2013.Https: / / clinicaltrials.gov / ct2 / show / NCT01892345(accessed January 25 2019).. 27.Paul F,Murphy O,Pardo S,Levy M.Investigational drugs in development to prevent neuromyelitis optica relapses.Expert Opin Investig Drugs 2018;27:265-71.

Claims

1. 1. A medicament for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in a subject in need thereof, comprising: the medicament comprises a composition comprising an anti-CD19 antibody comprising a variable heavy chain and a variable light chain comprising SEQ ID NO: 1 and SEQ ID NO: 2, respectively; the composition comprises 10 mg / mL of the antibody, 20 mM histidine / histidine hydrochloride, 70 mM NaCl, 106 mM trehalose dihydrate, and 0.01% (w / v) polysorbate 80; Medicine.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used so that the antibody is administered to a subject at a dose of 300 mg.

3. The pharmaceutical composition of claim 2, wherein the antibody is administered to a subject every six months at a dose of 300 mg.

4. 4. The method of claim 3, wherein the antibody is administered to a subject at a dose of 300 mg every six months for at least one year.

5. 5. The pharmaceutical composition of claim 3 or 4, wherein the pharmaceutical composition is used such that an initial 300 mg dose of the antibody is administered two weeks prior to the administration of the 300 mg dose of the antibody every six months.

6. said administering a. Worsening of the Kurtzke Expanded Disability Status Scale (EDSS) in said subject b. Magnetic resonance imaging (MRI) lesion counts; c. Number of new MRI lesions; d. Worsening of modified Rankin score; e. the subject's frequency of hospitalizations associated with NMOSD; f. the subject's risk of NMOSD-related seizures; g. Optic neuritis; h. the severity of NMOSD-related seizures; or Any combination of i.a. to h. The pharmaceutical composition according to any one of claims 1 to 5, which is effective in reducing

7. The pharmaceutical according to any one of claims 1 to 6, wherein the antibody is inebilizumab.

8. 1. A medicament for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in a subject in need thereof, comprising: the medicament comprises a composition comprising an anti-CD19 antibody comprising a variable heavy chain and a variable light chain comprising SEQ ID NO: 1 and SEQ ID NO: 2, respectively; the composition comprises 10 mg / mL of the antibody, 20 mM histidine / histidine hydrochloride, 70 mM NaCl, 106 mM trehalose dihydrate, and 0.01% (w / v) polysorbate 80; The medicament is co-administered to the subject with a corticosteroid drug in an amount sufficient to provide prophylaxis against NMOSD attacks. Medicine.

9. The pharmaceutical composition according to claim 8, wherein the antibody is administered to a subject at a dose of 300 mg.

10. The method of claim 9, wherein the antibody is administered to a subject every six months at a dose of 300 mg.

11. 11. The method of claim 10, wherein the antibody is administered to a subject at a dose of 300 mg every six months for at least one year.

12. 12. The medicament of claim 10 or 11, wherein the medicament is used such that an initial 300 mg dose of the antibody is administered two weeks prior to the administration of the 300 mg of the antibody every six months.

13. The pharmaceutical according to any one of claims 8 to 12, wherein the antibody is inebilizumab.

14. The method of any one of claims 8 to 13, wherein the corticosteroid drug is tapered.

15. The pharmaceutical composition according to any one of claims 8 to 14, wherein the corticosteroid drug is prednisone.

16. The pharmaceutical composition according to any one of claims 8 to 15, wherein the subject is AQP4-IgG seropositive.

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