WO2022094334A1 - Use of an anti-cd19 antibody to treat autoimmune disease - Google Patents

Use of an anti-cd19 antibody to treat autoimmune disease Download PDF

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Publication number
WO2022094334A1
WO2022094334A1 PCT/US2021/057443 US2021057443W WO2022094334A1 WO 2022094334 A1 WO2022094334 A1 WO 2022094334A1 US 2021057443 W US2021057443 W US 2021057443W WO 2022094334 A1 WO2022094334 A1 WO 2022094334A1
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Prior art keywords
patient
nmosd
antibody
vib551
months
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English (en)
French (fr)
Inventor
Dewei SHE
Jack RATCHFORD
Eliezer Katz
William Rees
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Viela Bio Inc
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Viela Bio Inc
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Priority to AU2021368769A priority Critical patent/AU2021368769A1/en
Priority to IL302294A priority patent/IL302294A/en
Priority to MX2023004794A priority patent/MX2023004794A/es
Priority to CN202180073551.9A priority patent/CN116583538A/zh
Priority to JP2023526226A priority patent/JP2023549075A/ja
Priority to KR1020237018007A priority patent/KR20230097118A/ko
Application filed by Viela Bio Inc filed Critical Viela Bio Inc
Priority to EP21887669.6A priority patent/EP4237447A4/en
Priority to CA3197022A priority patent/CA3197022A1/en
Publication of WO2022094334A1 publication Critical patent/WO2022094334A1/en
Priority to US18/303,303 priority patent/US20230287114A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Definitions

  • Neuromyelitis optica spectrum disorder is a severe, autoimmune, inflammatory, central nervous system disease with a prevalence of 0 ⁇ 5–4 ⁇ 4/100000.
  • NMOSD Neuromyelitis optica spectrum disorder
  • VIB551 is a humanised, affinity-optimised, afucosylated IgG1 kappa monoclonal antibody that binds to the B-cell surface antigen CD19.
  • anti-CD20 monoclonal antibodies that recognise and deplete a subset of CD20-expressing T lymphocytes (in addition to B lymphocytes) (Palanichamy A, Jahn S, Nickles D, et al.
  • Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients.
  • anti-CD19 antibodies recognise and deplete lymphocytes exclusively from the B-cell lineage.
  • NMOSD neuromyelitis optica spectrum disorder
  • the description provides for a method of treating NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the description provides for a method of treating neuromyelitis optica spectrum disorder (NMOSD), the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, and wherein the patient has not been treated with anti-CD20 for up to 6 months or up to 12 months prior to administering the anti-CD19 antibody VIB551, optionally, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • NMOSD neuromyelitis optica spectrum disorder
  • the description provides for a method of treating NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the description provides for a method of treating NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is an astrocyte water channel aquaporin-4 (AQP4)-IgG+ patient, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months, wherein the patient had been previously treated with an anti-CD20 antibody, and wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • AQP4 astrocyte water channel aquaporin-4
  • the description provides for a method of treating NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is an AQP4- IgG+ patient, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months, wherein the patient had been previously treated with an anti-CD20 antibody; and, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • the patient receives at least one initial dose of VIB551.
  • VIB551 is administered intravenously with a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and subsequent doses of 300 mg every 6 months following the first initial dose.
  • oral corticosteroids are co-administered to the patient with the initial VIB551 dose.
  • oral corticosteroids are administered daily for at least 2 weeks.
  • the anti-CD20 antibody is rituximab.
  • the treating is a reduction in worsening of Kurtzke Expanded Disability Severity Scale (EDSS) in the patient.
  • EDSS Kurtzke Expanded Disability Severity Scale
  • reduction in worsening of EDSS in the patient is: a worsening of fewer than 2 points in EDSS score if the patient has a baseline score of 0; a worsening of fewer than 1 point if the patient has a baseline score of 1 to 5; or a worsening of less than 0.5 point if the patient has a baseline score of 5.5 or more.
  • the treating is a reduction in number of active magnetic resonance imaging (MRI) lesions.
  • the active MRI lesions are enlarging T2 MRI lesions.
  • the treating is a reduction in number of new MRI lesions.
  • the treating is a reduction in worsening of modified Rankin Score in the patient.
  • the treating is a reduction in frequency of in-patient hospitalizations of the patient related to NMOSD.
  • the treating is a reduction of risk of an NMOSD-related attack of the patient.
  • the NMOSD-related attack is characterized by appearance of a new symptom or worsening of an existing symptom related to NMOSD.
  • the symptom is an eye symptom.
  • the eye symptom is eye pain, blurred vision, loss of vision, or appearance of an optic nerve lesion detected by MRI.
  • the symptom is a spinal cord symptom.
  • the spinal cord symptom is deep or radicular pain, extremity paraesthesia, weakness, sphincter dysfunction, Lhermitte’s sign, or a spinal cord lesion detectable by MRI.
  • the symptom is a brain or brain stem symptom.
  • the brain or brainstem symptom is nausea, double vision, oculomotor palsy, vertigo, intractable vomiting, intractable hiccups, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, or a brain or brain stem lesion detectable by MRI.
  • the reduction of risk of the NMOSD-related attack is between 60 and 85%.
  • the treating is a reduction in optic neuritis.
  • the treating is a reduction of severity of NMOSD-related attacks.
  • the reduction of severity of NMOSD-related attacks is the reduction in NMOSD-related attacks graded as major.
  • the reduction of severity of NMOSD- related attacks is the reduction in NMOSD attacks requiring in-patient hospitalization.
  • the treating is a decrease in NMOSD-related pain in the patient.
  • the decrease in NMOSD-related pain is determined by measuring pain in legs of the patient. [0013] In aspects, two weeks prior to the first administering the 300 mg VIB551 every 6 months, an initial 300 mg VIB551 dose is administered to the subject.
  • oral corticosteroids are co-administered to the patient with the initial 300 mg VIB551 dose.
  • the patient is AQP4-IgG seropositive.
  • the description provides for a method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • the description provides for a method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the description provides for a method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the description provides for a method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the description provides for a method of reducing AQP4-IgG titers in a AQP4- IgG+ patient in need of treatment for NMOSD, the method comprising: administering the anti- CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • the description provides for a method of reducing AQP4-IgG titers in a AQP4-IgG+ patient in need of treatment for NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the description provides for a method of reducing AQP4-IgG titers in a AQP4- IgG+ patient in need of treatment for NMOSD, the method comprising: administering the anti- CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the description provides for a method of reducing AQP4-IgG titers in a AQP4-IgG+ patient in need of treatment for NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the administration depletes at least 90% of circulating CD20+ B cells for at least six months.
  • the administration does not increase risk of infections in the patient.
  • the VIB551 depletes peripheral blood CD20- plasmablasts and plasma cells within 8 days following the administering.
  • the description provides for a method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • the description provides for a method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the description provides for a method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the description provides for a method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the reducing the NMOSD-related disability in the patient is a reduction in a rate of worsening of NMOSD-related disability in the patient.
  • the reducing the NMOSD-related disability in the patient is a lessening of NMOSD-related disability in the patient.
  • the NMOSD-related disability is neurological disability.
  • the reducing the NMOSD-related disability is determined using EDSS.
  • the description provides for a method of reducing NMOSD-related attacks in a patient in need of treatment for NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the description provides for a method of reducing NMOSD-related attacks in a patient in need of treatment for NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the description provides for a method of reducing NMOSD-related attacks in a patient in need of treatment for NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the NMOSD-related attacks suffered by the patient comprise any one or more of an optic neuritis, a myelitis, or a brainstem attack.
  • the NMOSD-related attacks suffered by the patient are clinically asymptomatic.
  • the patient receives at least one initial dose of VIB551.
  • the VIB551 is administered intravenously with a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and subsequent doses of 300 mg every 6 months following the first initial dose.
  • oral corticosteroids are co-administered to the patient with the initial 300 mg VIB551 dose.
  • the oral corticosteroids are administered daily for at least 2 weeks.
  • the anti-CD20 antibody is rituximab.
  • the VIB551 comprises a heavy chain variable region (VH) comprising the amino acid of SEQ ID NO:1 and a light chain variable region (VL) comprising the amino acid of SEQ ID NO: 2.
  • VH heavy chain variable region
  • VL light chain variable region
  • the description provides for a method of treating NMOSD, the method comprising: administering an anti-CD19 antibody to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • the description provides for a method of treating NMOSD, the method comprising: administering an anti-CD19 antibody to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • the description provides for a method of treating NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is an AQP4-IgG+ patient, wherein the VIB551 is administered intravenously with a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and subsequent doses of 300 mg every 6 months following the first initial dose, wherein patient had been previously treated with an anti-CD20 antibody, and wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • the description provides for a method of treating NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is an AQP4-IgG+ patient, wherein the VIB551 is administered intravenously with a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and subsequent doses of 300 mg every 6 months following the first initial dose, wherein the patient had been previously treated with an anti-CD20 antibody; and, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • Figure 1 Flow chart of the multiplicity adjustment strategy in N-MOmentum clinical trial.
  • FIG. 1 Study design flow diagram for N-MOmentum clinical trial.
  • AC adjudication committee
  • FU follow-up
  • i.v. intravenous
  • max maximum
  • min minimum
  • NMO/NMOSD neuromyelitis optica/neuromyelitis optica spectrum disorder
  • OLP open-label period
  • RCP randomised controlled period
  • Figure 3 N-MOmentum clinical trial CONSORT flow diagram. (*Efficacy endpoints were assessed in the intent-to-treat population, defined as participants who were randomised and received any investigational product and analysed according to their randomised treatment group, regardless of whether participants received an intervention other than the one planned.
  • FIG. 1 (SEQ ID NO:1) and VL (SEQ ID NO:2) amino acid sequences of the VIB551 antibody.
  • Figure 5. Attack history for N-MOmentum participants with prior Rituximab usage.
  • Figure 6. Attack-free probability stratified by prior Rituxumab use.
  • Figure 7. Absolute CD20+ B-cell counts of individual participants with prior rituximab use during the randomized control period (weeks 0-28) and open-label extension (>week 28). All participants received inebilizumab during the open-label extension.
  • AQP4-IgG titers in a AQP4-IgG + patient in need of treatment for NMOSD using VIB551, wherein the patients have received a previous anti-CD20 antibody treatment.
  • methods of reducing NMOSD-related disability in a patient diagnosed with NMOSD using VIB551, wherein the patients have received a previous anti-CD20 antibody treatment are also described herein.
  • VIB551 may be used to treat patients diagnosed with NMOSD who had one or more NMOSD attacks while being treated with the anti-CD20 antibody.
  • VIB551 may be used to treat patients diagnosed with NMOSD that had one or more NMOSD attacks within 6 months of the last dose of the anti-CD20 antibody.
  • the patient may be an astrocyte water channel aquaporin-4 (AQP4)-IgG+ patient.
  • the anti-CD20 antibody, with which the patient may have been previously treated with is rituximab (antibody C2B8 in WO94/11026, which is incorporated herein by reference in its entirety).
  • the anti-CD20 antibody with which the patient may have been previously treated with, is ABP-300 (Abpro); B-001 (Shanghai Pharmaceuticals Holding); BAT-4306F (Bio-Thera Solutions); BAT-4406F (Bio- Thera Solutions); BCD-132 (Biocad Biotechnology); BVX-20 (Vaccinex); CYT-202 (Cytovia Therapeutics); epcoritamab (Genmab); GB-261 (Genor Biopharma); GD-CO1620 (ManysmarT); glofitamab (Roche); HS-006 (Zhejiang Hisun Pharmaceutical); IGM-2323 (IGM Biosciences); IMM-0306 (ImmuneOnco Biopharma); MIL-62 (Beijing Mabworks Biotech); mosunetuzumab (Roche); MRG-001 (Shanghai Miracogen); obinutuzumab (Roche); ocrelizumab (Roche; Niogen);
  • the disclosure provides a method of treating neuromyelitis optica spectrum disorder (NMOSD), the method comprising administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, and wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • NMOSD neuromyelitis optica spectrum disorder
  • the disclosure provides a method of treating NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein patient had been previously treated with an anti- CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • VIB551 may treat the NMOSD by reducing the worsening of the patient’s Kurtzke Expanded Disability Severity Scale (EDSS), or by reducing the number of active magnetic resonance imaging (MRI) lesions in the patient, or by reducing the worsening of the modified Rankin score of the patient, or by reducing the frequency of in- patient hospitalization of the patient related to NMOSD, or by reducing the risk of an NMOSD- related attack of the patient, or by reducing optic neuritis, or by reducing the severity of the patient’s NMOSD-related attacks, or by decreasing the patient’s pain, or by reducing NMOSD- related damage in the patient, or by reducing NMOSD-related attacks in the patient.
  • EDSS Kurtzke Expanded Disability Severity Scale
  • MRI magnetic resonance imaging
  • the VIB551 treats the patient’s NMOSD by reducing the worsening of the patient’s EDSS score, and the patient has a baseline EDSS score of 0, then the patient’s EDSS score may worsen by fewer than 2 points, or worsen by fewer than 1 point, or worsen by fewer than .5 points.
  • This reduction of worsening of EDSS score for the patient with the baseline score of 0 may be over a time period of at least 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years.
  • the VIB551 treats the patient’s NMOSD by reducing the worsening of the patient’s EDSS score, and the patient has a baseline score of 1 to 5, then the patient’s EDSS score may worsen by fewer than 1 point, or worsen by fewer than .5 point.
  • This reduction of worsening for the patient with the baseline EDSS score of 1 to 5 may be reduction of worsening over a time period of over 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years.
  • the VIB551 treats the patient’s NMOSD by reducing the worsening of the patient’s EDSS score, and the patient has a baseline EDSS score of 5.5 or more, then the patient’s EDSS score may worsen by fewer than 0.5 point or worsen by fewer than .25 point.
  • This reduction of worsening for the patient with the baseline score of 5.5 or more may be reduction of worsening of EDSS score over a time period of over 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years.
  • the treating may be a reduction in the number of enlarging T2 MRI lesions or may be a reduction in the number of new MRI lesions, or may be a reduction in both the number of enlarging T2 MRI lesions and the number of new MRI lesions.
  • the reduction in lesions may 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 lesions in a combination of any two or more of brain, brainstem, spinal cord, and optic nerve.
  • the new MRI lesions may not be clinically symptomatic.
  • the reducing of worsening may be such that the patient’s modified Rankin score worsens by fewer than 2 points or by fewer than 1 point over a time period of at least 6 months, or of 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.
  • the patient’s risk of attack may be reduced by between 60% and 85%, or may be reduced by between 65% and 75%, or may be reduced by between 70% and 80%.
  • the patient’s risk of attack 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 risk of attack may be reduced by 70%, 75%, 76%, 77%, 78%, 79% or 80%.
  • the treated patient’s probability of having no NMOSD-related attack may be greater than 70% over at least 6 months following VIB551 treatment, or greater than 70% over at least 12 months following VIB551 treatment, or greater than 70% over at least 18 months following VIB551 treatment.
  • the treated patient’s probability of having no NMOSD-related attack may be greater than 75% over at least 6 months following VIB551 treatment, or greater than 75% over at least 12 months following VIB551 treatment, or greater than 75% over at least 18 months following VIB551 treatment.
  • the treated patient’s probability of having no NMOSD-related attack may be greater than 80% over at least 6 months following VIB551 treatment, or greater than 80% over at least 12 months following VIB551 treatment, or greater than 80% over at least 18 months following VIB551 treatment.
  • the treated patient’s probability of having no NMOSD-related attack may be greater than 85% over at least 6 months following VIB551 treatment, or greater than 85% over at least 12 months following VIB551 treatment, or greater than 85% over at least 18 months following VIB551 treatment.
  • the treated patient’s annualized risk of an NMOSD-related attack may be reduced to between 0.18 and 0.08, or it may be reduced to between 0.15 and 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.
  • the patient in treatment for NMOSD is AQP4-IgG seropositive, then the patient’s annualized risk of an NMOSD-related attack may be reduced to between 0.15 and 0.11, or reduced to between 0.14 and 0.12, or it may be reduced to 0.14, 0.13, 0.12, or 0.11. If the patient in treatment for NMOSD is AQP4-IgG seronegative, then the patient’s annualized risk of an NMOSD-related attack may be reduced to between 0.09 and 0.07, or it may be reduced to 0.09, 0.08, or 0.07.
  • the NMOSD-related attack may be an attack characterized by the appearance of a new NMOSD symptom or the worsening of an existing NMOSD symptom.
  • the new or existing symptom may be an eye symptom. If the new or existing symptom is an eye symptom it may be eye pain, a new optic nerve lesion, an enlarging optic nerve lesion, blurred vision, loss of vision, or a 5 or more character drop in low-contrast Landolt C Broken Rings Chart.
  • the new or existing symptom may be a spinal cord symptom.
  • the new or existing symptom is a spinal cord symptom, it may be a deep or radicular pain, extremity paraesthesia, weakness, sphincter dysfunction, Lhermitte’s sign, a new spinal cord lesion, or an enlarging spinal cord lesion.
  • the new or existing symptom may be a brain or brain stem symptom. If the new or existing symptom is a brain or brain stem symptom, it may be nausea, double vision, oculomotor palsy, vertigo, intractable vomiting, intractable hiccups, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, a new brain or brain stem lesion, or an enlarging brain or brain stem lesion.
  • the new or worsening symptom may a combination of any two or more of the eye, spinal cord, or brain/brain stem symptoms. It may be a combination of any two, three, or four of these symptoms. [0049] If the VIB551 treats the patient’s NMOSD by reducing optic neuritis, then the patient may experience reduced eye pain, reduced vision loss, reduced visual field loss, reduced loss of color vision, or reduced flashing or flickering of lights with movement of the eye. The reduction in optic neuritis may result in improved vision, and/or relief from eye pain.
  • the severity of any NMOSD-related attack suffered by the patient may be graded mild or moderate as opposed to graded as severe.
  • a mild attack may be an attack that is transient, may be an attack that requires only minimal treatment or therapeutic intervention, and/or is an attack that may not interfere with usual activities of daily living.
  • a moderate attack may be an attack that may be alleviated with specific additional therapeutic interventions. Any moderate attack may be one that interferes with usual activities of daily living, and/or causes discomfort, but that poses no significant or permanent risk of harm to the patient.
  • the reduction of severity of the patient’s NMOSD-related attacks may be a reduction in the attacks suffered by the patient as being graded as major.
  • Such a major attack may be an attack that requires intensive therapeutic intervention, interrupts usual activities of daily living, or that significantly affects the clinical status of the patient.
  • Such a major attack may require in-patient hospitalization.
  • the VIB551 treats the patient’s NMOSD by decreasing the patient’s pain
  • the decrease may be determined by a decrease in pain in the patient’s eyes, legs, arms, upper back, and/or lower back.
  • the decrease in pain may be in any one, any two, any three, any four, or all five of these regions.
  • the decrease in pain may be measured by the pain numeric rating scale (PRS).
  • PRS pain numeric rating scale
  • the decrease in pain may be monitored relative to a baseline PRS level over a scale of 1 to 10.
  • the decrease in pain may be a decrease in pain of at least one on the scale, at least 2 on the scale, at least 3 on the scale, at least 4 on the scale, or at least 5 on the scale.
  • the decrease in pain may be a decrease in pain of between 1-5 on the scale, or a decrease in pain of between 1-3 on the scale, or a decrease in pain of between 1-2 on the scale.
  • the NMOSD-related damage is the occurrence of a clinically asymptomatic new MRI lesion, it may occur in a patient who has not experienced symptoms of an NMOSD-related attack or in a patient who has experienced symptoms of an NMOSD- related attack.
  • VIB551 may reduce the occurrence, or likelihood of occurrence, of a new clinically asymptomatic MRI lesion in any one or more domains, e.g., brain/brain stem, optic nerve or spinal cord, of the patient.
  • the reduced occurrence, or likelihood of occurrence, of the new clinically asymptomatic MRI lesion may be a prevention of occurrence of the new clinically asymptomatic MRI lesion.
  • the patient who has not experienced symptoms of an NMOSD-related attack, and whose NMOSD-related damage is reduced by VIB551 may be one who has not experienced symptoms of an NMOSD- related attack 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 the patient who has not experienced symptoms of an NMOSD-related attack may reduce the occurrence, or likelihood of occurrence, of a new clinically asymptomatic MRI lesion for the duration of the patient’s treatment with VIB551.
  • the administration of VIB551 to the patient who has not experienced symptoms of an NMOSD-related attack may result in a reduced occurrence, or likelihood of occurrence, of a new MRI lesion beginning within 1 month, within 2 months, or within 3 months following administration of a 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 at least 48 months, at least 54 months or at least 60 months following administration of the first dose of VIB551.
  • the VIB551 may reduce the occurrence, or likelihood of occurrence, of a new clinically asymptomatic MRI lesion in a domain other than the domain in which the patient has experienced symptoms of the NMOSD- related attack. For instance, if the patient experienced symptoms of an NMOSD-related attack in the spinal cord, VIB551 may reduce the occurrence, or likelihood of occurrence, of a new MRI lesion in the optic nerve or brain/brain stem or both.
  • VIB551 reduces, or reduces likelihood of, occurrence of a new clinically asymptomatic MRI lesion in association with an NMOSD-related attack, it may completely reduce, i.e., prevent, the occurrence of the new clinically asymptomatic MRI lesion in the patient. Moreover, VIB551 may not only reduce, or reduce likelihood of, a new clinically asymptomatic MRI lesion in the patent experiencing symptoms of the NMOSD-related attack, it may also reduce, or reduce likelihood of, occurrence of a new MRI lesion in the domain in which the patient experiences the symptoms of the NMOSD-related attack. [0055] VIB551 may also be used in a method of reducing active MRI lesions in a patient diagnosed with NMOSD.
  • the disclosure provides a method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: administering the anti- CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • the disclosure provides a method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • the VIB551 may reduce the cumulative total of new and enlarging lesions in the patient. If the VIB551 is used in a method of reducing active MRI lesions in a patient diagnosed with NMOSD, then the VIB551 may reduce the cumulative total of new gadolinium [Gd]-enhancing lesions, new T2 lesions and enlarging T2 lesions in the patient. If the VIB551 is used in a method of reducing active MRI lesions in a patient diagnosed with NMOSD, then the VIB551 may reduce the number of new T2 lesions in the patient and the number of enlarging T2 lesions in the patient.
  • Gd gadolinium
  • the VIB551 may reduce the number of new T2 lesions in the patient or the number an enlarging T2 lesions in the patient.
  • the active MRI lesions reduced in the patient may be lesions in the brain/brain stem, spinal cord, and optic nerve cumulatively, or may be lesions in one or two of the brain/brain stem, spinal cord, or optic nerve.
  • the active MRI lesions reduced in the patient may be clinically symptomatic or clinically asymptomatic MRI lesions. If the MRI lesions are clinically asymptomatic, they may be new MRI lesions that occur in a patient who has not experienced symptoms of an NMOSD-related attack.
  • the VIB551 may also be used in a method of reducing AQP4-IgG titers in a AQP4- IgG + patient in need of treatment for NMOSD.
  • the disclosure provides a method of reducing AQP4-IgG titers in a AQP4-IgG+ patient in need of treatment for NMOSD, the method comprising administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody; and wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the disclosure provides a method of reducing AQP4-IgG titers in a AQP4- IgG+ patient in need of treatment for NMOSD, the method comprising: administering the anti- CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • the VIB551 may reduce the AQP4-IgG titers by 75% to 100%, or by 75% to 90%, or by 75% to 85%, or by 80% to 100%, or by 85% to 100%, or by 90% to 95%, or by 75%, 80%, 85%, 90%, 95 or 100%.
  • the VIB551 may reduce the AQP4-IgG titers for a sustained period of time 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 following administration of a VIB551 dose.
  • the VIB551 may also be used in a method of reducing NMOSD-related disability in a patient diagnosed with NMOSD.
  • the disclosure provides a method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • the disclosure provides a method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • the reducing of the NMOSD-related disability in the patient may be a reduction in the worsening of NMOSD-related disability in the patient or it may be a lessening of NMOSD-related disability in the patient.
  • the NMOSD-related disability may be neurological disability or a manifestation of a neurological disability
  • the NMOSD-related disability may be characterized by one or more of eye pain, a loss of color vision, an overall loss of vision, blurred vision, double vision, overall weakness or paralysis, weakness or paralysis in the arms or legs, radicular pain, uncontrollable hiccups, uncontrollable nausea or vomiting, loss of bladder or bowel control, paralysis, and/or fatigue.
  • the reducing the NMOSD-related disability may be determined using EDSS, or may be determined using the modified Rankin Scale (mRS), or may be determined using EDSS and mRS.
  • the reducing the NMOSD-related disability may be detectable within 6 to 12 months, within 6 to 8 months, or within 6 to 7 months of administering a dose of VIB551 or administering a first dose of VIB551. [0059] If the reducing the NMOSD-related disability is determined using EDSS, the reducing in NMOSD-related disability may be either a reduction in the worsening in the patient’s EDSS score or a lowering of the patient’s EDSS score.
  • the reduction in worsening may be such that, if the patient’s EDSS score worsens, it worsens to a score of .5, or to a score of no more than 1, or to a score of no more than 1.5, or to a score of nor more than 2 over a period of time.
  • the period of time in which the patient with the baseline score of 0 worsens to a score of .5, to no more than 1, to no more than 1.5, or to no more than 2 may be a period of time 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. If the reducing the NMOSD-related disability is a reduction in the worsening in the patient’s EDSS score, and the patient has a baseline EDSS score of 1 to 5, then the reduction in worsening may be a worsening of the patient’s EDSS score by .5 points or by no more than 1 point over a period of time.
  • the period of time in which the patient with the baseline score of 1 to 5 worsens by .5 points, or by no more than 1 point may be a period of time 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. If the reducing the NMOSD-related disability is a reduction in the worsening in the patient’s EDSS score, and the patient has a baseline EDSS score of 5.5 or more, then the reduction in worsening may be a worsening of the patient’s EDSS score by no more than .5 points.
  • the period of time in which the patient with the baseline score of 5.5 worsens by the no more than .5 points may be a period of time 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 EDSS score may be determined within approximately 1 month, 2 weeks, 1 week, 3 days, 2 days, or 1 day of administration of a first VIB551 dose.
  • the patient’s baseline EDSS score may be determined coincident with administration of a first VIB551 dose or it may be determined within 1 day, within 2 days, within 3 days, within 1 week, within 2 weeks, or within 1 month of administration of a first VIB551 dose.
  • the patient’s EDSS score may decrease by at least .5 points, or at least 1 point, or at least 1.5 points, or at least 2 points.
  • the lowering or decreasing of the patient’s EDSS score by the at least .5, at least 1, at least 1.5, or at least 2 points may occur over a period of time of approximately 2 weeks, approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 9 months, approximately 12 months, or approximately 18 months.
  • the period of time over which the patient’s EDSS score is lowered, or that the patient’s EDSS score decreases may begin within 1 month, 2 weeks, 1 week, 3 days, 2 days, or 1 day of administration of a first VIB551 dose; or it may be coincident with administration of a first VIB551 dose; or it may begin within 1 day, within 2 days, within 3 days, within 1 week, within 2 weeks, or within 1 month of administration of a first VIB551 dose.
  • the period of time over which the patient’s EDSS score is lowered or decreases may begin at the time of an NMOSD attack, or may begin within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days from the time of an NMOSD attack.
  • the reducing in NMOSD-related disability may be either a reduction in the worsening in the patient’s mRS score or a lowering of the patient’s mRS score.
  • the reduction in worsening in mRS score may be a worsening of the patient’s baseline mRS score by no more than .5 points or by no more than 1 point, or by no more than 1.5 points, or by no more than 2 points over a period of time.
  • the period of time in which the patient’s baseline mRS score worsens by the no more than .5 points, no more than 1 point, no more than 1.5 point, or no more than 2 points may be a period of time 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 may be the patient’s mRS score at approximately 1 month, approximately 2 weeks, approximately 1 week, approximately 3 days, approximately 2 days, or approximately 1 day prior to administration of a first VIB551 dose.
  • the patient’s baseline mRS score may be the patient’s mRS score at the time of administration of a first VIB551 dose or it may 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 a first VIB551 dose.
  • the patient’s mRS score may lower or decrease by at least .5 points, or at least 1 point, or at least 1.5, or at least 2 points.
  • the lowering or decrease of the patient’s mRS score by the at least .5, at least 1, at least 1.5, or at least 2 points may be a lowering or decrease that occurs over a period of time of approximately 2 weeks, approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 9 months, approximately 12 months, or approximately 18 months.
  • the period of time over which the patient’s mRS score is lowered may begin within 1 month, 2 weeks, 1 week, 3 days, 2 days, or 1 day of administration of a first VIB551 dose; or it may be coincident with administration of a first VIB551 dose; or it may occur within 1 day, within 2 days, within 3 days, within 1 week, within 2 weeks, or within 1 month of administration of a first VIB551 dose.
  • the period of time over which the patient’s mRS score is lowered may begin at the time of an NMOSD attack, or may begin within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days from the time of an NMOSD attack.
  • the VIB551 may also be used in a method of reducing NMOSD-related attacks in a patient in need of treatment for NMOSD, wherein the patient has previously received an anti- CD20 antibody.
  • the disclosure provides a method of reducing NMOSD-related attacks in a patient in need of treatment for NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • the disclosure provides a method of reducing NMOSD-related attacks in a patient in need of treatment for NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 at a dose of about 300 mg to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient did not have an NMOSD attack while being treated with the anti-CD20 antibody.
  • the patient may have received anti-CD20 antibody therapy for up to 1 month, up to 2 months, up to 4 month, up to 6 months, up to 12 months, up to 2 years, up to 3 years, up to 4 years, up to 5 years, up to 6 years, or longer.
  • the prior anti-CD-20 antibody is received for at least about 12 months prior to administering VIB551.
  • the VIB551 may be administered in a dose of about 300 mg VIB551, optionally followed by one or more subsequent additional doses of 300 mg VIB551 every 6 months thereafter.
  • the VIB551 may also be used in methods of treating NMOSD in a patient.
  • the method comprises administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, optionally as a monotherapy, wherein the patient had been previously treated with an anti-CD20 antibody for at least 12 months and up to 5 years, and wherein one or more doses of about 300 mg of the anti-CD19 antibody VIB551 is administered after cessation of anti-CD20 therapy, each dose of VIB551 being administered about 6 months apart.
  • the method of treating NMOSD in a patient comprises administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, optionally as a monotherapy, wherein the patient had been previously treated with an anti-CD20 antibody, wherein following 1, 2 or 3 NMOSD-related attacks the anti-CD20 therapy was stopped and wherein one or more doses of about 300 mg of the anti-CD19 antibody VIB551 is administered after the cessation of anti-CD20 therapy, each dose of VIB551 being administered about 6 months apart.
  • the disclosure provides a method of reducing NMOSD-related attacks in a patient in need of treatment for NMOSD, the method comprising: administering the anti- CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • the reducing of the NMOSD- related attacks in the patient may be a reduction in number of NMOSD-related attacks suffered by the patient in a first time period relative to a second time period.
  • the first time period may occur following administration of a first VIB551 dose and the second time period may occur preceding the administration of the first VIB551 dose.
  • the first time period may begin immediately following administration of a first VIB551 dose and the second time period may end immediately preceding the administration of the first VIB551 dose.
  • the first and the second time period may be of an equal length in time.
  • the first and the second time period may 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 30 months, or at least 36 months, or 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 or 60 months.
  • the reduction in number of NMOSD-related attacks suffered by the patient in the first time period relative to the second time period may such that the patient suffers at least 1 fewer attack, or 1 fewer attack, or at least 2 fewer attacks, or 2 fewer attacks, or at least 3 fewer attacks, or 3 fewer attacks, or at least 4 fewer attacks, or 4 fewer attacks, or at least 5 fewer attacks, or 5 fewer attacks in the first time period relative to the second time period.
  • the NMOSD-related attacks suffered by the patient in the first and/or the second time period may be NMOSD-related attacks that are optic neuritis attacks, myelitis attacks, or brainstem attacks.
  • the NMOSD-related attack may or may not be in the same domain, e.g., optic nerve, spinal cord or brain/brain stem, as an NMOSD-related attack(s) suffered by the patient in the second time period.
  • the NMOSD-related attacks suffered by the patient may be NMOSD-related attacks characterized by the appearance of a new NMOSD symptom, or the worsening of an existing NMOSD symptom, or the appearance of a new MRI lesion that may or may not be symptomatic.
  • the new or worsening symptom may be an eye symptom. If the new or worsening symptom is an eye symptom it may be eye pain, a new optic nerve lesion, an enlarging optic nerve lesion, blurred vision, loss of vision, or a 5 or more character drop in low-contrast Landolt C Broken Rings Chart.
  • the NMOSD-related attack may further/alternatively meet any one or more of the following criteria: >15-character drop in high-contrast Landolt C Broken Ring Chart from most recent clinical visit as measured in a previously affected eye and QR ⁇ RWKHU ⁇ RSKWKDOPRORJLFDO ⁇ H[SODQDWLRQ ⁇ 5HGXFWLRQ ⁇ RI ⁇ VWHSV ⁇ LQ ⁇ &) (counting fingers) to NLP (no light perception) from most recent clinical visit as measured in a previously affected eye DQG ⁇ QR ⁇ RWKHU ⁇ RSKWKDOPRORJLFDO ⁇ H[SODQDWLRQ ⁇ 5HGXFWLRQ ⁇ RI ⁇ FKDUDFWHUV ⁇ LQ ⁇ ORZ-contrast Landolt C Broken Ring Chart from most recent clinical visit as measured in either eye alone (monocular) and a new RAPD (relative afferent pupillary defect) in affected eye, Re
  • the new or worsening symptom may be a spinal cord symptom. If the new or worsening symptom is a spinal cord symptom, it may be a deep or radicular pain, extremity paraesthesia, weakness, sphincter dysfunction, Lhermitte’s sign, a new spinal cord lesion, or an enlarging spinal cord lesion.
  • the NMOSD-related attack characterized by a new spinal cord symptom or the worsening of an existing spinal cord symptom, may further/alternatively meet any one or more of the following criteria: Worsening RI ⁇ SRLQWV ⁇ LQ ⁇ DW ⁇ OHDVW ⁇ RQH ⁇ RI ⁇ WKH ⁇ UHOHYDQW ⁇ S ⁇ UDPLGDO ⁇ EODGGHU ⁇ ERZHO ⁇ VHQVRU ⁇ )66 ⁇ FRPSDUHG ⁇ ZLWK ⁇ PRVW ⁇ UHFHQW ⁇ FOLQLFDO ⁇ YLVLW ⁇ :RUVHQLQJ ⁇ RI ⁇ SRLQW ⁇ LQ ⁇ ('66 ⁇ VFRUH ⁇ FRPSDUHG ⁇ ZLWK ⁇ PRVW ⁇ UHFHQW ⁇ FOLQLFDO ⁇ YLVLW ⁇ LI ⁇ SUHYLRXV ⁇ ('66 ⁇ VFRUH ⁇ :RUVHQLQJ ⁇ RI ⁇ SRLQW ⁇ LQ ⁇ DW ⁇ OHDVW ⁇ WZR ⁇ RI ⁇ WKH ⁇ relevant (pyramidal,
  • the new or worsening symptom may be a brain or brain stem symptom.
  • the new or existing symptom may be nausea, double vision, oculomotor palsy, vertigo, intractable vomiting, intractable hiccups, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, a new brain or brain stem lesion, or an enlarging brain or brain stem lesion.
  • the NMOSD-related attack characterized by a new brain/brain stem symptom or the worsening of an existing brain/brain stem symptom, may further/alternatively meet any one or more of the following criteria: Isolated (not present at most recent clinical visit) intractable nausea, vomiting, and/or hiccups lasting >48 hours and a new Gd-enhancing or new/enlarging T2 MRI lesion in the brainstem, :RUVHQLQJ ⁇ RI ⁇ SRLQWV ⁇ LQ ⁇ DW ⁇ OHDVW ⁇ RQH ⁇ RI ⁇ WKH ⁇ UHOHYDQW ⁇ EUDLQVWHP ⁇ FHUHEHOODU ⁇ )66 ⁇ FRPSDUHG ⁇ with most recent clinical visit and a new Gd-enhancing or new/enlarging T2 MRI lesion in the EUDLQVWHP ⁇ RU ⁇ :RUVHQLQJ ⁇ RI ⁇ ⁇ SRLQWV ⁇ LQ at least one of the relevant (cerebral, sensory, S ⁇ UDPLG
  • the NMOSD-related attack may be an attack characterized by any combination of new and/or worsening symptoms of any one, two, or more of the eye, spinal cord, or brain/brain stem.
  • the NMOSD-related attack may be an attack characterized by any combination of two, three, or four of the symptoms or other criteria identified for any of the one or more of the eye, spinal cord or brain/brain stem.
  • the NMOSD-related attack may be an attack characterized by the appearance of new MRI lesions in the patient.
  • the new MRI lesions may be, but are not necessarily, symptomatic.
  • the NMOSD patient to which the VIB551 is administered in the methods disclosed herein may or may not be AQP4-IgG seropositive.
  • the NMOSD patient may be screened for AQP4-IgG prior to VIB551 administration.
  • VIB551 may be administered to a patient with an increase in serum Nfl levels over a baseline level in any of the methods disclosed herein (as described in U.S. Prov. Appl.
  • VIB551 is administered to a patient with a sGFAP concentration of about 160 pg/mL, about 165 pg/mL, about 166 pg/mL, about 167 pg/mL, about 168 pg/mL, about 169 pg/mL, about 170 pg/mL, about 171 pg/mL, about 172 pg/mL, or about 173 pg/mL or greater. (as described in U.S. Prov. Appl. No. 63/046,133, which is incorporated herein by reference in its entirety).
  • VIB551 is administered to the patient with the sGFAP concentration of about 160 pg/mL, about 165 pg/mL, about 166 pg/mL, about 167 pg/mL, about 168 pg/mL, about 169 pg/mL, about 170 pg/mL, about 171 pg/mL, about 172 pg/mL, or about 173 pg/mL or greater
  • the patient’s sGFAP concentration may be determined to be about 160 pg/mL, about 165 pg/mL, about 166 pg/mL, about 167 pg/mL, about 168 pg/mL, about 169 pg/mL, about 170 pg/mL, about 171 pg/mL, about 172 pg/mL, or about 173 pg/mL or greater prior to the administering.
  • an anti-CD19 antibody other than VIB551, e.g., MOR00208 (also referred to as Xmab 5574 or tafasitamab; disclosed in U.S. Patent Application No. 20170137516), may be used in the methods of treatment disclosed herein.
  • the disclosure provides a method of treating NMOSD, the method comprising: administering an anti-CD19 antibody to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • the disclosure provides a method of treating NMOSD, the method comprising: administering an anti-CD19 antibody to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • the anti-CD20 antibody may be rituximab (antibody C2B8 in WO94/11026).
  • the anti-CD20 antibody the patient may previously have been treated with is ABP-300 (Abpro); B-001 (Shanghai Pharmaceuticals Holding); BAT-4306F (Bio-Thera Solutions); BAT-4406F (Bio-Thera Solutions); BCD-132 (Biocad Biotechnology); BVX-20 (Vaccinex); CYT-202 (Cytovia Therapeutics); epcoritamab (Genmab); GB-261 (Genor Biopharma); GD-CO1620 (ManysmarT); glofitamab (Roche); HS- 006 (Zhejiang Hisun Pharmaceutical); IGM-2323 (IGM Biosciences); IMM-0306 (ImmuneOnco Biopharma); MIL-62 (Beijing Mabworks Biotech); mosunetuzumab (Roche); MRG-001 (Shanghai Miracogen); obinutuzumab (Roche); ocrelizumab (Roche; Niogen); odron
  • the anti-CD19 antibody administered to the patient may be any of, for example, MOR00208 (also referred to as Xmab 5574 or tafasitamab; disclosed in U.S. Patent Application No.
  • 20170137516 which is incorporated herein by reference in its entirety); blinatumomab (Amgen; Astellas; MicroMet); loncastuximab tesirine (ADC Therapeutics); GTB-1550/ OXS-1550 (Oxis Biotech Inc); obexelimab/ XmAb5871 (Xencor Inc); AFM11 (Affimed); or coltuximab/ravtansine (ImmunoGen Inc).
  • the VIB551 may have the VH amino acid sequence and a VL amino acid sequence as shown in Figure 4
  • the VIB551 may comprise a heavy chain variable region (VH) comprising the amino acid of SEQ ID NO:1 and a light chain variable region (VL) comprising the amino acid of SEQ ID NO: 2.
  • VH heavy chain variable region
  • VL light chain variable region
  • the VIB551 administered in the methods may have the VH amino acid sequence and the VL amino acid sequence as shown in Figure 4, but for one or more changes in amino acid residues that do not alter the function of the VIB551 amino acid sequence.
  • the number of amino acid changes may be 1 amino acid residue change, 2 amino acid residue changes, 3 amino acid residue changes, 4 amino acid residue changes, or 5 amino acid residue changes.
  • the VIB551 used in the methods disclosed herein is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or identical to the VH and VL sequences disclosed in Figure 4.
  • the VIB551 administered in the methods may contain the Complementarity Determining Region (CDR) amino acid sequences of the VH and the VL sequences as shown in Figure 4 and Sequence Table 1, but may have one or more alterations in the framework regions (i.e residues other than the CDR residues) of the VH and the VL domain sequences shown in Figure 4 and Table 1.
  • the VIB551 administered in any of the methods disclosed herein may have a heavy chain amino acid sequence and a light chain amino acid sequence as shown in Figure 9
  • the VIB551 may comprise a heavy chain comprising the amino acid of SEQ ID NO:3 and a light chain comprising the amino acid of SEQ ID NO: 4.
  • the VIB551 administered in the methods may have the heavy chain amino acid sequence and the light chain amino acid sequence as shown in Figure 9, but for one or more changes in amino acid residues that do not alter the function of the VIB551 amino acid sequence.
  • the number of amino acid changes may be 1 amino acid residue change, 2 amino acid residue changes, 3 amino acid residue changes, 4 amino acid residue changes, or 5 amino acid residue changes.
  • the VIB551 used in the methods disclosed herein is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or identical to the heavy chain and light chain sequences disclosed in Figure 9. Table 1.
  • VIB551 In any method disclosed herein, if VIB551 is the anti-CD19 antibody administered to a patient in need, then the VIB551 may be administered at a dose of about 300 mg. In aspects, the VIB551 may be administered at a dose of about 250 mg to about 350 mg, about 275 mg to about 325 mg, about 290 mg to about 310 mg, about 205 mg to about 305 mg, or it may be a dose of 300 mg. In aspects, the patient may receive one or more initial doses of VIB551. In one aspect, the patient may receive, one, two, three or more initial doses. In particular aspects, the initial dose may be about 300 mg.
  • the VIB551 may be administered at an initial dose of about 250 mg to about 350 mg, about 275 mg to about 325 mg, about 290 mg to about 310 mg, about 205 mg to about 305 mg, or an initial dose of 300 mg.
  • VIB551 may be administered intravenously with a first initial dose of about 300 mg, a second initial dose of about 300 mg two weeks after the first initial dose, and subsequent doses of about 300 mg every 6 months following the first initial dose. [0081] If VIB551 is administered in the methods disclosed herein, it may be administered at an interval of once about every 6 months. In aspects, the VIB551 may be administered intravenously.
  • the approximately every 6 months may be administration every 6 months, every 180 days, every between 170 and 190 days, every between 175 and 185 days, every between 175 and 190 days, or every between 170 and 185 days.
  • the approximately every 6 months may be administration every 26 weeks, every 25 weeks, every 27 weeks, every between 25 and 27 weeks, every between 25 and 26 weeks, or every between 26 and 27 weeks.
  • an initial VIB551 dose may be administered to the NMOSD patient.
  • the initial VIB551 dose may be administered approximately 2 weeks before the approximately every 6 month VIB551 dosing.
  • the administering the initial VIB551 dose approximately 2 weeks before the every approximately 6 month VIB551 dosing may be the administering of the initial VIB551 dose 12 days, 13 days, 14 days, 15 days, or 16 days before the approximately 6 months VIB551 dosing
  • the initial VIB551 dose may or may not be co administered with oral corticosteroids [0082]
  • the disclosure provides a method of treating NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is an AQP4-IgG+ patient, wherein the VIB551 is administered intravenously with a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and subsequent doses of 300 mg every 6 months following the first initial dose, wherein patient had been previously treated with an anti-CD20 antibody, and wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • the disclosure provides a method of treating NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is an AQP4-IgG+ patient, wherein the VIB551 is administered intravenously with a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and subsequent doses of 300 mg every 6 months following the first initial dose, wherein the patient had been previously treated with an anti-CD20 antibody; and, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • the anti-CD20 antibody is rituximab (antibody C2B8 in WO94/11026).
  • NMOSD in the pediatric patients may be determined according to the criteria of Wingerchuk et al. “International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology.” 2015;85(2):177- 89. While the subjects are typically seropositive for AQP4-IgG, subjects having NMOSD but who are seronegative for AQP4-IgG are also contemplated. In aspects, the patient will have presented with one or more NMOSD acute relapses within the last year prior to treatment, or 2 or more NMOSD acute relapses within the last 2 years.
  • the pediatric subjects may be male or female and may range in age from 2 to ⁇ 18; for example, 2 to ⁇ 6, 6 to ⁇ 12, 12 to ⁇ 18 or 2 to ⁇ 12.
  • the dose administered to the pediatric patient is determined by weight. If the subject’s weight is ⁇ NJ, then 8 mg/kg IV is administered. If the patient’s weight is > 37.5 kg, then the subject receives 300 mg IV. Subjects who transition from ⁇ 37.5 kg to > 37.5 kg while on anti-CD19 antibody VIB551 therapy may switch regimens from 8 mg/kg to 300 mg.
  • the anti-CD19 antibody VIB551 is typically administered as a monotherapy. Following a first dose, one or more subsequent doses may be administered.
  • the subsequent doses may be about 24 to 28 weeks apart, about 12 months apart, about 30 months apart, about 36 months apart, or about 48 months apart, with therapy maintained as long as needed.
  • the anti-CD19 antibody VIB551 is typically administered as a monotherapy
  • corticosteroids may be co- administered during the early stages of treatment of pediatric patients.
  • the corticosteroid therapy is typically tapered off shortly after antibody therapy is initiated; for example, 1 week, 2 weeks, 3 weeks or 4 weeks after the first dose is administered.
  • the VIB551 is administered intravenously with a first initial dose of 300 mg
  • a second initial dose of 300 mg two weeks after the first initial dose and subsequent doses of 300 mg every 6 months following the first initial dose.
  • Monoclonal antibody VIB 551 may be administered to Hepatitis B virus carriers.
  • Hepatitis B virus carriers who previously received anti-CD20 monoclonal antibody therapies that reduce B cell numbers, deaths due to fulminant hepatitis, aggravated hepatitis, or hepatic failure, during or after treatment, have been reported. Hepatitis B virus reactivation has also been reported in these patients. These reactions have not been reported with anti-CD 19 monoclonal antibody VIB 551, however.
  • patients may have their HBV status assessed before beginning VIB 551 therapy and/or may be monitored for signs and symptoms of hepatitis B virus reactivation through periodic liver function tests and hepatitis virus marker monitoring.
  • Patients already on therapy with HBV infection may have their liver status monitored using parameters such as elevated or fluctuating of ALT (alanine aminotransferase) /AST (aspartate aminotransferase) ratio and a serum viral load increases. (Villadolid et al., “Hepatitis B reactivation and rituximab in the oncology practice.” Oncologist. 2010;15(10):1113-21).
  • HBsAg HBs antigen ⁇ hereinafter HBsAg
  • VIB551 HBsAg
  • HBcAb HBc antibody
  • HBsAb HBsAb
  • HBsAg, HBcAb, or HBsAb may be measured by ELISA or CLIA (including equivalent FEIA/ECLIA/CLEIA/BLEIA), using the respective antibody or antigen detection/measurement reagents.
  • HBsAg may be measured by CLEIA, using STACIA CLEIA HBs antigen (LSI Rulece Corp.
  • HBcAb may be measured by CLIA, using ARCHITECT G06277R09 (Abbott Japan LLC; www.info.pmda.go.jp/downfiles /ivd/PDF/100159_22100AMX02283000 _A_02_01.pdf) and samples with a cut-off index greater than or equal to 1 will be considered positive.
  • HBsAb may be measured by CLIA, using ARCHITECT G06255R03 (Abbott Japan LLC.) (www.info.pmda.go.jp/downfiles/ ivd/PDF/100159_21000 AMY00120000_A_01_10.pdf) .
  • the VIB551 may be packaged in a 10-mL vial filled with a nominal 10-mL solution of VIB551.
  • VIB551 may be formulated at a concentration of 10 mg/mL.
  • the VIB551 formulation may comprise 20 mM histidine/histidine hydrochloride, 70 mM NaCl, 106 mM (4% [w/v]) trehalose dehydrate, and 0.01% (w/v) polysorbate 80, pH 6.0.
  • to dose of VIB551 to be administered to the patient is determined by weight. If the subject’s weight is ⁇ NJ, then 8 mg/kg IV is administered. If the patient’s weight is > 37.5 kg, then the subject receives 300 mg IV. Subjects who transition from ⁇ 37.5 kg to > 37.5 kg while on anti-CD19 antibody VIB551 therapy may switch regimens from 8 mg/kg to 300 mg.
  • the anti-CD19 antibody VIB551 is typically administered as a monotherapy.
  • the dose of VIB551 that may be used in a method of treating a patient in need of treatment for NMOSD may be a VIB551 dose that depletes at least 90% of circulating CD20+ B cells for at least six months, and does not increase risk of infections in the patient. It may be a dose of about 250 mg to about 350 mg, about 275 mg to about 325 mg, about 290 mg to about 310 mg, about 205 mg to about 305 mg, or it may be a dose of 300 mg.
  • the patient may receive one or more initial doses of VIB551. In one aspect, the patient may receive one, two, three or more initial doses.
  • the initial dose may be about 300 mg.
  • the VIB551 may be administered at an initial dose of about 250 mg to about 350 mg, about 275 mg to about 325 mg, about 290 mg to about 310 mg, about 205 mg to about 305 mg, or an initial dose of 300 mg.
  • VIB551 may be administered intravenously with a first initial dose of about 300 mg, a second initial dose of about 300 mg two weeks after the first initial dose, and subsequent doses of about 300 mg every 6 months following the first initial dose.
  • the dose of VIB551 that may 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 six months, and does not increase risk of infections in the patient, may be a dose administered intravenously at an interval of once about every 6 months, once about every 7 months, once about every 8 months, once about every 9 months, once about every 10 months, once about every 11 months, or about once a year.
  • the VIB551 may also be used in a method of treating a patient in need of treatment for NMOSD in which the VIB551 is administered at a dose that (i) depletes at least 90% of circulating CD20+ B cells for at least six months, and (ii) does not increase risk of infections in the patient.
  • the dose that depletes the at least 90% of circulating CD20+ B cells for at least six months may also deplete peripheral blood CD20- plasmablasts and plasma cells.
  • the dose that depletes the at least 90% of circulating CD20+ B cells for at least six months may also reduce the plasma cell gene signature of the patient in need of treatment for NMOSD, or it may ablate the plasma cell gene signature of the patient in need of treatment for NMOSD.
  • the dose that depletes the at least 90% of circulating CD20+ B cells may deplete the circulating CD20+ B cells for longer than six months. It may deplete the at least 90% of circulating CD20+ B cells for at least 9 months or at least 1 year.
  • the dose of VIB551 that depletes at least 90% of circulating CD20+ B cells for at least six months in the method of treating also does not increase risk of infections in the NMOSD patient.
  • the risk of infection may not be increased in the NMOSD patient relative to his or her risk of infections prior to the administration of VIB551.
  • the risk of infection may not be increased in the NMOSD patient in comparison to an NMOSD patient not treated with VIB551.
  • the risk of infection may be a risk of infection by or resulting in typical pneumonia, beta haemolytic streptococcal infection, bronchitis, conjunctivis, viral conjunctivis, fungal skin infection, gastroenteritis viral, gastrointestinal infection, gingivitis, cystitis, herpes zoster, influenza, laryngitis, meningitis viral, 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.
  • any of the methods provided herein may further comprise, prior to the administering the anti-CD19 antibody, e.g., VIB551, steps of: (i) identifying the patient as having previously been treated with the anti-CD20 antibody, (ii) determining that the patient suffered at least one NMOSD attack while being treated with the anti-CD20 antibody or had suffered at least one NMOSD attack within 6 months of the last dose of the anti-CD20 antibody, and (iii) selecting the patient for the administering the anti-CD19 antibody as a result of the determining.
  • a method of treating neuromyelitis optica spectrum disorder comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, and wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • NMOSD neuromyelitis optica spectrum disorder
  • Embodiment 2 A method of treating NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • Embodiment 4 A method of treating NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is an astrocyte water channel aquaporin-4 (AQP4)- Immunoglobulin (Ig)G + patient, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months, wherein the patient had been previously treated with an anti-CD20 antibody, and wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • AQP4 astrocyte water channel aquaporin-4
  • Ig Immunoglobulin
  • a method of treating NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is an AQP4-IgG + patient, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months, wherein the patient had been previously treated with an anti-CD20 antibody; and, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • Embodiment 6. The method of any one of embodiments 3-5, wherein the patient receives at least one initial dose of VIB551.
  • EDSS Kurtzke Expanded Disability Severity Scale
  • Embodiment 12 The method of embodiment 11, wherein the reduction in worsening of EDSS in the patient is: a worsening of fewer than 2 points in EDSS score if the patient has a baseline score of 0; a worsening of fewer than 1 point if the patient has a baseline score of 1 to 5; or a worsening of less than 0.5 point if the patient has a baseline score of 5.5 or more.
  • Embodiment 13 The method of any one of embodiments 1-10, wherein the treating is a reduction in number of active magnetic resonance imaging (MRI) lesions.
  • MRI active magnetic resonance imaging
  • Embodiment 14 The method of embodiment 13 wherein the active MRI lesions are enlarging T2 MRI lesions.
  • Embodiment 15. The method of any one of embodiments 1-10, wherein the treating is a reduction in number of new MRI lesions.
  • Embodiment 16. The method of any one of embodiments 1-10, wherein the treating is a reduction in worsening of modified Rankin Score in the patient.
  • Embodiment 17. The method of any one of embodiments 1-10, wherein the treating is a reduction in frequency of in-patient hospitalizations of the patient related to NMOSD.
  • Embodiment 18. The method of any one of embodiments 1-10, wherein the treating is a reduction of risk of an NMOSD-related attack of the patient.
  • Embodiment 20 The method of embodiment 19, wherein the symptom is an eye symptom.
  • Embodiment 21 The method of embodiment 20, wherein the eye symptom is eye pain, blurred vision, loss of vision, or appearance of an optic nerve lesion detected by MRI.
  • Embodiment 22 The method of embodiment 19, wherein the symptom is a spinal cord symptom.
  • Embodiment 23 The method of embodiment 22, wherein the spinal cord symptom is deep or radicular pain, extremity paraesthesia, weakness, sphincter dysfunction, Lhermitte’s sign, or a spinal cord lesion detectable by MRI.
  • Embodiment 24 The method of embodiment 19, wherein the symptom is a brain or brain stem symptom.
  • Embodiment 25 The method of embodiment 24, wherein the brain or brainstem symptom is nausea, double vision, oculomotor palsy, vertigo, intractable vomiting, intractable hiccups, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, or a brain or brain stem lesion detectable by MRI.
  • Embodiment 26 The method of embodiment 18, wherein the reduction of risk of the NMOSD-related attack is between 60 and 85%.
  • Embodiment 27 The method of any one of embodiments 1-10, wherein the treating is a reduction in optic neuritis.
  • Embodiment 28 The method of any one of embodiments 1-10, wherein the treating is a reduction in optic neuritis.
  • the method of any one of embodiments 1-10, wherein the treating is a reduction of severity of NMOSD-related attacks.
  • Embodiment 29. The method of embodiment 28, wherein the reduction of severity of NMOSD-related attacks is the reduction in NMOSD-related attacks graded as major.
  • Embodiment 30. The method of embodiment 28, wherein the reduction of severity of NMOSD- related attacks is the reduction in NMOSD attacks requiring in-patient hospitalization.
  • Embodiment 31 The method of any one of embodiments 1-10, wherein the treating is a decrease in NMOSD-related pain in the patient.
  • Embodiment 32. The method of embodiment 31, wherein the decrease in NMOSD- related pain is determined by measuring pain in legs of the patient.
  • Embodiment 34 The method of embodiment 33, wherein oral corticosteroids are co- administered to the patient with the initial 300 mg VIB551 dose.
  • Embodiment 35 The method of embodiment 1 or embodiment 2, wherein the patient is AQP4-IgG seropositive.
  • Embodiment 36 The method of any one of embodiments 1-5, wherein two weeks prior to the first administering the 300 mg VIB551 every 6 months, an initial 300 mg VIB551 dose is administered to the subject.
  • a method of reducing active MRI lesions in a patient diagnosed with NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • Embodiment 37 A method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • Embodiment 38 A method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody
  • Embodiment 39 A method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • Embodiment 40 A method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • a method of reducing active MRI lesions in a patient diagnosed with NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • a method of reducing AQP4-IgG titers in a AQP4-IgG + patient in need of treatment for NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • Embodiment 42 administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • a method of reducing AQP4-IgG titers in a AQP4-IgG + patient in need of treatment for NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • Embodiment 43 The method of embodiment 41 or 42, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • a method of reducing AQP4-IgG titers in a AQP4-IgG + patient in need of treatment for NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • a method of reducing AQP4-IgG titers in a AQP4-IgG + patient in need of treatment for NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • Embodiment 46 The method of any one of embodiments 1-45, wherein the administration depletes at least 90% of circulating CD20+ B cells for at least six months.
  • Embodiment 47 Embodiment 47.
  • Embodiment 48 The method of any one of embodiments 1-46, wherein the administration does not increase risk of infections in the patient.
  • Embodiment 48 The method of any one of embodiments 1-47, wherein the VIB551 depletes peripheral blood CD20- plasmablasts and plasma cells within 8 days following the administering.
  • Embodiment 49 A method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • Embodiment 50 Embodiment 50.
  • a method of reducing NMOSD-related disability in a patient diagnosed with NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • Embodiment 51 The method of embodiment 49 or 50, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • Embodiment 52 is administered intravenously at a dose of 300 mg every 6 months.
  • a method of reducing NMOSD-related disability in a patient diagnosed with NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • a method of reducing NMOSD-related disability in a patient diagnosed with NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • Embodiment 54 The method of any one of embodiments 49-53, wherein the reducing the NMOSD-related disability in the patient is a reduction in a rate of worsening of NMOSD- related disability in the patient.
  • Embodiment 55 The method of any one of embodiments 49-53, wherein the reducing the NMOSD-related disability in the patient is a reduction in a rate of worsening of NMOSD- related disability in the patient.
  • a method of reducing NMOSD-related attacks in a patient in need of treatment for NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • a method of reducing NMOSD-related attacks in a patient in need of treatment for NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • Embodiment 60 The method of embodiment 58 or 59, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • a method of reducing NMOSD-related attacks in a patient in need of treatment for NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • a method of reducing NMOSD-related attacks in a patient in need of treatment for NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody; and, wherein the VIB551 is administered intravenously at a dose of 300 mg every 6 months.
  • Embodiment 63 The method of embodiment 61 or embodiment 62, wherein the NMOSD-related attacks suffered by the patient comprise any one or more of an optic neuritis, a myelitis, or a brainstem attack.
  • Embodiment 64 Embodiment 64.
  • Embodiment 65 The method of any one of embodiments 36-64, wherein the patient receives at least one initial dose of VIB551.
  • Embodiment 66 The method of embodiment 65, wherein the VIB551 is administered intravenously with a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and subsequent doses of 300 mg every 6 months following the first initial dose.
  • Embodiment 67 The method of embodiment 66, wherein oral corticosteroids are co- administered to the patient with the initial 300 mg VIB551 dose.
  • Embodiment 68 Embodiment 68.
  • Embodiment 67 wherein the oral corticosteroids are administered daily for at least 2 weeks.
  • Embodiment 69 The method of any one of embodiments 36-68, wherein the anti- CD20 antibody is rituximab.
  • Embodiment 70 The method of any one of embodiments 1-69, wherein the VIB551 comprises a heavy chain variable region (VH) comprising the amino acid of SEQ ID NO:1 and a light chain variable region (VL) comprising the amino acid of SEQ ID NO: 2.
  • VH heavy chain variable region
  • VL light chain variable region
  • a method of treating NMOSD comprising: administering an anti-CD19 antibody to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • Embodiment 72 A method of treating NMOSD, the method comprising: administering an anti-CD19 antibody to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • Embodiment 73 Embodiment 73.
  • a method of treating NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is an AQP4-IgG + patient, wherein the VIB551 is administered intravenously with a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and subsequent doses of 300 mg every 6 months following the first initial dose, wherein patient had been previously treated with an anti-CD20 antibody, and wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • Embodiment 74 Embodiment 74.
  • a method of treating NMOSD comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is an AQP4-IgG + patient, wherein the VIB551 is administered intravenously with a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and subsequent doses of 300 mg every 6 months following the first initial dose, wherein the patient had been previously treated with an anti-CD20 antibody; and, wherein the patient had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody.
  • Embodiment 75 Embodiment 75.
  • any one of embodiments 1-74 further comprising, prior to the administering: identifying the patient as having previously been treated with the anti-CD20 antibody; determining that the patient: (i) suffered at least one NMOSD attack while being treated with the anti-CD20 antibody; or (ii) had suffered at least one NMOSD attack within 6 months of the last dose of the anti-CD20 antibody; and selecting the patient for the administering the anti-CD19 antibody as a result of the determining (i) or (ii).
  • Embodiment 76 Embodiment 76.
  • a method of treating neuromyelitis optica spectrum disorder comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient had been previously treated with an anti-CD20 antibody, and wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody, comprising obtaining a blood sample from the patient before administration of anti-CD19 antibody VIB551, testing for the presence of HBs antigen, HBc antibody and HBs antibody in the sample, and administering the anti-CD19 antibody VIB551 to a patient whose HBs antigen test is negative, and whose HBc antibody or HBs antibody, or both, are positive, and optionally, monitoring for periodic liver function tests and hepatitis virus marker monitoring during and after treatment with the anti-CD19 antibody VIB551.
  • Embodiment 77 A method of treating neuromyelitis optica spectrum disorder (NMOSD), comprising: administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is HBs antigen-negative, and either HBs antibody-positive, HBc antibody positive, or both.
  • Embodiment 78. The method of embodiment 77, wherein the patient had been previously treated with an anti-CD20 antibody.
  • Embodiment 79. The method of embodiment 78, wherein the patient had an NMOSD attack while being treated with the anti-CD20 antibody.
  • EXAMPLES Example 1 – Rationale for Elements of Clinical Trial Design [0099] Overview.
  • NMOSD clinical trial, N-MOmentum was designed as a randomised, placebo-controlled, double-blind, 197-day, phase 2/3 study with an open-label extension period to assess the efficacy and safety of VIB551 (also referred to as VIB551 or MedI551), an anti-CD19, B-cell depleting antibody, in patients with NMOSD, recruited from 99 sites in 24 countries. Participants were randomised (3:1) using an interactive voice response system/interactive web response system, to intravenous VIB551 300 mg or placebo, respectively, administered on Days 1 and 15. Efficacy endpoints were assessed in the intent- to-treat population, and safety endpoints in the as-treated population.
  • the primary endpoint was time to first adjudicated attack; secondary endpoints included disability worsening, magnetic resonance imaging (MRI) lesion activity, and hospitalisations.
  • MRI magnetic resonance imaging
  • a more detailed description of the N-Momentum clinical trial can be found in Cree et al., Lancet 394: 1352- 1363 (2019), and Int’l Appl. No. PCT/US20/29613, which is incorporated herein by reference in its entirety.
  • Arm selection The placebo-comparator treatment arm was chosen because there are no currently approved medications for the treatment of neuromyelitis optica spectrum disorder.
  • the study was designed to limit the actual duration of placebo exposure to a maximum of 197 days or time to onset of an attack, whichever occurred earlier, after which all patients had the option to enter the open-label period and to receive VIB551.
  • patients Prior to randomisation, patients were stratified based on AQP4-IgG serostatus (determined at screening) and region (Japan vs non-Japan). Within each stratum, patients were randomised in a 3:1 ratio using an interactive voice response system/ interactive web response system (IVRS/IWRS) with a permuted block randomisation scheme to a treatment group and assignment of blinded investigational product kit numbers.
  • IVRS/IWRS interactive voice response system/ interactive web response system
  • VIB551 is known to deplete CD19+ B cells; therefore, the results of flow cytometry to count B cells were potentially unblinding. These data were not made available to investigation sites post randomisation throughout the remainder of the study.
  • Primary endpoint Time (in days) from day 1 to onset of an adjudication- committee-determined neuromyelitis optica spectrum disorder attack on or before day 197. The definition of an attack was the presence of a new symptom(s) or worsening of an existing symptom(s) related to neuromyelitis optica that met at least one of the protocol-defined criteria for a neuromyelitis optica spectrum disorder attack.
  • Four key secondary endpoints 1. Worsening from baseline in EDSS score at last visit during the randomised, controlled period.
  • the EDSS assessment in the study was performed by an independent and blinded assessor at each site using an electronic data capture system, developed by the University of Basel and Neurostatus GmBH, which contained an internal algorithm providing feedback to the assessor on inconsistencies in the EDSS assessment; 2. Change from baseline in low-contrast visual acuity binocular score measured by low-contrast Landolt C Broken Ring Chart at last visit during the randomised controlled period; 3. Cumulative total number of active MRI lesions (new gadolinium-enhancing or new/enlarging T2 lesions) during the randomised controlled period; 4. Number of neuromyelitis optica-related inpatient hospitalisations, with inpatient hospitalisation defined as more than an overnight stay.
  • 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 to participate in the study based on the inclusion and exclusion criteria. All subjects who fulfilled eligibility criteria were randomized into the study.
  • Randomization The subjects were randomized into the study in a 3:1 ratio to receive intravenously VIB551 (30mg) or placebo as described in Table 2. Randomization occurred on Day 1 and was stratified by AQP4-IgG serostatus (in a ratio of approximately 80:20 seropositive and seronegative subjects, respectively) and by region (Japan vs non-Japan).
  • Randomized-controlled period treatment regimen [0115] Randomized-controlled period (Day 1 to Day 197). Following randomization on Day 1, the subjects were treated with VIB551 or placebo on Day 1 and Day 15. An oral corticosteroid course was initiated on Day 1 (prednisone 20 mg/day or equivalent oral glucocorticoid) and continued until Day 14. Tapering of the oral corticosteroids occurred from Day 15 to Day 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 completed.
  • Open-label period Subjects were given the option to enter the open label period if they: (1) completed 197 days of the randomized control period; (2) experienced an adjudication committee-determined NMO/NMOSD attack during the randomized control period; (3) were in the randomized control period at the time when 67 adjudication committee- determined NMO/NMOSD attacks had occurred; or (4) were in the randomized control period when enrollment was discontinued upon recommendation of the DMC based on evidence of efficacy and safety.
  • Patients who discontinued the randomised controlled period for reasons other than an adjudicated attack or the occurrence of 67 adjudicated attacks were not eligible for the open- label period. Reasons for patients not entering the open-label period were captured.
  • the OLP will continue for a minimum of 1 year after the last subject enters and a maximum of 3 years (after the last subject enters), or until regulatory approval for MEDI-551 in the participating country, or until the Sponsor discontinues development of MED1-551 in this indication, whichever occurs first.
  • Subjects can choose to exit the OLP at any time for any reason, including seeking alternative treatment options, at which point they will enter the SFP (unless consent is withdrawn).
  • [0120] During the open-label period, patients were followed up at scheduled study visits and continued to receive VIB551 therapy for a maximum of 3 years (after the last patient entered), until regulatory approval for VIB551 in each participating country or until discontinuation of the development of VIB551 by the sponsor in this indication, whichever occurred first.
  • Safety follow-up period The safety follow-up period started when a patient prematurely discontinued from the randomised controlled or open-label periods. The length of the safety follow-up period was determined by the time elapsed from the time of the last dose to the time of the premature discontinuation, to complete 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.
  • Example 4 Summary of Studied Outcomes
  • Primary endpoint Time (in days) from day 1 to onset of an adjudication- committee-determined neuromyelitis optica spectrum disorder attack on or before day 197. The definition of an attack was the presence of a new symptom(s) or worsening of an existing symptom(s) related to neuromyelitis optica that met at least one of the protocol-defined criteria for a neuromyelitis optica spectrum disorder attack.
  • Secondary endpoints Time (in days) from day 1 to onset of an adjudication- committee-determined neuromyelitis optica spectrum disorder attack on or before day 197. The definition of an attack was the presence of a new symptom(s) or worsening of an existing symptom(s) related to neuromyelitis optica that met at least one of the protocol-defined criteria for a neuromyelitis optica spectrum disorder attack.
  • Participant demographics were broadly similar between treatment groups in the overall and AQP4-IgG seropositive populations (table 4).
  • Table 4 Patient demographic and baseline characteristics Table 5.
  • AC Adjudication Committee
  • AQP4-IgG autoantibodies against aquaporin-4
  • ITT intent-to-treat
  • NMOSD neuromyelitis optica spectrum disorders
  • ON optic neuritis
  • RCP randomized-controlled period
  • sero+ seropositive
  • sero- seronegative.
  • an annualized attack rate could not also be calculated for the placebo treatment period because subjects were removed from the placebo-controlled portion of the study after an AC- adjudicated attack Accordingly any such calculation in the placebo period would have been biased and would have potentially overestimated the attack rate.
  • Subjects in the VIB551 treatment group remained in the study receiving VIB551 following an attack, and therefore, an estimate of annualized attack rate could be calculated for the period in which subjects were treated with VIB551.
  • the annualized AC-determined NMOSD attack rate in any subject treated with VIB551 was low, at 0.126. See Table 6.
  • LSM differences in the change in LCVAB score were assessed using an analysis of covariance model with treatment, serostatus, and baseline Landolt C Broken Ring Chart binocular score as explanatory variables and last non-missing low-contrast visual acuity score.
  • ⁇ Cumulative number of active MRI lesions from baseline (includes gadolinium-enhancing or new/enlarging T2 lesions), with RRs assessed using negative binomial regression, with treatment and serostatus as explanatory variables
  • ⁇ RR analysis is based on the entire population, not just those who had an event.
  • AQP4-IgG 161 aquaporin-4-immunoglobulin G; CI, confidence interval; EDSS, Expanded Disability Status Scale; ITT, intent-to-treat; LCVAB, low-contrast visual acuity binocular; LSM, least-squares mean; MRI, magnetic resonance imaging; OR, odds ratio; RR, rate ratio; SD, standard deviation; SE, standard error.
  • Example 6 Safety and Efficacy of VIB551 in those with previous rituximab exposure
  • Demographics and baseline characteristics of participants in N-MOmentum with prior rituximab use are shown in Table 8, including that median time between the last rituximab use and randomization was 1.5 years.
  • Table 8 Characteristics of Participants in N-MOmentum with Prior Rituximab Use AQP4, aquaporin-4; AAR, annualized attack rate, IgG, immunoglobulin G; IQR, interquartile range [0134]
  • a summary of the attack history for the each of the 17 N-MOmentum participants with prior rituxumab usage is presented in Figure 5.
  • the annualized attack rate (AAR) prior to and after inebilizumab administration was 0.78 (median: 1.08), and 0.11 (95% CI 0.02 – 0.33), respectively; and the AAR for those with and without prior rituximab exposure was .083 and .102, respectively.
  • the three rituximab-experienced participants who had attacks while taking inebilizumab had 1 attack each during their time in the study (1.54 years for the participant randomized to inebilizumab; 0.51 and 2.74 years for the participants randomized to placebo). All 3 attacks were myelitis, one of which was graded as mild by the opticospinal impairment scale.
  • Adverse events of interest in this group included infusion reaction (2), infections (16), and cytopenia (1 ).
  • Table 10 provides a summary of treatment emergent adverse events of subjects having had prior, versus those not having had prior, rituximab use.
  • Table 10 TEAEs, Serious TEAEs, and TEAES of Special Interest After Receiving
  • PML progressive multifocal leukoencephalopathy
  • TEAE treatment-emergent adverse event

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