Anti-c5 antibody for treatment of neuromyelitis optica spectrum disorder

Abstract

To provide an anti-C5 antibody for treatment of neuromyelitis optica spectrum disorder.SOLUTION: Provided are methods for clinical treatment of neuromyelitis optica spectrum disorder (NMOSD) using an anti-C5 antibody, or antigen binding fragment thereof. The present disclosure provides a method of treating neuromyelitis optica spectrum disorder (NMOSD) in a subject in need thereof by administering an antibody that specifically binds to a complement component 5 (C5). In certain embodiments, the antibody that specifically binds to the C5 reduces a rate at which the C5 is cleaved in vivo into C5a and C5b. In other embodiments, the antibody that specifically binds to the C5 binds to one or both of the C5a and / or C5b fragments. In any of these embodiments, the antibody that specifically binds to the C5 reduces a complement cascade at the C5, thereby reducing release of proinflammatory mediators and formation of a cytolytic pore.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 945,644, filed Dec. 9, 2019, the entire content of which is incorporated herein by reference for all purposes.

[0002] Reference to Electronically Submitted Sequence Listing The content of the sequence listing electronically submitted in an ASCII text file (name: 710476_AX9-007PC_ST25_Sequence_Listing.txt; size: 56.0 KB; and creation date: Dec. 8, 2020) is incorporated herein by reference in its entirety.

Background Art

[0003] Neuromyelitis spectrum disorder (NMOSD), including neuromyelitis optica (NMO), also known as Devic's disease or Devic's syndrome, is a rare and severe autoimmune inflammatory disease of the central nervous system (CNS) that mainly affects the optic nerve and spinal cord and often leads to blindness, mono- / di- / tetraplegia, and respiratory failure. NMOSD is characterized by a relapsing disease course, and recovery from it can be poor because significant neurological impairments accumulate step by step.

[0004] The clinical features of NMO are acute optic neuritis and transverse myelitis that frequently affect more than three vertebral levels and are described as longitudinally extensive transverse myelitis (LETM). These clinical events can occur simultaneously or alone. Signs and symptoms due to lesions beyond the optic nerve and spinal cord can also occur in NMO patients and are reported in about 15% of patients. The clinical picture of NMO is extremely diverse, and there may even be confusion in diagnosis at the first or second episode.

[0005] Aquaporin-4 (AQP4) is a water channel protein mainly expressed in the CNS by astrocytes. AQP4 immunoglobulin G (IgG) is an antibody present in 65 - 88% of patients with NMOSD and is the first biomarker specific to inflammatory, demyelinating CNS disorders. Preclinical data indicate that AQP4-IgG induces the complement cascade, leading to inflammation and the formation of complement-mediated membrane attack complexes (MAC). AQP4-IgG-induced MAC is involved in astrocyte destruction and bystander nerve injury but is not seen in the presence of complement inhibitors. With the discovery of NMO-IgG, the diagnostic criteria for NMO were revised in 2006 to include testing for this disease-specific antibody.

[0006] Given that NMO is a disease that can cause severe disabilities, the ability to recognize NMO and related diseases and distinguish them from other demyelinating diseases is important from a clinical perspective. The prognosis of relapsing NMO is poor. The 5-year mortality rate of NMO has been reported to be 30%, and 50% have persistent severe disabilities, visual impairment (blindness in one or both eyes) or mobility impairment (requiring a wheelchair). Most deaths are due to neurogenic respiratory failure secondary to high cervical spinal cord or brainstem lesions. Frequent early relapses predict a poor prognosis. Therefore, relapse prevention is a major therapeutic imperative.

[0007] Treatment options for NMO have been approved in recent years (in an open-label trial of 14 AQP4-IgG positive patients, Soliris® (eculizumab) has been shown to reduce relapse frequency), but standard treatment options include steroids and other immunosuppressive drugs. This is supportive therapy based on experience and consensus. Acute NMO relapses are generally treated with high-dose intravenous steroids, often accompanied by plasma exchange (PE), which is used as rescue therapy for patients who do not respond. Supportive therapy for relapses currently uses broad-spectrum or selective B-lymphocyte immunosuppressive drugs. Summary of the Invention Problems to be Solved by the Invention

[0008] Among immunosuppressive agents, corticosteroids, AZA, mycophenolate mofetil, and rituximab are probably the most commonly used for long-term prevention. Depending on regional medical options, the options for supportive therapy for NMO can vary. In the United States, the options include corticosteroids, AZA, MMF, rituximab, and mitoxantrone, while in Japan, corticosteroids including oral prednisone or pulse high-dose steroids (IV) are common treatments. A significant number of patients (over 50%) will continue to have attacks that result in further permanent neurological deficits and disabilities. Considering the severity of the disease and the limited treatment options, a significant unmet medical need for effective and safe treatment for NMO still exists.

Means for Solving the Problems

[0009] This specification describes materials and methods for the treatment of NMOSD (e.g., NMO). In particular, such materials and methods include C5 inhibitors (e.g., ravulizumab).

[0010] In one embodiment, the present disclosure is a method of treating neuromyelitis optica spectrum disorder (NMOSD) in a human subject in need thereof, comprising administering to the human subject an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises an Fc region comprising the amino acid sequence set forth in SEQ ID NO: 13, the amino acid sequence comprising up to four amino acid substitutions in the amino acid sequence set forth in SEQ ID NO: 13, the amino acid substitutions not including leucine 307 and serine 313, thereby treating NMOSD in the subject. In certain embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO: 12 and a light chain variable region set forth in SEQ ID NO: 8. In certain embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a heavy chain constant region set forth in SEQ ID NO: 13. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 11. In certain embodiments, the anti-C5 antibody or antigen-binding fragment thereof has an affinity dissociation constant (K D ) in the range of 0.1 nM ≦ K D ≦ 1 nM for binding to human C5 at pH 7.4 and 25°C. In certain embodiments, the anti-C5 antibody or antigen-binding fragment thereof has a K DIt binds to human C5. In certain embodiments, the subject is 18 years of age or older. In certain embodiments, the subject is positive for anti-AQP4 antibodies. In certain embodiments, the subject has had at least one attack or recurrence in the past 12 months. In certain embodiments, the subject has an Expanded Disability Status Scale (EDSS) score of ≤ 7. In certain embodiments, the anti-C5 antibody is administered without additional immunosuppressive therapy (IST). In certain embodiments, the anti-C5 antibody is administered with at least one IST. In certain embodiments, at least one IST is selected from the group consisting of corticosteroids, azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), and tacrolimus (TAC). In certain embodiments, the subject weighs at least 40 kg. In certain embodiments, the therapeutically effective dose is based on the weight of the subject. In certain embodiments, the subject exhibits at least one symptom of NMOSD. In certain embodiments, the subject weighs ≥ 40 kg and < 60 kg, and (a) the anti-C5 antibody is administered as a loading dose of 2400 mg on day 1 of the dosing cycle; and (b) a maintenance dose of 3000 mg is administered on day 15 of the dosing cycle and every 8 weeks thereafter. In certain embodiments, the subject weighs ≥ 60 kg and < 100 kg, and (a) the anti-C5 antibody is administered as a loading dose of 2700 mg on day 1 of the dosing cycle; and (b) a maintenance dose of 3300 mg is administered on day 15 of the dosing cycle and every 8 weeks thereafter. In certain embodiments, the subject weighs ≥ 100 kg, and (a) the anti-C5 antibody is administered as a loading dose of 3000 mg on day 1 of the dosing cycle; and (b) a maintenance dose of 3600 mg is administered on day 15 of the dosing cycle and every 8 weeks thereafter. In certain embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or its antigen-binding fragment of 100 μg / mL or more during the dosing cycle. In certain embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or its antigen-binding fragment of 200 μg / mL or more during the dosing cycle. In certain embodiments, the treatment maintains a free C5 concentration of 0.309 to 0.5 μg / mL or less.In certain embodiments, the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of 3000 mg, 3300 mg, or 3600 mg every 8 weeks for up to 2 years after the dosing cycle. In certain embodiments, the anti-C5 antibody or antigen-binding fragment thereof is formulated for intravenous administration. In certain embodiments, the patient has not been previously treated with a complement inhibitor. In certain embodiments, the dosing cycle is a total of 26 weeks of treatment. In certain embodiments, the treatment results in terminal complement inhibition. In certain embodiments, the subject undergoes plasma exchange (PE) / plasmapheresis (PP), and the subject optionally receives an additional dose of ravulizumab, such as 1200 - 1800 mg of anti-C5 antibody, within 4 hours after completion of PE / PP. In certain embodiments, the human subject experiences a clinically meaningful improvement in one or more clinical markers related to NMOSD progression after administration of ravulizumab. In certain embodiments, the clinical markers related to NMOSD progression are selected from the group consisting of adjudicated On-Trial ARR, EDSS score, EQ-5D, SF-36, HAI, and OSIS during the evaluated trial.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0012] The present disclosure provides a method of treating neuromyelitis optica spectrum disorder (NMOSD) in a subject in need thereof by administering an antibody that specifically binds to complement component 5 (C5). In certain embodiments, the antibody that specifically binds to C5 reduces the rate at which C5 is cleaved to C5a and C5b in vivo. In other embodiments, the antibody that specifically binds to C5 binds to one or both of the C5a and / or C5b fragments. In any of these embodiments, the antibody that specifically binds to C5 reduces the complement cascade at C5, thereby reducing the release of pro-inflammatory mediators and the formation of cytolytic pores.

[0013] In certain embodiments, the antibody that specifically binds to C5 is ravulizumab or a fragment thereof. Ravulizumab (also known as BNJ441, ALXN1210 or Ultomiris®) is an anti-C5 antibody comprising a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 14 and 11, respectively, or an antigen-binding fragment and variant thereof. Ravulizumab is described in PCT Publication No. WO 2015 / 019225 and U.S. Patent No. 9,079,949, the entire teachings of which are incorporated herein by reference. Ravulizumab selectively binds to human complement protein C5 and inhibits its cleavage to C5a and C5b during complement activation. This inhibition preserves the proximal or early components of complement activation (e.g., C3 and C3b), which are essential for opsonization of microorganisms and clearance of immune complexes, while preventing the release of the pro-inflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC), C5b-9.

[0014] Definitions As used herein, the terms "subject" or "patient" are human patients (e.g., patients having neuromyelitis optica spectrum disorder (NMOSD)). As used herein, the terms "subject" and "patient" are interchangeable.

[0015] As used herein, the phrase "requiring chronic plasma exchange" to maintain clinical stability refers to the regular use of plasma exchange therapy in a patient to manage muscle strength decline at least every three months over the past twelve months.

[0016] As used herein, "effective treatment" refers to a treatment that produces a beneficial effect (e.g., the resolution of at least one symptom of a disease or disorder). The beneficial effect can take the form of an improvement above baseline, i.e., an improvement above the measurements or observations made prior to the initiation of treatment by the method. An effective treatment can refer to the alleviation of at least one symptom of NMOSD.

[0017] The term "effective amount" refers to the amount of an agent that provides a desired biological, therapeutic, and / or prophylactic result. The result can be a decrease, resolution, alleviation, reduction, delay, and / or mitigation of one or more of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. In one example, an "effective amount" is the amount of an anti-C5 antibody or antigen-binding fragment thereof that has been clinically demonstrated to reduce at least one symptom of NMOSD. The effective amount can be administered in one or multiple administrations.

[0018] As used herein, the terms "induction" and "induction phase" are used interchangeably and refer to the first phase of treatment in a clinical trial.

[0019] As used herein, the terms "maintenance" and "maintenance phase" are used interchangeably and refer to the second stage of treatment in a clinical trial. In certain embodiments, the treatment is continued as long as a clinical benefit is observed or until untreatable toxicity or disease progression occurs. The maintenance phase of administration of lovelizumab can last from 6 weeks to the lifetime of the subject. According to other embodiments, the maintenance phase continues for 26 - 52, 26 - 78, 26 - 104, 26 - 130, 26 - 156, 26 - 182, 26 - 208 weeks or longer. In other embodiments, the maintenance phase continues for more than 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 78, 104, 130, 156 or 182 weeks. According to other embodiments, the maintenance phase continues for 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 years or longer. In certain embodiments, the maintenance phase continues for the remainder of the subject's lifetime.

[0020] In certain embodiments, the LEMTRADA multi-stage dosing regimen includes a third stage. This third stage is used when an NMOSD patient must receive rescue therapy to maintain clinical stability and includes administering plasma exchange / plasmapheresis (PE / PP). At this stage after plasma exchange, one dose of LEMTRADA is administered to replenish the drug lost during plasma exchange / plasmapheresis. According to certain embodiments, when a PE / PP rescue therapy is provided on a non-dose day, additional investigational drug (or placebo) administration is required. In another embodiment, when a PE / PP infusion is provided on a dose day, this must be done prior to investigational drug administration. In some embodiments, if PE / PP is administered during an unscheduled dosing visit, the patient receiving PE / PP is administered an additional dose within 1, 2, 3, 4, 5, 6, 7, or 8 hours after the PE / PP session is completed. In some embodiments, if PE / PP is administered during an unscheduled dosing visit, the patient receiving PE / PP is administered an additional dose within 4 hours after the PE / PP session is completed. In certain embodiments, the additional dose may or may not vary according to the PE / PP. In other embodiments, when PE / PP is administered during a scheduled dosing visit, follow the regular dosing 60 minutes after completion of the PE / PP. In certain embodiments, no gap is required between the additional dose and the regular scheduled dose.

[0021] In some embodiments, the additional dose of ravulizumab is administered at 1000-2000 mg. In some embodiments, the additional dose of ravulizumab is administered at approximately half of the most recent loading or maintenance dose of ravulizumab. In some embodiments, when the most recent loading dose is 2200 mg to 3000 mg of ravulizumab, the additional dose is 1000-1500 mg of ravulizumab. In some embodiments, when the most recent loading dose is approximately 2400 mg of ravulizumab, the additional dose is approximately 1200 mg of ravulizumab. In some embodiments, when the most recent loading dose is 2400 mg of ravulizumab, the additional dose is 1200 mg of ravulizumab. In some embodiments, when the most recent loading dose is approximately 2700 mg of ravulizumab, the additional dose is approximately 1500 mg of ravulizumab. In some embodiments, when the most recent loading dose is 2700 mg of ravulizumab, the additional dose is 1500 mg of ravulizumab. In some embodiments, when the most recent loading dose is approximately 3000 mg of ravulizumab, the additional dose is approximately 1500 mg of ravulizumab. In some embodiments, when the most recent loading dose is 3000 mg of ravulizumab, the additional dose is 1500 mg of ravulizumab. In some embodiments, when the most recent maintenance dose is approximately 3000 mg of ravulizumab, the additional dose is approximately 1500 mg of ravulizumab. In some embodiments, when the maximum maintenance loading dose is 3000 mg of ravulizumab, the additional dose is 1500 mg of ravulizumab. In some embodiments, when the most recent maintenance dose is approximately 3300 mg of ravulizumab, the additional dose is approximately 1800 mg of ravulizumab. In some embodiments, when the maximum maintenance loading dose is 3300 mg of ravulizumab, the additional dose is 1800 mg of ravulizumab. In some embodiments, when the most recent maintenance dose is approximately 3600 mg of ravulizumab, the additional dose is approximately 1800 mg of ravulizumab. In some embodiments, when the maximum maintenance loading dose is 3600 mg of ravulizumab, the additional dose is 1800 mg of ravulizumab.

[0022] As used herein, the term "loading dose" refers to the initial dose administered to a patient. In some embodiments, the loading dose is 2000 - 4000 mg of ravulizumab. In some embodiments, the loading dose is 2100 - 2700 mg, 2400 - 3000 mg or 2700 - 3300 mg of ravulizumab. In some embodiments, the loading dose is 2300 - 2500 mg, 2600 - 2800 mg or 2900 - 3100 mg of ravulizumab. In some embodiments, the loading dose is approximately 2400 mg, approximately 2700 mg or approximately 3000 mg of ravulizumab. In some embodiments, the loading dose is 2400 mg, 2700 mg or 3000 mg of ravulizumab. The loading dose can be titrated based on body weight.

[0023] In some embodiments, patients having a body weight of 40 kg or more but less than 60 kg are administered 2100 - 2700 mg, 2300 - 2500 mg, approximately 2400 mg or 2400 mg of ravulizumab. In some embodiments, patients having a body weight of 60 kg or more but less than 100 kg are administered 2400 - 3000 mg, 2600 - 2800 mg, approximately 2700 mg or 2700 mg of ravulizumab. In some embodiments, patients having a body weight exceeding 100 kg are administered 2700 - 3300 mg, 2900 - 3100 mg, approximately 3000 mg or 3000 mg of ravulizumab.

[0024] As used herein, the term "maintenance dose" or "maintenance phase" refers to the dose administered to a patient after a loading dose. In some embodiments, the loading dose is 2000 - 4000 mg of ravulizumab. In some embodiments, the loading dose is 2800 - 3200 mg, 3100 - 3500 mg or 3400 - 3800 mg of ravulizumab. In some embodiments, the loading dose is 2900 - 3100 mg, 3200 - 3400 mg or 3500 - 3700 mg of ravulizumab. In some embodiments, the loading dose is about 3000 mg, about 3300 mg or about 3600 mg of ravulizumab. In some embodiments, the loading dose is 3000 mg, 3300 mg or 3600 mg of ravulizumab. The maintenance dose can be increased gradually based on body weight.

[0025] In some embodiments, patients having a body weight of 40 kg or more but less than 60 kg are administered 2800 - 3200 mg, 2900 - 3100 mg, about 3000 mg or 3000 mg of ravulizumab. In some embodiments, patients having a body weight of 60 kg or more but less than 100 kg are administered 3100 - 3500 mg, 3200 - 3400 mg, about 3300 mg or 3300 mg of ravulizumab. In some embodiments, patients having a body weight exceeding 100 kg are administered 3400 - 3800 mg, 3500 - 3700 mg, about 3600 mg or 3600 mg of ravulizumab.

[0026] As used herein, the term "serum trough level" refers to the lowest level at which a drug (e.g., an anti-C5 antibody or an antigen-binding fragment thereof) or a medicament is present in serum. In contrast, "peak serum level" refers to the highest level of a drug in serum. "Average serum level" refers to the average level of a drug in serum over time.

[0027] In one embodiment, the described treatment regimen is sufficient to maintain a specific serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof. In one embodiment, for example, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395 or 400 μg / mL or more. In one embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 100 μg / mL or more. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 150 μg / mL or more. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 200 μg / mL or more. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 250 μg / mL or more. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 300 μg / mL or more. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 100 μg / mL to 200 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at about 175 μg / mL.

[0028] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains at least 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 150 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 255 μg or 260 μg of antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains 50 μg to 250 μg of antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains 100 μg to 200 μg of antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains approximately 175 μg of antibody per milliliter of the patient's blood.

[0029] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains the minimum free C5 concentration. In one embodiment, for example, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains a free C5 concentration of 0.2 μg / mL, 0.3 μg / mL, 0.4 μg / mL, 0.5 μg / mL or less. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains a free C5 concentration of 0.309 to 0.5 μg / mL or less. In another embodiment, the treatment described herein reduces the free C5 concentration by more than 99% throughout the treatment period. In another embodiment, the treatment reduces the free C5 concentration by more than 99.5% throughout the treatment period.

[0030] The term "terminal complement inhibition" refers to the inhibition of the late stages of the complement cascade. In one embodiment, terminal complement inhibition refers to inhibiting the cleavage of complement component 5 ("C5") into C5a and C5b by C5 convertase.

[0031] The term "antibody" describes a polypeptide that includes at least one antigen-binding site derived from an antibody (e.g., VH / VL region or Fv or CDR). Antibodies include known forms of antibodies. An antibody can be, for example, a human antibody, a humanized antibody, a camel antibody, a bispecific antibody or a chimeric antibody. An antibody can also be a Fab, Fab’2, ScFv, SMIP, Affibody, nanobody or domain antibody. An antibody can be of any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD and IgE. An antibody can be a naturally occurring antibody or an antibody modified by protein engineering techniques (e.g., by mutation, deletion, substitution, binding to a non-antibody moiety). An antibody can include, for example, one or more variant amino acids (compared to a naturally occurring antibody) that change the properties of the antibody (e.g., functional properties), which, for example, change the properties of the antibody (e.g., functional properties). A number of such modifications that affect the half-life, effector function and / or immune response to the antibody in a patient are known in the art. The term "antibody" also includes artificial or engineered polypeptide constructs that include at least one antigen-binding site derived from an antibody.

[0032] C5-binding protein The term "antibody" describes a polypeptide that includes at least one antibody-derived antigen-binding site (e.g., VH / VL region or Fv or CDR). Antibodies include known forms of antibodies. The antibody can be, for example, a human antibody, a humanized antibody, a camel antibody, a bispecific antibody or a chimeric antibody. The antibody can also be a Fab, Fab’2, ScFv, SMIP, Affibody, nanobody or domain antibody. The antibody can be of any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD or IgE. The antibody can be a naturally occurring antibody or an antibody modified by protein engineering techniques (e.g., by mutation, deletion, substitution, or conjugation to a non-antibody moiety). The antibody can include, for example, one or more variant amino acids (compared to a naturally occurring antibody) that alter the properties of the antibody (e.g., functional properties), which can, for example, alter the properties of the antibody (e.g., functional properties). Such modifications that affect the half-life, effector function and / or immune response to the antibody in a patient are known in the art. The term antibody also includes artificial or engineered polypeptide constructs that include at least one antibody-derived antigen-binding site.

[0033] The anti-C5 antibodies described herein bind to complement component C5 (e.g., human C5) and inhibit cleavage of C5 into its fragments C5a and C5b. Anti-C5 antibodies (or VH / VL domains derived therefrom) suitable for use in the methods described herein can be generated using methods known in the art. Alternatively, anti-C5 antibodies recognized in the art can be used. Antibodies that compete with any of these antibodies recognized in the art for binding to C5 can also be used.

[0034] Eculizumab (also known as Soliris®) is an anti-C5 antibody comprising a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 10 and 11, respectively, or an antigen-binding fragment and variant thereof. Eculizumab is described in PCT / U.S. Patent Application Publication No. 2007 / 006606, the teachings of which are incorporated herein by reference. In one embodiment, the anti-C5 antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of eculizumab having the sequence shown in SEQ ID NO: 7 and the CDR1, CDR2, and CDR3 domains of the VL region of eculizumab having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences shown in SEQ ID NOs: 7 and 8, respectively.

[0035] Ravulizumab (also known as BNJ441, ALXN1210, or Ultomiris®) is an anti-C5 antibody comprising a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 14 and 11, respectively, or an antigen-binding fragment and variant thereof. Ravulizumab is described in PCT / U.S. Patent Application Publication No. 2015 / 019225 and U.S. Patent No. 9,079,949, the teachings of which are incorporated herein by reference. Ravulizumab selectively binds to human complement protein C5 and inhibits its cleavage into C5a and C5b during complement activation. This inhibition prevents the release of the pro-inflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC) C5b-9 while preserving the proximal or early components of complement activation (e.g., C3 and C3b) that are essential for microbial opsonization and immune complex clearance.

[0036] In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of ravulizumab. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of ravulizumab having the sequence shown in SEQ ID NO: 12 and the CDR1, CDR2, and CDR3 domains of the VL region of ravulizumab having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences shown in SEQ ID NOs: 12 and 8, respectively.

[0037] Another exemplary anti-C5 antibody is antibody BNJ421 or an antigen-binding fragment and variant thereof comprising a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 20 and 11, respectively. BNJ421 (also known as ALXN1211) is described in PCT Publication No. WO 2015 / 019225 and U.S. Patent No. 9,079,949, the teachings of which are incorporated herein by reference.

[0038] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of BNJ421 having the sequence shown in SEQ ID NO: 12 and the CDR1, CDR2, and CDR3 domains of the VL region of BNJ421 having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences shown in SEQ ID NOs: 12 and 8, respectively.

[0039] The exact boundaries of the CDRs are defined differently according to different methods. In some embodiments, the positions of the CDRs or framework regions within the light or heavy chain variable domains can be as defined by Kabat et al. [(1991) “Sequences of Proteins of Immunological Interest.” NIH Publication No. 91-3242, U.S. Department of Health and Human Services, Bethesda, MD]. In such cases, the CDRs can be referred to as “Kabat CDRs” (e.g., “Kabat LCDR2” or “Kabat HCDR1”). In some embodiments, the positions of the CDRs of the light or heavy chain variable regions can be as defined by Chothia et al., Nature, 342:877-83, 1989. Thus, these regions can be referred to as “Chothia CDRs” (e.g., “Chothia LCDR2” or “Chothia HCDR3”). In some embodiments, the positions of the CDRs of the light and heavy chain variable regions can be as defined by the Kabat-Chothia combined definition. In such embodiments, these regions can be referred to as the “combination of Kabat-Chothia CDRs”. Thomas et al. (Mol. Immunol., 33:1389-401, 1996) illustrate the identification of CDR boundaries according to the definitions of Kabat and Chothia.

[0040] Another exemplary anti-C5 antibody is the 7086 antibody described in U.S. Patent Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see U.S. Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 21, 22, and 23, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 24, 25, and 26, respectively. In another embodiment, the antibody or antigen-binding fragment thereof comprises the VH region of the 7086 antibody having the sequence set forth in SEQ ID NO: 27 and the VL region of the 7086 antibody having the sequence set forth in SEQ ID NO: 28.

[0041] Another exemplary anti-C5 antibody is the 8110 antibody, which is also described in U.S. Patent Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 29, 30, and 31, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 32, 33, and 34, respectively. In another embodiment, the antibody comprises the VH region of the 8110 antibody having the sequence set forth in SEQ ID NO: 35 and the VL region of the 8110 antibody having the sequence set forth in SEQ ID NO: 36.

[0042] Another exemplary anti-C5 antibody is the 305LO5 antibody described in U.S. Patent Application Publication No. 2016 / 0176954A1. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 37, 38, and 39, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 40, 41, and 42, respectively. In another embodiment, the antibody comprises the VH region of the 305LO5 antibody having the sequence set forth in SEQ ID NO: 43 and the VL region of the 305LO5 antibody having the sequence set forth in SEQ ID NO: 44.

[0043] Another exemplary anti-C5 antibody is the SKY59 antibody described in Fukuzawa, T. et al. (Sci. Rep., 7:1080, 2017). In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 45 and a light chain comprising SEQ ID NO: 46.

[0044] Another exemplary anti-C5 antibody is the H4H12166PP antibody described in PCT / U.S. Patent Application Publication No. 2017 / 037226 and U.S. Patent Application Publication No. 2017 / 0355757A1. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the H4H12166PP antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises the VH region of the H4H12166PP antibody having the sequence set forth in SEQ ID NO: 47 and the VL region of the H4H12166PP antibody having the sequence set forth in SEQ ID NO: 48. In another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 49 and a light chain comprising SEQ ID NO: 50.

[0045] In one embodiment, a patient is treated with eculizumab and then switched to treatment with 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, H4H12166PP antibody, or ravulizumab. In another embodiment, a patient is switched from an anti-C5 antibody (e.g., eculizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or H4H12166PP antibody) to another anti-C5 antibody (e.g., ravulizumab) during the course of treatment. In certain embodiments, a patient is switched from eculizumab to ravulizumab during the course of treatment.

[0046] In some embodiments, the anti-C5 antibodies described herein comprise or consist of a heavy chain CDR1 having the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19). In some embodiments, the anti-C5 antibodies described herein comprise or consist of a heavy chain CDR2 having the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO: 18). In some embodiments, the anti-C5 antibodies described herein have the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGEILPGSGHTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSSPNWYFDVWGQGTLVTVSS (SEQ ID NO: 12) and comprise a heavy chain variable region.

[0047] In some embodiments, the anti-C5 antibodies described herein comprise a light chain variable region having the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIK (SEQ ID NO: 8). and comprise a light chain variable region.

[0048] In some embodiments, the anti-C5 antibodies described herein may include a modified human Fc constant region that binds to the human neonatal Fc receptor (FcRn) with a higher affinity than the native human Fc constant region from which the modified human Fc constant region is derived. For example, the Fc constant region may include one or more (e.g., 2, 3, 4, 5, 6, 7, or 8 or more) amino acid substitutions compared to the native human Fc constant region from which the modified human Fc constant region is derived. The substitutions can increase the binding affinity of an IgG antibody comprising the modified Fc constant region for FcRn at pH 6.0 while maintaining the pH-dependence of the interaction. Methods for testing whether one or more substitutions in the Fc constant region of an antibody increase the affinity of the Fc constant region for FcRn at pH 6.0 (while maintaining the pH-dependence of the interaction) are known in the art and are exemplified in the working examples (PCT / US Patent Application Publication No. 2015 / 019225 and U.S. Patent No. 9,079,949, the disclosures of each of which are incorporated herein by reference in their entirety).

[0049] Substitutions that enhance the binding affinity of an antibody Fc constant region for FcRn are known in the art and include, for example, (1) the M252Y / S254T / T256E triple substitution described by Dall‘Acqua, W. et al. (J. Biol. Chem., 281:23514-24, 2006); (2) the M428L or T250Q / M428L substitutions described by Hinton, P. et al. (J. Biol. Chem., 279:6213-6, 2004) and Hinton, P. et al. (J. Immunol., 176:346-56, 2006); and (3) the N434A or T307 / E380A / N434A substitutions described by Petkova, S. et al. (Int. Immunol., 18:1759-69, 2006). Additional alternative pairs: P257I / Q311I, P257I / N434H, and D376V / N434H have also been described (Datta-Mannan, A. et al., J. Biol. Chem., 282:1709-17, 2007, the disclosure of which is incorporated herein by reference in its entirety).

[0050] In some embodiments, the modified constant region has a substitution at EU amino acid residue 255 for valine. In some embodiments, the modified constant region has a substitution at EU amino acid residue 309 for asparagine. In some embodiments, the modified constant region has a substitution at EU amino acid residue 312 for isoleucine. In some embodiments, the modified constant region has a substitution at EU amino acid residue 386.

[0051] In some embodiments, the modified Fc constant region comprises 30 or fewer (e.g., 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 or fewer) amino acid substitutions, insertions, or deletions relative to the native constant region from which it is derived. In some embodiments, the modified Fc constant region comprises one or more amino acid substitutions selected from the group consisting of M252Y, S254T, T256E, N434S, M428L, V259I, T250I, and V308F. In some embodiments, the modified human Fc constant region comprises methionine at position 428 and asparagine at position 434 in each EU numbering. In some embodiments, the modified Fc constant region comprises the 428L / 434S double substitution, as described, for example, in U.S. Patent No. 8,088,376.

[0052] In some embodiments, the exact positions of these mutations can be shifted from the native human Fc constant region positions due to antibody engineering. The 428L / 434S double substitution is found, for example, in BNJ441 (ravulizumab) when used in an IgG2 / 4 chimeric Fc and may correspond to 429L and 435S as in the M429L and N435S variants described in U.S. Patent No. 9,079,949, the disclosure of which is incorporated herein by reference in its entirety.

[0053] In some embodiments, the modified constant region comprises substitutions at amino acid positions 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, 384, 385, 386, 387, 389, 424, 428, 433, 434 or 436 (EU numbering) relative to the native human Fc constant region. In some embodiments, the substitutions are methionine for glycine at position 237; alanine for proline at position 238; lysine for serine at position 239; isoleucine for lysine at position 248; alanine, phenylalanine, methionine, glutamine, serine, valine, tryptophan or tyrosine for threonine at position 250; phenylalanine, tryptophan or tyrosine for methionine at position 252; threonine for serine at position 254; glutamic acid for arginine at position 255; aspartic acid, glutamic acid or glutamine for threonine at position 256; alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine or valine for proline at position 257; histidine for glutamic acid at position 258; alanine for aspartic acid at position 265; phenylalanine for aspartic acid at position 270; alanine or glutamic acid for asparagine at position 286; histidine for threonine at position 289; alanine for asparagine at position 297; glycine for serine at position 298; alanine for valine at position 303; alanine for valine at position 305; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan or tyrosine for threonine at position 307; alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine or threonine for valine at position 308; alanine, aspartic acid, glutamic acid, proline or arginine for leucine or valine at position 309;Alanine, histidine, or isoleucine for glutamine at position 311; alanine or histidine for aspartic acid at position 312; lysine or arginine for leucine at position 314; alanine or histidine for asparagine at position 315; alanine for lysine at position 317; glycine for asparagine at position 325; valine for isoleucine at position 332; leucine for lysine at position 334; histidine for lysine at position 360; alanine for aspartic acid at position 376; alanine for glutamic acid at position 380; alanine for glutamic acid at position 382; alanine for asparagine or serine at position 384; aspartic acid or histidine for glycine at position 385; proline for glutamine at position 386; glutamic acid for proline at position 387; alanine or serine for asparagine at position 389; alanine for serine at position 424; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, or tyrosine for methionine at position 428; lysine for histidine at position 433; alanine, phenylalanine, histidine, serine, tryptophan, or tyrosine for asparagine at position 434; and histidine for tyrosine or phenylalanine at position 436 (in all EU numberings), selected from the group consisting of;

[0054] In some embodiments, suitable anti-C5 antibodies for use in the methods described herein comprise a heavy chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 14 and / or a light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 11. Alternatively, in some embodiments, anti-C5 antibodies for use in the methods described herein comprise a heavy chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 20 and / or a light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 11.

[0055] In one embodiment, the antibody binds to C5 with an affinity dissociation constant of at least 0.1 (e.g., at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95 or 0.975) nM at pH 7.4 and 25 °C (or other physiological conditions). In some embodiments, the KD of the anti-C5 antibody or antigen-binding fragment thereof is 1 nM or less (e.g., 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3 or 0.2 nM or less).

[0056] In other embodiments, [(K of the antibody for C5 at pH 6.0 at 25 °C) D ) / (K of the antibody for C5 at pH 7.4 at 25 °C) D is greater than 21 (e.g., greater than 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500 or 8000).

[0057] Methods for determining whether an antibody binds to a protein antigen and / or the affinity with which the antibody binds to the protein antigen are known in the art. For example, the binding of an antibody to a protein antigen can be detected and / or quantified using a variety of techniques such as Western blot, dot blot, surface plasmon resonance (SPR) methods (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.) or enzyme-linked immunosorbent assay (ELISA) (Benny K.C. Lo (2004) “Antibody Engineering: Methods and Protocols,” Humana Press (ISBN: 1588290921); Johne, B. et al., J. Immunol. Meth., 160:191 - 8, 1993; Joensson, U. et al., Ann. Biol. Clin., 51:19 - 26, 1993; and Joensson, U. et al., Biotechniques, 11:620 - 7, 1991), but are not limited thereto. Further, methods for measuring affinity (e.g., dissociation constant and association constant) are described in the working examples.

[0058] As used herein, the term “k a ” refers to the rate constant of association of an antibody with an antigen. The term “k d ” refers to the rate constant of dissociation of an antibody from an antibody / antigen complex. Also, the term “K D ” refers to the equilibrium dissociation constant of an antibody - antigen interaction. The equilibrium dissociation constant is estimated from the ratio of the kinetic rate constants k D = K a / K d Such determinations are preferably made at 25°C or 37°C (see the working examples). For example, the kinetics of an antibody that binds to human C5 can be determined by surface plasmon resonance (SPR) at pH 8.0, 7.4, 7.0, 6.5, and 6.0 using the anti - Fc capture method to immobilize the antibody on a BIAcore 3000 instrument.

[0059] In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof blocks the production or activity of the C5a and / or C5b active fragments of C5 protein (e.g., human C5 protein). Due to this blocking effect, the antibody inhibits, for example, the inflammation-inducing effect of C5a and the formation of C5b-9 membrane attack complex (MAC) on the cell surface.

[0060] Methods for determining whether a particular antibody described herein inhibits C5 cleavage are known in the art. Inhibition of human complement component C5 can reduce the lytic ability of complement in the body fluid of a subject. Such a reduction in the lytic ability of complement present in the body fluid can be measured by conventional hemolytic assays such as those described in Kabat and Mayer (eds.), “Experimental Immunochemistry, 2nd Edition,” 135-240, Springfield, IL, CC Thomas (1961), pages 135-139, or conventional variants of such assays such as the chicken erythrocyte hemolysis method (Hillmen, P. et al., N. Engl. J. Med., 350:552-9, 2004), methods known in the art. Methods for determining whether a candidate compound inhibits the cleavage of human C5 into its C5a and C5b forms are known in the art (Evans, M. et al., Mol. Immunol., 32:1183-95, 1995). The concentration and / or biological activity of C5a and C5b in the body fluid can be measured, for example, by methods known in the art. For C5b, as discussed herein, a hemolytic assay or an assay for soluble C5b-9 can be used. Other assays known in the art can also be used. These or other suitable types of assays can be used to screen for candidate agents that can inhibit human complement component C5.

[0061] Using immunological techniques, such as but not limited to ELISA, the protein concentration of C5 and / or its split products can be measured to determine the ability of an anti-C5 antibody or its antigen-binding fragment to inhibit the conversion of C5 into biologically active products. In some embodiments, C5a generation is measured. In some embodiments, a C5b-9 neoepitope-specific antibody is used to detect the formation of the terminal complement.

[0062] In some embodiments, C5 activity or its inhibition is quantified using the CH50eq assay. The CH50eq assay is a method for measuring the total classical complement activity in serum. This test is a lysis assay that uses antibody-sensitized red blood cells as activators of the classical complement pathway and determines the amount required to give 50% lysis (CH50) using various dilutions of the test serum. The percent hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measurement of terminal complement complex (TCC) formation because the TCC itself is directly involved in the hemolysis being measured.

[0063] For example, inhibition related to terminal complement activity includes a decrease of at least 5% (e.g., at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60%) of the activity of the terminal complement compared to the effect of a control antibody (or its antigen-binding fragment) under similar conditions and at equimolar concentrations. Substantial inhibition as used herein refers to inhibition of at least 40% (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% or more) of a given activity (e.g., terminal complement activity). In some embodiments, the anti-C5 antibodies described herein contain one or more amino acid substitutions relative to the CDRs of eculizumab (i.e., SEQ ID NOs: 1-6), but retain at least 30% (e.g., at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%) of the complement inhibitory activity of eculizumab.

[0064] The anti-C5 antibodies described herein have a serum half-life in humans of at least 20 days (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55 days). In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of at least 40 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of about 43 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of 39 to 48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof described herein has a serum half-life that is at least 20% (e.g., at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 400 or 500%) greater than the serum half-life of eculizumab, as measured in one of the mouse model systems described in the working examples (e.g., the C5-deficient / NOD / scid mouse or the hFcRn transgenic mouse model system).

[0065] In one embodiment, the antibody competes for binding to the same epitope on C5 as the antibodies described herein and / or binds to that epitope. The term "binds to the same epitope" with respect to two or more antibodies means, as determined by a given method, that the antibodies bind to the same portion of the amino acid residues. Techniques for determining whether an antibody binds to the "same epitope on C5" as the antibodies described herein include, for example, epitope mapping methods such as x-ray analysis of crystals of the antigen:antibody complex that provide atomic resolution of the epitope and hydrogen / deuterium exchange mass spectrometry (HDX-MS). Other methods monitor the binding of the antibody to peptide antigen fragments or variants of the antigen, where loss of binding due to modification of amino acid residues within the antigen sequence is often considered an indicator of the epitope component. Additionally, computational combinatorial methods for epitope mapping can also be used. These methods rely on the ability of the antibody to affinity isolate specific short peptides from a combinatorial phage display peptide library. Antibodies having the same VH and VL or the same CDR1, 2, and 3 sequences are expected to bind to the same epitope.

[0066] An antibody that "competes with another antibody for binding to the target" refers to an antibody that (partially or completely) inhibits the binding of the other antibody to the target. Whether two antibodies compete with each other for binding to the target, i.e., whether one antibody inhibits the binding of the other antibody to the target and to what extent, can be determined using known competition assays. In certain embodiments, the antibody competes with and inhibits the binding of another antibody to the target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. The level of inhibition or competition can vary depending on which antibody is the "blocking antibody" (i.e., the cold antibody that is first incubated with the target). Competing antibodies bind to the same epitope, overlapping epitopes, or adjacent epitopes (e.g., as demonstrated by steric hindrance).

[0067] In the methods described herein, the anti-C5 antibodies or antigen-binding fragments thereof described herein can be generated using a variety of techniques recognized in the art. Monoclonal antibodies can be obtained by a variety of techniques well known to those skilled in the art. Briefly, spleen cells from an animal immunized with the desired antigen are generally immortalized by fusion with myeloma cells (Koehler, G. & Milstein, C., Eur. J. Immunol., 6:511-9, 1976). Alternative methods of immortalization include transformation by Epstein-Barr virus, oncogenes or retroviruses or other methods well known in the art. Colonies arising from a single immortalized cell are screened for the production of antibodies of the desired specificity and affinity for the antigen, and the yield of monoclonal antibodies produced by such cells can be enhanced by a variety of techniques including injection into the peritoneal cavity of a vertebrate host. Alternatively, DNA sequences encoding monoclonal antibodies or their binding fragments can be isolated by screening a DNA library from human B cells (Huse, W. et al., Science, 246:1275-81, 1989).

[0068] Composition Pharmaceutical compositions comprising ravulizumab alone or in combination with a prophylactic, therapeutic and / or pharmaceutically acceptable carrier are provided. The pharmaceutical compositions comprising ravulizumab provided herein are for use in the diagnosis, detection or monitoring of a disorder, the prevention, treatment, management or recovery of a disorder or one or more of its symptoms and / or research, but are not limited thereto. Formulations of pharmaceutical compositions alone or in combination with a prophylactic, therapeutic and / or pharmaceutically acceptable carrier are known to those skilled in the art.

[0069] In one embodiment, the composition comprises an anti-C5 antibody comprising the CDR1, CDR2 and CDR3 domains in the heavy chain variable region having the sequence shown in SEQ ID NO: 12 and the CDR1, CDR2 and CDR3 domains in the light chain variable region having the sequence shown in SEQ ID NO: 8. In another embodiment, the anti-C5 antibody comprises a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 14 and 11, respectively.

[0070] The composition can be formulated as a pharmaceutical solution for administration to a subject, for example, for the treatment or prevention of NMOSD. The pharmaceutical composition generally includes a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, etc. that are physiologically compatible and includes them. The composition can include pharmaceutically acceptable salts, for example, acid addition salts or base addition salts, sugars, carbohydrates, polyols and / or osmotic pressure regulators.

[0071] The composition can be formulated according to standard methods. Pharmaceutical formulations are well-established techniques and are further described, for example, in Gennaro (2000) “Remington: The Science and Practice of Pharmacy,” 20th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 7th Edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association,” 3rd Edition (ISBN: 091733096X). In some embodiments, the composition can be formulated as a buffer solution suitable for storage at 2-8 °C (e.g., 4 °C) at an appropriate concentration. In some embodiments, the composition can be formulated for storage at a temperature below 0 °C (e.g., -20 °C or -80 °C). In some embodiments, the composition can be formulated for storage at 2-8 °C (e.g., 4 °C) for up to two years (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years or 2 years). Thus, in some embodiments, the compositions described herein are stable in storage for at least one year at 2-8 °C (e.g., 4 °C).

[0072] Pharmaceutical compositions can be in various forms. These forms include, for example, liquid, semi-solid and solid dosage forms such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories). The preferred dosage form depends, in part, on the intended mode of administration and therapeutic application. For example, a composition intended for systemic or local delivery can be in the form of an injectable or infusible solution. The composition can be formulated for administration by a parenteral mode (e.g., intravenous, subcutaneous, intraperitoneal or intramuscular injection). As used herein, "parenteral administration", "administered parenterally" and other grammatically equivalent phrases generally refer to modes of administration other than enteral and topical administration by injection, and include, but are not limited to, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, internal carotid and intrasternal injection and infusion. In one embodiment, the antibody is formulated for intravenous administration.

[0073] An exemplary non-limiting range for a therapeutically or prophylactically effective amount of ravulizumab or other anti-C5 antibody, such as eculizumab, BNJ 421, 7086, 8110, SKY59 and H4H12166PP provided herein, is 600 - 5000 mg, such as 900 - 2000 mg. It should be noted that the dosage values can vary depending on the type and severity of the condition being alleviated. For any particular subject, a specific dosing regimen can be prepared over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and it should be further understood that the dosing ranges shown herein are for illustration only and are not intended to limit the scope or practice of the claimed method.

[0074] Method for treating neuromyelitis optica The present disclosure provides a method of treating a subject suffering from NMOSD by administering an antibody that specifically binds to C5. As used herein, the terms "subject" and "patient" are interchangeable. In certain embodiments, the subject and / or patient is a mammal including, for example, primates such as humans, rodents, rabbits, camels, ungulates, dogs, and cats. In certain embodiments, the subject or patient suffering from NMOSD described herein is a human.

[0075] NMOSD is characterized by a relapsing disease course, and since significant neurological impairments accumulate step by step, recovery therefrom may be poor. Neuromyelitis optica (NMO), also known as Devic's disease or Devic's syndrome, is part of NMOSD, mainly invades the optic nerve and spinal cord, and often leads to blindness, mono- / di- / tetraplegia, and respiratory failure, and is an autoimmune inflammatory disease with rare and severe disorders of the central nervous system (CNS).

[0076] In some embodiments, NMO is characterized by NMO-IgG antibodies (anti-AQP4) against aquaporin 4. In some embodiments, a subset of NMO patients is anti-AQP4 + Another embodiment, a subset of NMO patients is anti-MOG + (myelin oligodendrocyte glycoprotein).

[0077] In some embodiments, AQP4 autoantibodies are found in patients with NMO-like symptoms that do not meet the clinical requirements to be diagnosed as NMO. In some embodiments, one of the requirements to be diagnosed as NMO is relapsing and simultaneous optic nerve and spinal cord inflammation.

[0078] In some embodiments, NMOSD includes limited forms of Devic's disease such as a single or relapsing event of longitudinally extensive myelitis and bilateral simultaneous or relapsing optic neuritis. In some embodiments, NMOSD is Asian opticospinal multiple sclerosis (OSMS) or AQP4 +It includes OSMS. In some embodiments, NMOSD further includes longitudinally extensive myelitis or optic neuritis associated with systemic autoimmune diseases and optic neuritis or myelitis associated with lesions in specific brain regions such as the hypothalamus, periventricular nucleus, and brainstem.

[0079] In certain embodiments, the treatment of NMOSD includes the recovery or improvement of one or more symptoms associated with NMOSD. Symptoms associated with NMOSD include visual impairment, decreased visual acuity, visual field defects, loss of color vision, spinal cord dysfunction, muscle weakness, sensory loss, and loss of bladder or bowel control.

[0080] In other embodiments, the treatment of NMOSD includes the improvement of clinical markers related to NMOSD progression. These markers include, for example, time to relapse, annual relapse rate (ARR), expanded disability status scale score (EDSS), modified Rankin scale (mRS), quality of life (EQ-5D), Hauser ambulation index (HAI), change in visual acuity using a Snellen chart, and severity of relapse using the opticospinal impairment score (OSIS).

[0081] An NMOSD relapse is evidenced by the symptoms of NMOSD occurring in a subject whose symptoms have previously recovered successfully. A relapse is indicated by the onset or worsening of symptoms related to vision or sensation. Visual changes associated with an NMOSD relapse include the rapid onset of eye pain, blurred vision, colors that do not look right, absence of a visual field, spots or dots within the visual field, flickering or dimming within the visual field, difficulty focusing, difficulty reading, and the sensation that the visual field seems inaccurate. Sensory changes associated with an NMOSD relapse include pain, tingling, numbness, the feeling that the arms, legs, or face are falling asleep, loss of position sense in space, loss of sensation in the limbs, slight contact being painful, clothing or bedsheets causing pain, and the subject being unable to detect injury to the subject. The annual relapse rate (ARR) is the average number of relapses per year.

[0082] In certain embodiments, subjects treated for NMOSD have had three or more relapses in the 24 months prior to administration of lulizumab. In other embodiments, subjects treated for NMO have had 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more relapses in the 24 months prior to administration of lulizumab. In certain embodiments, subjects treated for NMOSD have an ARR of 1.0 or greater in the 24 months prior to administration of lulizumab. In other embodiments, subjects treated for NMOSD have an ARR of at least 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0 or greater in the 24 months prior to administration of lulizumab.

[0083] The disorder can be evaluated based on the EDSS score comparing the change from baseline in the two treatment groups. The Kurtzke Expanded Disability Status Scale score (EDSS) is a method for quantifying disability in multiple sclerosis. The EDSS replaced the previous disability status scales used in multiple sclerosis (MS). The EDSS quantifies disability into eight functional systems (FS), allowing a neurologist to assign a functional system score (FSS) to each of them. The functional systems are pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral, and others. EDSS steps 1.0 to 4.5 refer to MS patients who are fully ambulatory. EDSS steps 5.0 to 9.5 are defined by walking disability. The disorder can also be evaluated based on the mRS score comparing the change from baseline in the two treatment groups. The mRS score is evaluated by the treating physician at the time points specified in the clinical trial protocol.

[0084] In certain embodiments, the subject being treated for NMOSD has an EDSS score of at least 1.0 during the 24 months prior to the administration of lulizumab. In other embodiments, the subject being treated for NMOSD has an EDSS score of at least 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0 or more during the 24 months prior to the administration of lulizumab. In other embodiments, the subject being treated for NMOSD has an EDSS score of 1.0 to 7.0 during the 24 months prior to the administration of lulizumab. In certain embodiments, the subject being treated for NMOSD has an HAI score of at least 2.0 during the 24 months prior to the administration of lulizumab. In other embodiments, the subject being treated for NMOSD has an HAI score of at least 0.0, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0 or 9.0 during the 24 months prior to the administration of lulizumab. In other embodiments, the subject being treated for NMOSD has an HAI score of 0.0 to 8.0 during the 24 months prior to the administration of lulizumab. In certain embodiments, the subject being treated for NMOSD has an mRS score of at least 0.0 during the 24 months prior to the administration of lulizumab. In other embodiments, the subject being treated for NMOSD has an mRS score of at least 0.0, 1.0, 2.0, 3.0, 4.0, 5.0 or more during the 24 months prior to the administration of lulizumab. In other embodiments, the subject being treated for NMOSD has an mRS score of 0.0 to 2.5 during the 24 months prior to the administration of lulizumab.

[0085] The quality of life (QOL) can be evaluated by the patient's self-assessment questionnaires EQ-5D and SF-36 at the time points specified in the clinical trial protocol. A sample questionnaire of EQ-5D is shown in Figure 5. EUROQOL (EQ-5D) is a well-validated survey of the health status in five domains of mobility, self-care, usual activities, pain / discomfort, and anxiety / depression that the subject fills in. Each domain has three levels: level 1 (no problem), level 2 (some problem), and level 3 (extreme problem). EQ-5D is administered on day 1, and at weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, and 104, or at ET (days 2, 6, 8, 10, 16, 22, 28, 34, 40, 46, 52, and 56 of the hospital visit or ET). Clinically meaningful improvement in the patient's EQ-5D is reflected as an increase in the score after 26 weeks of treatment. A sample questionnaire of SF-36 is shown in Figure 5.

[0086] The walking function can be evaluated, for example, by the HAI scale. The vision can be evaluated, for example, using the Snellen chart. The severity of recurrence can be evaluated, for example, using the Optic Neuromyelitis Optic Spinal Score (OSIS). The OSIS score is summarized in Table 1.

[0087] According to certain embodiments, a subject administered with Lulizumab shows an increase in the time interval between relapses of NMOSD. In certain embodiments, the subject has a pre-relapse period exceeding 6 weeks. In other embodiments, the pre-relapse period is 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, 102 weeks or more. In other embodiments, the pre-relapse period is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 weeks or more. In other embodiments, the pre-relapse period exceeds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years. In other embodiments, the pre-relapse period is 6 - 52 weeks, 6 - 26 weeks, 6 - 10 weeks, 26 - 52 weeks, 1 - 2 years, 1 - 5 years, 5 - 10 years, or relapses do not occur throughout the life of the subject. In other embodiments, the pre-relapse period exceeds 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, 102 months or more.

[0088] According to certain embodiments, the course of treatment with Lulizumab continues for 108 weeks. According to other embodiments, the course of treatment continues for 26 - 52, 26 - 78, 26 - 120, 26 - 130, 26 - 156, 26 - 104, 26 - 130, 26 - 156, 26 - 182, 26 - 208 weeks or more. In other embodiments, the course of treatment continues for more than 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 78, 104, 130, 156 or 182 weeks. According to other embodiments, the course of treatment continues for 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 years or more. In certain embodiments, the course of treatment continues for the remainder of the subject's life.

[0089] According to certain embodiments, during treatment, one or more symptoms or scores associated with NMOSD improve during the treatment process and are maintained at the improved level throughout the treatment. The EDSS can improve, for example, after 26 weeks of treatment with a therapeutic antibody that specifically binds to C5, and then remain at the improved level during treatment, which can be, for example, 52 weeks of treatment with a therapeutic antibody that specifically binds to C5. An example of a therapeutic antibody that binds to C5 is ravulizumab.

[0090] In certain embodiments, the first signs of improvement occur by 26 weeks of treatment with a therapeutic antibody that specifically binds to C5. According to other embodiments, the first signs of improvement occur at weeks 1 - 26, 26 - 52, 52 - 78, 78 - 104, 104 - 130, 130 - 156, 156 - 182, or 182 - 208 of treatment with a therapeutic antibody that specifically binds to C5. In other embodiments, the first signs of improvement occur at week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 78, 104, 130, 156, or 182 of treatment.

[0091] According to certain embodiments, the first signs of improvement are maintained for several weeks during treatment with a binding protein that specifically binds to C5, such as ravulizumab. According to certain embodiments, this number of weeks is at least 26. According to other embodiments, this number of weeks is 1 - 26, 26 - 52, 52 - 78, 78 - 104, 104 - 130, 130 - 156, 156 - 182, or 182 - 208. In other embodiments, this number of weeks is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 78, 104, 130, 156, or 182. According to certain embodiments, when the first signs of improvement are maintained, this means that the metric for the treatment of NMOSD does not fall below the value of the first signs of improvement. The metric can continue to improve, which is still defined as the maintenance of the first signs of improvement.

[0092] In one embodiment, an anti - C5 antibody (e.g., ravulizumab) or an antigen - binding fragment thereof is administered once on the first day of a dosing cycle, once on the 15th day of the dosing cycle, and then every 8 weeks. In one embodiment, the anti - C5 antibody or an antigen - binding fragment thereof is administered for an extended period of up to 2 years (e.g., at a dose of 3000 mg, 3300 mg, or 3600 mg) every 8 weeks after the dosing cycle.

[0093] In another embodiment, an anti - C5 antibody (e.g., ravulizumab) or an antigen - binding fragment thereof is administered over one or more dosing cycles. In one embodiment, the dosing cycle is 26 weeks. In another embodiment, the treatment includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 cycles. In another embodiment, the treatment is continued throughout the life of the human patient.

[0094] In another embodiment, a method of treating a human patient with NMOSD is provided, the method comprising administering to the patient during an administration cycle an effective amount of an anti-C5 antibody (e.g., ravulizumab) or an antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences shown in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences shown in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered (a) once on day 1 of the administration cycle at a dose of 2400 mg for patients weighing ≧40 to <60 kg, 2700 mg for patients weighing ≧60 to <100 kg, or 3000 mg for patients weighing ≧100 kg; and (b) on day 15 of the administration cycle and every 8 weeks thereafter at a dose of 3000 mg for patients weighing ≧40 to <60 kg, 3300 mg for patients weighing ≧60 to <100 kg, or 3600 mg for patients weighing ≧100 kg.

[0095] In another embodiment, a method of treating a human patient with NMOSD is provided, the method comprising administering to the patient during an administration cycle an effective amount of an anti-C5 antibody (e.g., ravulizumab) or an antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences shown in SEQ ID NOs: 19, 18, and 3, respectively, CDR1, CDR2, and CDR3 light chain sequences shown in SEQ ID NOs: 4, 5, and 6, respectively, and a modified human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the modified human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at the residues corresponding to methionine 428 and asparagine 434 (EU numbering, respectively), and the anti-C5 antibody (e.g., ravulizumab) or antigen-binding fragment thereof is administered (a) once on day 1 of the administration cycle at a dose of 2400 mg for patients weighing ≧40 to <60 kg, 2700 mg for patients weighing ≧60 to <100 kg, or 3000 mg for patients weighing ≧100 kg; and (b) on day 15 of the administration cycle and every 8 weeks thereafter at a dose of 3000 mg for patients weighing ≧40 to <60 kg, 3300 mg for patients weighing ≧60 to <100 kg, or 3600 mg for patients weighing ≧100 kg.

[0096] In another embodiment, an anti-C5 antibody (e.g., ravulizumab) or an antigen-binding fragment thereof is administered to patients weighing ≧40 to <60 kg at a dose of 2400 mg once on day 1 of the dosing cycle; and at a dose of 3000 mg on day 15 of the dosing cycle and every 8 weeks thereafter.

[0097] In another embodiment, an anti-C5 antibody (e.g., ravulizumab) or an antigen-binding fragment thereof is administered to patients weighing ≧60 to <100 kg at a dose of 2700 mg once on day 1 of the dosing cycle; and at a dose of 3300 mg on day 15 of the dosing cycle and every 8 weeks thereafter.

[0098] In another embodiment, an anti-C5 antibody (e.g., ravulizumab) or an antigen-binding fragment thereof is administered to patients weighing ≧100 kg at a dose of 3000 mg once on day 1 of the dosing cycle; and at a dose of 3600 mg on day 15 of the dosing cycle and every 8 weeks thereafter.

[0099] In another embodiment, a patient switches the receipt of one C5 inhibitor to a different C5 inhibitor during the course of treatment. Different anti-C5 antibodies can be administered during separate treatment periods. In one embodiment, for example, a method of treating a human patient having a complement-related disorder (e.g., NMOSD, e.g., NMO) being treated with eculizumab is provided, the method comprising discontinuing treatment with eculizumab and switching the patient to treatment with an alternative complement inhibitor (e.g., ravulizumab). In another embodiment, a method of treating a human patient having a complement-related disorder being treated with ravulizumab is provided, the method comprising discontinuing treatment with ravulizumab and switching the patient to treatment with an alternative complement inhibitor.

[0100] Exemplary alternative complement inhibitors include, but are not limited to, antibodies or antigen-binding fragments thereof, small molecules, polypeptides, polypeptide analogs, peptidomimetics, siRNA, and aptamers. In one embodiment, the alternative complement inhibitor inhibits one or more of complement components C1, C2, C3, C4, C5, C6, C7, C8, C9, factor D, factor B, properdin, MBL, MASP-1, MASP-2, or biologically active fragments thereof. In another embodiment, the alternative complement inhibitor inhibits one or both of the generation of anaphylatoxin activity associated with C5a and / or the assembly of the membrane attack complex associated with C5b. In another embodiment, the alternative complement inhibitor is selected from the group consisting of CR1, LEX-CR1, MCP, DAF, CD59, factor H, cobra venom factor, FUT-175, compstatin, and K76 COOH.

[0101] In another embodiment, a method of treating a human patient having a complement-related disorder being treated with eculizumab is provided, the method comprising discontinuing treatment with eculizumab and switching the patient to treatment with an alternative anti-C5 antibody. In another embodiment, a method of treating a human patient having a complement-related disorder being treated with ravulizumab is provided, the method comprising discontinuing treatment with ravulizumab and switching the patient to treatment with an alternative anti-C5 antibody.

[0102] Exemplary alternative anti-C5 antibodies include, but are not limited to, (i) eculizumab, (ii) an antibody or antigen-binding fragment thereof comprising heavy chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 21, 22, and 23, respectively, and light chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 24, 25, and 26, respectively, (iii) an antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising SEQ ID NO: 27 and a light chain variable region comprising SEQ ID NO: 28, (iv) an antibody or antigen-binding fragment thereof comprising heavy chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 29, 30, and 31, respectively, and light chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 32, 33, and 34, respectively, (v) an antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising SEQ ID NO: 35 and a light chain variable region comprising SEQ ID NO: 36, (vi) an antibody or antigen-binding fragment thereof comprising heavy chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 37, 38, and 39, respectively, and light chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 40, 41, and 42, respectively, (vii) an antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising SEQ ID NO: 43 and a light chain variable region comprising SEQ ID NO: 44, and (viii) an antibody or antigen-binding fragment thereof comprising a heavy chain comprising SEQ ID NO: 45 and a light chain comprising SEQ ID NO: 46.

[0103] In another embodiment, a patient is treated with ravulizumab and then switched to treatment with the 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, H4H12166PP antibody, or eculizumab. In another embodiment, a patient is switched during treatment from an anti-C5 antibody (e.g., eculizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or H4H12166PP antibody) to another anti-C5 antibody (e.g., ravulizumab). In certain embodiments, a patient is switched during treatment from eculizumab to ravulizumab.

[0104] In another aspect, the described treatment regimen is sufficient to maintain a specific serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof. In one embodiment, for example, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof of 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395 or 400 μg / mL or more. In one embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof of 100 μg / mL or more. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof of 150 μg / mL or more. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof of 200 μg / mL or more. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof of 250 μg / mL or more. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof of 300 μg / mL or more. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof of 100 μg / mL to 200 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof of about 175 μg / mL.

[0105] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains at least 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 150 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 255 μg or 260 μg of antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains 50 μg to 250 μg of antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains 100 μg to 200 μg of antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains approximately 175 μg of antibody per milliliter of the patient's blood.

[0106] In one embodiment, the anti-C5 antibody is administered (or is for administration) according to a particular clinical dosing regimen (e.g., at a particular dose and / or according to a particular dosing schedule).

[0107] In another embodiment, the dosage of the anti-C5 antibody is based on the patient's body weight. In one embodiment, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 mg, 5600 mg, 5700 mg, 5800 mg, 5900 mg, 6000 mg, 6100 mg, 6200 mg, 6300 mg, 6400 mg, 6500 mg, 6600 mg, 6700 mg, 6800 mg, 6900 mg, 7000 mg, 7100 mg, 7200 mg, 7300 mg, 7400 mg, 7500 mg, 7600 mg, 7700 mg, 7800 mg, 7900 mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg,An anti-C5 antibody or an antigen-binding fragment thereof at 10900 mg or 11000 mg is administered to a patient with a body weight of ≧40 to <60 kg.

[0108] In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof at 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 mg, 5600 mg, 5700 mg, 5800 mg, 5900 mg, 6000 mg, 6100 mg, 6200 mg, 6300 mg, 6400 mg, 6500 mg, 6600 mg, 6700 mg, 6800 mg, 6900 mg, 7000 mg, 7100 mg, 7200 mg, 7300 mg, 7400 mg, 7500 mg, 7600 mg, 7700 mg, 7800 mg, 7900 mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg, 10900 mg or 11000 mg isIt is administered to patients with a body weight of ≧60 to <100 kg.

[0109] In another embodiment, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 mg, 5600 mg, 5700 mg, 5800 mg, 5900 mg, 6000 mg, 6100 mg, 6200 mg, 6300 mg, 6400 mg, 6500 mg, 6600 mg, 6700 mg, 6800 mg, 6900 mg, 7000 mg, 7100 mg, 7200 mg, 7300 mg, 7400 mg, 7500 mg, 7600 mg, 7700 mg, 7800 mg, 7900 mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg, 10900 mg or 11000 mg is administered to a patient with a body weight ≧ 100 kg.In certain embodiments, the dosing regimen is adjusted to provide an optimal desired response (e.g., an effective response).

[0110] In another embodiment, the anti-C5 antibody is administered at a milligram per kilogram (mg / kg) dosage. For example, in one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1.0 mg / kg, 1.25 mg / kg, 1.50 mg / kg, 1.75 mg / kg, 2.0 mg / kg, 2.25 mg / kg, 2.50 mg / kg, 2.75 mg / kg, 3.0 mg / kg, 3.25 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.0 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.0 mg / kg, 5.25 mg / kg, 5.50 mg / kg, 5.75 mg / kg, 6.0 mg / kg, 6.25 mg / kg, 6.50 mg / kg, 6.75 mg / kg, 7.0 mg / kg, 7.25 mg / kg, 7.50 mg / kg, 7.75 mg / kg, 8.0 mg / kg, 8.25 mg / kg, 8.50 mg / kg, 8.75 mg / kg, 9.0 mg / kg, 9.25 mg / kg, 9.50 mg / kg, 9.75 mg / kg, 10.0 mg / kg, 11.25 mg / kg, 11.50 mg / kg, 11.75 mg / kg, 12.0 mg / kg, 12.25 mg / kg, 12.50 mg / kg, 12.75 mg / kg, 13.0 mg / kg, 13.25 mg / kg, 13.50 mg / kg, 13.75 mg / kg, 14.0 mg / kg, 14.25 mg / kg, 14.50 mg / kg, 14.75 mg / kg, 15.0 mg / kg, 15.25 mg / kg, 15.50 mg / kg, 15.75 mg / kg, 16.0 mg / kg, 16.25 mg / kg, 16.50 mg / kg, 16.75 mg / kg, 17.0 mg / kg, 17.25 mg / kg, 17.50 mg / kg, 17.75 mg / kg, 18.0 mg / kg, 18.25 mg / kg, 18.50 mg / kg, 18.75 mg / kg, 19.0 mg / kg, 19.25 mg / kg, 19.50 mg / kg, 19.75 mg / kg, 20.0 mg / kg, 20.25 mg / kg, 20.50 mg / kg, 20.75 mg / kg, 21.0 mg / kg, 21.25 mg / kg, 21.50 mg / kg, 21.75 mg / kg, 22.0 mg / kg, 22.25 mg / kg, 22.50 mg / kg, 22.75 mg / kg, 23.0 mg / kg, 23.25 mg / kg, 23.It is administered at a dose of 50 mg / kg, 23.75 mg / kg, 24.0 mg / kg, 24.25 mg / kg, 24.50 mg / kg, 24.75 mg / kg or 25.0 mg / kg.

[0111] In one embodiment, the anti-C5 antibody is administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week or daily. In another embodiment, the anti-C5 antibody is administered twice a day. In another embodiment, the anti-C5 antibody is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks or once every twelve weeks. In another embodiment, the anti-C5 antibody is administered as a loading dose on day 1, followed by different maintenance doses on day 15 and every 8 weeks thereafter.

[0112] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains a minimum free C5 concentration. In one embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains a free C5 concentration of 0.2 μg / mL, 0.3 μg / mL, 0.4 μg / mL, 0.5 μg / mL or less. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains a free C5 concentration of 0.309 - 0.5 μg / mL or less.

[0113] In some embodiments, a patient being treated according to the methods described herein has been vaccinated against meningococcal infection within 3 years prior to starting the investigational drug or at the time of initiation. In one embodiment, a patient who starts treatment less than 2 weeks after receiving the meningococcal vaccine receives treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. In another embodiment, a patient being treated according to the methods described herein is vaccinated against meningococcal serogroups A, C, Y, W135 and / or B.

[0114] According to the present disclosure, conventional molecular biology, microbiology, and recombinant DNA techniques can be used within the scope of those skilled in the art. Such techniques are all described in the literature. For example, see Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (referred to herein as "Sambrook et al., 1989"); DNA Cloning: A Practical Approach, Volumes I and II (D.N. Glover ed. 1985); Oligonucleotide Synthesis (M.J. Gait ed. 1984); Nucleic Acid Hybridization [B.D. Hames & S.J. Higgins eds. (1985)]; Transcription And Translation [B.D. Hames & S.J. Higgins, eds. (1984)]; Animal Cell Culture [R.I. Freshney, ed. (1986)]; Immobilized Cells And Enzymes [IRL Press, (1986)]; B. Perbal, A Practical Guide To Molecular Cloning (1984); F.M. Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994). Each of these references is hereby incorporated by reference in its entirety.

[0115] Unless otherwise specified, the sequence identity / similarity values provided herein refer to the values obtained using the BLAST 2.0 suite of programs with default parameters (Altschul, S. et al., Nucleic Acids Res., 25: 3389-402, 1997, which is hereby incorporated by reference in its entirety).

[0116] As used herein, "sequence identity" or "identity" in the context of two polypeptide sequences includes reference to residues in two sequences that are the same when aligned with maximum correspondence over a specified comparison window. When percentage of sequence identity is used in reference to a protein, the positions of residues that are not identical often differ by conservative amino acid substitutions, where amino acid residues are substituted for other amino acid residues with similar chemical properties (e.g., charge or hydrophobicity), and it is recognized that such substitutions do not change the functional properties of the molecule. When sequences differ in conservative substitutions, the percent sequence identity can be adjusted upwards to correct for the conservative nature of the substitution. Sequences that differ by such conservative substitutions are said to have "sequence similarity" or "similarity". Means for making this adjustment are known to those of skill in the art (typically, this involves scoring conservative substitutions as partial rather than complete mismatches, thereby increasing the percentage of sequence identity). Thus, for example, if a score of 1 is given to identical amino acids and a score of 0 is given to non-conservative substitutions, a score between 0 and 1 is given to conservative substitutions. Scoring of conservative substitutions is calculated, for example, according to the algorithm of Meyers, E. and Miller, W. (Compute. Appl. Biosci., 4:11-7, 1988), as implemented, for example, in the program PC / GENE (Intelligenetics, Mountain View, Calif., USA). Each of these references is hereby incorporated by reference in its entirety.

[0117] As used herein, "percent sequence identity" means a value determined by comparing two optimally aligned sequences over a comparison window, wherein a portion of the polynucleotide sequence in the comparison window may include additions or deletions (i.e., gaps) as compared to the reference sequence (which does not include additions or deletions) for optimal alignment of the two sequences. The percent is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences, obtaining the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window, and multiplying the result by 100 to obtain the percent sequence identity.

[0118] The terms "substantially identical" or "substantially the same" in the context of a polynucleotide sequence means that the polynucleotide comprises a sequence having 50-100% sequence identity, such as at least 50% sequence identity, at least 60% sequence identity, at least 70%, at least 80%, at least 90% or at least 95% sequence identity, when compared to a reference sequence using standard parameters with one of the described alignment programs. One of ordinary skill in the art will recognize that these values can be appropriately adjusted to determine the corresponding identity of the proteins encoded by two nucleotide sequences by taking into account codon degeneracy, amino acid similarity, reading frame position, and the like. Substantial identity of amino acid sequences for these purposes typically means 55-100%, such as at least 55%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% sequence identity.

Example

[0119] Example 1. Efficacy and Safety of Ravulizumab in the Treatment of Neuromyelitis Optica Spectrum Disorder (NMOSD) in Adult Patients 1. Study Design 1.1. Overall Design This is a Phase 3, externally placebo-controlled, open-label, multi-center, joint trial to evaluate the efficacy and safety of lebrikizumab in adult patients with NMOSD. Approximately 55 eligible adult patients with NMOSD from North America, Europe, the Asia-Pacific, and Japan will be enrolled in this trial.

[0120] This trial has four phases: a screening period, a primary treatment period, a long-term extension period, and a safety follow-up period (Figure 1). Patients will be screened for eligibility for up to 6 weeks during the screening period. The primary treatment period ends when all patients have completed their 26-week visit or discontinued early, at which point the long-term extension period begins, followed by the completion of the end-of-primary-treatment (EOPT) visit. All patients will continue to receive lebrikizumab throughout the long-term extension period for up to 2 years or until lebrikizumab is approved and / or available (in accordance with country-specific regulations), whichever occurs first. Based on the estimated enrollment rate of NMOSD patients, the total treatment period for each patient is up to 4 years. After the last dose of the investigational drug or early discontinuation (ED), patients will be followed for 8 weeks.

[0121] If an eligible patient enrolls in the trial, the patient will receive an intravenous infusion of lebrikizumab. The lebrikizumab dose for each patient is based on body weight. The dosing regimen consists of a loading dose followed by maintenance doses every 8 weeks (q8w). The maintenance doses must begin 2 weeks after the loading dose.

[0122] For each patient, the total duration of trial participation is up to 4 years and 14 weeks, including the screening period (up to 6 weeks), the primary treatment period (26 weeks to 2 years), the long-term extension period (up to 2 years), and the safety follow-up period (8 weeks).

[0123] 1.2. Scientific Rationale for the Trial Design This trial is designed to provide data to appropriately characterize the benefit-risk profile of lebrikizumab for the treatment of patients with NMOSD, and uses placebo data from another trial that considered the use of eculizumab for the treatment of NMOSD as an external control.

[0124] Using a single-group design with the placebo group of the NCT01892345 trial (conducted from 2014 to 2018) as an external placebo control, it becomes possible to reliably evaluate lebrikizumab as a treatment option for NMOSD. In order to ensure a valid comparison to the greatest extent possible, including incorporating a similar patient population, and maintaining consistency with the NCT01892345 trial, concomitant medications, evaluation procedures, and endpoints are allowed.

[0125] 1.2.1. Rationale for the Selected Endpoints 1.2.1.1. Efficacy Endpoints In NMOSD, measurable biological aspects include relapses and disabilities. Disabilities in NMOSD are a direct result of relapses, supporting the relevance of measuring relapses as an efficacy endpoint.

[0126] In this trial, the occurrence of relapses is evaluated using the primary endpoint TFR and the secondary endpoint ARR. The time to the first relapse provides useful information regarding the efficacy of lebrikizumab. Since the efficacy of treatment may be based on the delay and / or reduction of relapses, TFR is an appropriate endpoint for efficacy in prospectively designed trials in NMOSD. The external placebo group of the NCT01892345 trial also has TFR as the primary endpoint of that trial, and considering that the adjudication process and relapse definition are consistent between the two trials, it is used as an appropriate control group. Additionally, the impact of lebrikizumab on the frequency of relapses is measured using the Adjudicated On-Trial ARR. The 95% confidence interval is calculated around the ARR. The objectives and endpoints of this trial are summarized in Table 1 below.

[0127]

Table 1-1

[0128]

Table 1-2

[0129] 1.2.2. Rationale for the primary treatment period In this trial, the primary treatment period ends when all patients complete their 26-week visit or discontinue early. At that point, based on the estimated enrollment rate, it is expected that the first-enrolled patients will have been in treatment for approximately two years, and the remaining patients will have treatment durations within the range of 26 weeks to two years (inclusive).

[0130] The cut-off value of 26 weeks for the last patient is selected for several reasons. In previous trials on eculizumab, the primary observations could be obtained by that time. Two out of three evaluated on-treatment relapses observed in the eculizumab group were seen, and in the placebo group, 12 out of 20 evaluated on-treatment relapses were observed. This design ensures that in the analysis of the time to the first evaluated on-treatment relapse, the number of patients censored within the first 26 weeks is limited. Also, based on the expected enrollment timeline, many patients will have been in treatment for over a year by the time the last patient completes their 26-week visit, and it is recognized that robust time-course data on efficacy and safety can be obtained for a valid comparison with data collected in a similar time frame in the placebo group of the NCT01892345 trial.

[0131] 1.2.3. Rationale for the selected patient population Complement activation is a major determinant of disease etiology in anti-AQP4 positive NMOSD patients. Therefore, inhibition of terminal complement activation by ravulizumab represents a biologically rational approach to treating anti-AQP4 positive NMOSD patients. The inclusion criteria for the trial are carefully selected to reflect an adult patient population that is consistent with the anti-AQP4 positive NMOSD population likely to receive treatment with ravulizumab in the clinical setting.

[0132] 1.3. Dose justification 1.3.1. Ravulizumab As a treatment strategy in the treatment of NMOSD patients, targeting complete terminal complement inhibition has been verified by the data of the eculizumab clinical program. The dosing regimen of ravulizumab is designed to target immediate, complete, and sustained inhibition of terminal complement in patients. The weight-based dosing of ravulizumab in previous PNH programs was based on the PK / PD data of early and late clinical development trials in healthy adult volunteers and PNH patients. The proposed ravulizumab dosing regimen (Sections 3.1, 5.1.6.1) is the approved regimen for PNH patients (Ultomiris® United States Prescribing Information (USPI)), and the same dosing regimen is also included in the first marketing authorization application (MAA) in the EU. Therefore, in this trial, the same dosing regimen is selected.

[0133] 1.3.2. Additional Dose Patients who receive plasma exchange (PE) / plasmapheresis (PP) (Section 3.5.1.3) as acute treatment after recurrence during the trial can be administered an additional dose of ravulizumab (Section 5.1.6.2). The additional dose of ravulizumab is selected based on PK simulations. Consistent with the prescribing information of eculizumab approved for the treatment of adult and pediatric patients with aHUS, adult patients with generalized myasthenia gravis (gMG), and adult patients with NMOSD, in the setting of PP / PE combination therapy, an additional dose of 50% of ravulizumab (rounded if not an integral value of 300 mg due to vial composition) is administered.

[0134] 1.4. End of Induction Treatment After all patients complete their visit at week 26 or discontinue early, the patients return within 14 days for the End of Induction Treatment (EOPT) visit: · If the EOPT visit is concurrent with a future scheduled study visit, the patient needs to complete all evaluations for the EOPT visit and can also receive the scheduled dose of ravulizumab. · If the patient is in the recurrence evaluation period for the first recurrence (defined as the first recurrence after the first day), the recurrence evaluation visit at the 6th week is the patient's EOPT visit.

[0135] The end of the primary treatment period is defined as the day when all patients have completed their visit at the 26th week or stopped earlier and then completed their EOPT visit.

[0136] 1.5. Definition of End of the Trial A patient is considered to have completed the trial by meeting any one of the following conditions: · The patient completes all stages of the trial, including the final visit shown in the activity schedule. · The patient completes the trial early because Lovelizumab has been registered or approved.

[0137] The end of the trial is defined as the final visit date of the last patient in the worldwide clinical trial (Figure 2).

[0138] 2. Trial Population Forward approval of deviations from the clinical trial protocol from the inclusion and registration criteria, also known as waivers or exclusions from the clinical trial protocol, is not permitted.

[0139] 2.1. Selection Criteria Participants are eligible to be included in the trial only if all the criteria in 2.2.1. to 2.2.5. apply.

[0140] 2.1.1. Age At the time of signing the informed consent, the patient must be 18 years of age or older.

[0141] 2.1.2. Patient Type and Disease Characteristics Patient and disease characteristics for inclusion are as follows: · Diagnosis of NMOSD defined by anti-AQP4 Ab positivity and the 2015 International Consensus Diagnostic Criteria (Wingerchuk, D. et al., Neurology, 85:177-89, 2015). Past positive anti-AQP4 Ab tests are acceptable if they were performed using an acceptable validated cell-based assay from a laboratory where the test is accredited. In this case, prior to initiating test treatment, past test results and related information need to be reviewed and approved by the medical monitor of the trial sponsor. · At least one attack or relapse in the past 12 months prior to the screening period (Note: If an attack occurred in the past 12 months, a patient with a single lifetime attack is considered to meet this selection criterion.) · Expanded Disability Status Scale (EDSS) score ≤ 7 · For patients participating in a trial receiving supportive IST (e.g., corticosteroids, azathioprine [AZA], mycophenolate mofetil [MMF], methotrexate [MTX], and tacrolimus [TAC]) either in combination or as monotherapy for relapse prevention, they must have received a stable dosing regimen for a sufficient period prior to screening and there should be no plan to change the dose during the trial period as follows: a. If a patient participating in the trial is receiving AZA, the patient must have received AZA for at least 6 months and have been on a stable dose for more than 2 months prior to screening. b. If a patient participating in the trial is receiving another IST (e.g., MMF, MTX, or TAC), the patient must have received the IST for at least 3 months and have been on a stable dose for more than 4 weeks prior to screening. c. If a patient participating in the trial is receiving oral corticosteroids, they must have been on a stable dose for more than 4 weeks prior to screening. d. If a patient receiving oral corticosteroids with or without other ISTs enters the trial, the daily corticosteroid dose prior to screening must be prednisone 20 mg / day (or equivalent dose) or less. · Vaccination against Neisseria meningitidis within 3 years before starting Lovelizumab or at the start. Patients who start treatment with the investigational drug less than 2 weeks after receiving the meningococcal vaccine must receive appropriate prophylactic antibiotics until 2 weeks after vaccination.

[0142] 2.1.3. Weight The weight is 40 kg or more.

[0143] 2.1.4. Gender For both men and women, the use of contraception methods by male or female should be in line with the local regulations regarding contraception methods for participants in the clinical trial. Male patients should agree to use contraception during the treatment period and at least 8 months after the final dose of the investigational drug, and should refrain from providing sperm during this period.

[0144] Female patients are eligible to participate if they are not pregnant, not breastfeeding, and at least one of the following applicable conditions is met: · Not a woman of childbearing potential (WOCBP), or · A WOCBP and using a highly effective or acceptable contraception method during the treatment period and at least 8 months after the final dose of the investigational drug. ○ The principal investigator of the trial shall evaluate the effectiveness of the contraception method in relation to the first dose of the investigational drug. WOCBP must have a negative highly sensitive pregnancy test (serum pregnancy test) within 24 hours before the first dose of the investigational drug. The principal investigator of the trial is responsible for considering the medical history, menstrual history, and recent sexual behavior to reduce the risk of selecting women in whom pregnancy has not been detected early.

[0145] 2.1.5. Informed Consent An informed consent form (ICF) and a signed informed consent including compliance with the requirements and restrictions listed in this trial implementation plan can be provided.

[0146] 2.2. Exclusion Criteria If any of the criteria from 2.2.1 to 2.2.4 apply, exclude the patient from the trial.

[0147] 2.2.1. Medical condition · History of Neisseria meningitidis infection. · Human immunodeficiency virus (HIV) infection (proven by HIV-1 or HIV-2 antibody titer) · History of undiagnosed infection · Active systemic bacterial, viral, or fungal infection within 14 days before administration of the investigational drug on Day 1 · Presence of fever of 38°C (100.4°F) or higher within 7 days before administration of the investigational drug on Day 1 · Hypersensitivity to one of the excipients of mouse protein or ravulizumab · Any medical condition that, in the judgment of the principal investigator of the trial, may interfere with the patient's participation in the trial, increase the patient's risk, or cause confusion in the patient's evaluation.

[0148] 2.2.2. Prior / concurrent therapy · Previously or currently treated with a complement inhibitor. · Use of rituximab within 3 months before screening. · Use of mitoxantrone within 3 months before screening. · Use of intravenous immunoglobulin (IVIg) within 3 weeks before screening.

[0149] 2.2.3. Experience in prior / concurrent clinical trials and other exclusions · Participation in any other investigational drug trial or exposure to an investigational drug or device within either 30 days from screening or the longer of the 5 half-lives of the test drug. · Pregnancy, lactation, or intention to become pregnant during the trial

[0150] 2.3. Considerations regarding lifestyle There are no lifestyle restrictions for this trial.

[0151] 2.4. Screening failure Screening failure is defined as patients who consented to participate in the clinical trial but were not subsequently treated with the investigational drug. Individuals who do not meet the inclusion criteria for this trial for reasons of expected or recovered recovery (screening failure) may be re-screened based on the agreement and consent of the principal investigator and the medical monitor. Patients who experience a recurrence during the screening period that meets the definition of the investigational protocol for recurrence during the trial (section 5.2.3.2) are considered screening failures. Such patients may be re-screened for enrollment in the trial if, after receiving treatment for the recurrence and based on the opinion of the principal investigator and the medical monitor, the patient is medically stable (section 2.1; section 2.2). To participate in this trial, patients must meet the enrollment criteria at the time of re-screening.

[0152] 3. Investigational Drug The investigational drug is defined as any investigational drug, marketed product, placebo, or medical device intended to be administered to the trial patients in accordance with the investigational protocol.

[0153] 3.1. Investigational Drug to be Administered In this trial, patients will receive Labrizumab under non-blind conditions throughout the entire treatment period (see Table 2; refer to section 5.1.6 for the dosage and administration of the investigational drug, and refer to the SoA (Figure 2) for the administration schedule).

[0154]

Table 2

[0155] 3.2. Responsibility for Preparation / Handling / Storage / Explanation Upon arrival of the investigational drug at the investigational medical institution, remove the investigational drug kit from the shipping container and store it in the original carton under refrigeration at 2 - 8°C (35 - 47°F), protected from light. Labrizumab should not be frozen. The investigational drug is stored in a secure and restricted access storage location while monitoring the temperature daily.

[0156] The infusion of the investigational drug must be prepared using aseptic techniques. Labrizumab is further diluted at a 1:1 ratio with a compatible diluent. Labrizumab is filtered through a 0.2 micron filter during injection. Additionally, the injection of the investigational drug shall comply with the following regulations: · The principal investigator or the designee shall confirm that appropriate temperature conditions have been maintained during the transportation of all received investigational drugs, report any discrepancies, and resolve them prior to the use of the investigational drug. · Only the patients enrolled in the trial can receive the investigational drug, and only the authorized healthcare institution staff can supply or administer the investigational drug. All investigational drugs shall be stored in a secure, environmentally controlled, and monitored (manual or automated) area with restricted access to the principal investigator and the authorized healthcare institution staff, in accordance with the indicated storage conditions. · The principal investigator, the healthcare institution, or the head of the healthcare institution (if applicable) shall be responsible for the accountability, reconciliation, and maintenance of records (e.g., receipt, reconciliation, and final disposition records) of the investigational drug. · Further guidance and information regarding the final disposition of unused investigational drugs are provided in the pharmacy manual.

[0157] 3.3. Measures to Minimize Bias: Randomization and Blinding This is a single-group, non-blinded trial. All trial patients, healthcare institution staff directly involved in the conduct of the trial, designees of the trial sponsor, and all staff are unblinded regarding the treatment assignment of the patients.

[0158] To minimize the potential for bias in this open-label trial, operational measures regarding the efficacy endpoints and evaluation processes are adopted. The trial database is monitored according to pre-specified guidelines to confirm that all potential recurrences are collected and analyzed. An independent recurrence evaluation committee evaluates the recurrences during each trial and checks whether they meet the criteria defined in the NMOSD recurrence trial protocol (Section 5.2.3.2). Furthermore, although the EDSS assessors are aware that all patients are receiving lulizumab, the EDSS assessors are not informed of all the trial data when conducting the assessment.

[0159] 3.4. Compliance with the investigational medicinal product The injection of the investigational medicinal product to the patients is under the supervision of the responsible investigator of the trial or his / her designee to ensure that the patients receive the appropriate dose at the appropriate time during the trial.

[0160] Record the date and time of each dose administered at the clinic in the source documents and record it in the case report form (CRF).

[0161] At the time of administration, the dose of the investigational medicinal product and the identification of the trial patient are confirmed by the medical staff of the trial site other than the person administering the investigational medicinal product.

[0162] 3.5. Concomitant therapy Any medications (including over-the-counter or prescription drugs, vitamins, minerals and / or herbal supplements) or vaccines that the patient is receiving at the time of enrollment or during the trial are recorded in the patient's source documents / medical records and the electronic case report form (eCRF) together with the following: · Reason for use · Date of administration including the start date and end date of administration · Dosage information including the dose and frequency

[0163] If there is a change in the concomitant medication, it is also recorded in the patient's source documents / medical records and the eCRF. If possible, record the concomitant medication from the first injection of lulizumab until the patient discontinues or completes the trial.

[0164] Collect information on the use of IST containing steroids. Also record meningococcal vaccination administered for the prevention of meningococcal infection and antibiotics (if applicable).

[0165] Concomitant medications determined to be necessary for the patient's care during the trial or for the treatment of AEs determined to be necessary can be administered at the discretion of the principal investigator of the clinical trial, together with other medications other than the prohibited medications in Section 3.5.2. However, the principal investigator of the clinical trial is responsible for completely and reliably recording details of all medications in the patient's original medical records and eCRF.

[0166] If there are any questions regarding combination therapy or pre-treatment, contact the medical monitor.

[0167] 3.5.1. Permitted Drugs and Treatments In this trial, the following concomitant medications and treatments are permitted.

[0168] 3.5.1.1. Palliative Care and Supportive Therapy For underlying diseases, palliative care and supportive therapy are permitted during the trial.

[0169] 3.5.1.2. Immunosuppressants Supportive immunosuppressive therapy (IST) for preventing recurrence is recognized as follows at the discretion of the principal investigator of the clinical trial, either in combination therapy or monotherapy: · Corticosteroids · Azathioprine (AZA) · Mycophenolate mofetil (MMF) · Methotrexate (MTX) · Tacrolimus (TAC) · Cyclosporine · Cyclophosphamide

[0170] If the patient has received supportive IST before the trial and continues stable maintenance therapy during the trial, refer to the selection criteria for IST requirements (Section 2.1) to ensure that the patient is being administered at a stable dose within the limits required for this trial, as described in the trial criteria (Section 2).

[0171] Except when the patient experiences a recurrence or a safety event and the treating physician determines that a change in the IST dose or regimen is necessary to ensure the patient's safety, for each patient, no adjustment of the IST dose will be made and no new IST will be permitted for the first 106 weeks.

[0172] Changes in immunosuppressive therapy are recorded in the source documents of concomitant medications and on the eCRF pages.

[0173] 3.5.1.3. Standard Treatment for Recurrence Treatment of recurrence is at the discretion of the treating physician. In accordance with expert opinion, the following standardized treatment regimens (Section 5.2.3.2) for confirmed in-trial recurrence are recommended: Administer 1 gram (1g) of methylprednisolone (IVMP) intravenously daily for 3 - 5 days, followed by tapering of oral prednisone. · If the patient improves, continue the trial evaluation according to the schedule in this trial protocol. · If there is no response to IVMP or the response is minimal, PE / PP is permitted at the discretion of the treating neurologist. For the treatment of seizures that do not respond to IVMP, 5 cycles of PE, each removing 1.0 - 1.5 volumes of circulating plasma, are recommended. ○ If the patient receives PE / PP for in-trial recurrence during the treatment period, an additional dose of the investigational drug must be administered after each PE / PP, as described in the additional doses in Section 5.1.6.2. After receiving the additional dose, the patient continues with the dosing schedule specified in the trial protocol of SoA (Figure 2).

[0174] 3.5.2. Prohibited Drugs and Treatments During the trial, the following drugs and treatments are prohibited. · Mitoxantrone · Other biological agents such as rituximab or tocilizumab · Immunomodulatory therapies including interferon β-1b; interferon β-1a, glatiramer acetate, natalizumab, alemtuzumab, dimethyl fumarate, teriflunomide, siponimod and fingolimod. · IVIg for relapse prevention · PE for relapse prevention

[0175] 3.6. Dose modification In this study, dose modification is not permitted.

[0176] 3.7. Interventions after study completion Patients who have received their last scheduled dose will not be provided with lubeluzumab (Figures 2 and 3). Safety of all patients will be followed for an additional 8 weeks after the final dose of the investigational medicinal product or early termination.

[0177] 4. Discontinuation of investigational medicinal product and patient discontinuation or withdrawal 4.1. Discontinuation of investigational medicinal product Rarely, patients may need to permanently discontinue the investigational medicinal product (final discontinuation). If the investigational medicinal product is finally discontinued, the patient will continue in the study for safety follow-up evaluation. For data to be collected at the time of discontinuation of the investigational medicinal product and at follow-up, and for further evaluations to be completed, please refer to the SoA (Figures 2 and 3).

[0178] If any of the following occur during the study, the patient should consider discontinuing the investigational medicinal product: · Severe allergic reaction; · Uncontrolled severe infection; · Use of prohibited medications as defined in Section 3.5.2 · Pregnancy or planned pregnancy; or · As determined necessary by the study sponsor or the study responsible physician for the patient.

[0179] 4.2. Patient discontinuation / withdrawal from the study Before conducting the screening procedure, every effort should be made to ensure that the patient has the intention to comply with the trial participation. The trial staff shall notify all trial withdrawals to the trial requester and the monitor of the implementing medical institution as soon as possible. Record the reasons for the patient's discontinuation in the source documents and eCRF. · The patient can withdraw from the trial at any time upon their own request, or can be withdrawn at any time at the discretion of the principal investigator of the clinical trial due to safety, compliance with behavior, or administrative reasons. This is expected to be rare. · When the trial is terminated, if possible, conduct an early termination visit as shown in the SoA (Figure 2). Patients who terminated early need to be followed up for safety for an additional 8 weeks and followed up for any further evaluations that need to be completed. · The patient shall permanently discontinue both the investigational drug and the trial at that time. · If the patient withdraws consent for future disclosure of information, the trial requester may store and continue to use the data collected before such withdrawal of consent.

[0180] 4.3. Unable to Follow Up If the patient does not return or is unavailable for a scheduled visit within an acceptable visit time frame (Figure 2), the trial staff of the implementing medical institution shall contact the patient and make a reasonable attempt to determine the reason for the missed appointment.

[0181] Patients who did not return for a scheduled visit shall receive contact from the trial staff of the implementing medical institution to determine the reason for the missed appointment. Obtaining the visit information of patients who did not come to the visit is important to ensure that the patients who did not come to the visit are not due to the possibility of AE or recurrence. Therefore, every effort shall be made to implement the safety follow-up procedures specified in the clinical trial implementation plan.

[0182] In exceptional circumstances where the patient cannot or does not come to the investigational medical institution for the examination, the patient is instructed to seek consultation from a neurologist or physician in the area. In this case, if possible, the treating physician or designee contacts the neurologist or physician in the area to obtain as much information as possible about the patient's medical and neurological status and provides clinical guidance as needed. The investigational medical institution obtains the relevant medical records from the examination by the local physician as a document and enters the relevant data into the recurrence evaluation visit form or the AE form as needed.

[0183] If the patient repeatedly fails to return for a scheduled visit and cannot be contacted by the investigational medical institution, it is considered lost to follow-up.

[0184] If the patient does not return to the clinic for a required test visit, the following measures are taken: · The implementing medical institution contacts the patient, reschedules the missed visit as soon as possible, counsels the patient on the importance of maintaining the assigned visit schedule, and confirms whether the patient wishes to and / or should continue with the test. · Before the patient is determined to be lost to follow-up, the principal investigator or designee makes every effort to regain contact with the patient (if possible, three phone calls and, if necessary, a certified mail to the patient's last known mailing address or an equivalent method in the area). These attempts at contact are recorded in the patient's medical record. · If the patient remains unreachable, it is considered lost to follow-up.

[0185] 5. Evaluation and Procedures of the Test Summarize the test procedures and their timings in the SoA (Figure 2). Waivers or exclusions from the clinical trial protocol are not permitted. When an immediate safety concern is expressed or recognized, discuss with the trial sponsor immediately to determine whether the patient should receive the investigational drug. Compliance with the test design requirements, including those specified in the SoA, is essential and necessary for the conduct of the trial. Complete and review all screening evaluations to confirm that potential patients meet all eligibility criteria. The principal investigator of the trial should maintain a screening log to record details of all screened patients, confirm eligibility, and record the reasons for screening failure if necessary. Procedures that are part of the patient's routine clinical management (e.g., blood counts) and obtained before the signature of the ICF can be used for screening or baseline purposes if the procedure meets the criteria specified in the clinical trial protocol and is performed within the time frame defined in the SoA.

[0186] 5.1. General Assessments and Procedures 5.1.1. Informed Consent The principal investigator of the trial or a qualified designee shall obtain a signed and dated informed consent from each patient before conducting the test procedure. Make every effort to ensure that the patient has the intention to comply with trial participation before performing the screening procedure.

[0187] 5.1.2. Treating Physician The treating physician is the principal investigator (PI) / sub-investigator for the trial, responsible for overall patient management, including assessment of patient eligibility, supervision of investigational drug administration, recording and treatment of AEs, and monitoring of safety assessments.

[0188] At recurrence, the treating physician shall perform a complete neurological examination to determine whether the patient's symptoms and signs meet the criteria for recurrence during the trial (Section 5.2.3.2). The treating physician may treat the patient's recurrence according to the recommended recurrence treatment regimen during the trial. Ultimately, the treatment and treatment options for recurrence during the trial and changes to IST after recurrence during the trial are at the discretion of the treating physician.

[0189] 5.1.3. Medical History and NMOSD History The principal investigator of the trial considered the patient's medical history and diagnosis and recorded the following at the screening visit: · Date of NMOSD diagnosis and previous magnetic resonance imaging (MRI) contributing to the diagnosis. Confirmation of NMOSD diagnosis according to the International Panel on NMO Diagnosis (IPND) criteria (section 7.1), including the specific criteria the patient meets for diagnosis. Only patients who are anti-AQP4 antibody positive and otherwise meet the 2015 IPND criteria are eligible to participate. · Record all available information regarding relapses that occurred prior to screening and meet the definition of relapse in the trial protocol (section 5.2.3.1), including the following ○ Number of relapses (date of onset) ○ Clinical picture of each relapse (e.g., optic neuritis [ON], transverse myelitis [TM], brainstem, last area, or other) ○ Treatments and dosing regimens during the acute and maintenance phases, and ○ Any disability measurements, such as the EDSS score.

[0190] 5.1.4. Prevention with Vaccines and Antibiotics Similar to terminal complement antagonists, the use of ravulizumab increases patients' susceptibility to meningococcal infection (Neisseria meningitidis). To reduce the risk of meningococcal infection, all patients are vaccinated against meningococcal infection within 3 years prior to or at the start of the investigational medicinal product. · Patients who start the investigational medicinal product less than 2 weeks after receiving the meningococcal vaccine will receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. · Patients will be vaccinated or revaccinated according to current national vaccination guidelines or local practice for the use of vaccines with complement inhibitors (e.g., eculizumab, ravulizumab). · To prevent common pathogenic meningococcal serotypes, vaccines against serotypes A, C, Y, W135, and B are recommended if available. ·Vaccination may not be sufficient to prevent meningococcal infection. The appropriate use of antibacterial agents is considered in accordance with public guidance and local practices. ·Monitor all patients for early signs of meningococcal infection, evaluate immediately if infection is suspected, and treat with appropriate antibiotics if necessary.

[0191] 5.1.5. Selection / Exclusion Criteria All selection criteria (Section 2.1) and exclusion criteria (Section 2.2) are considered by the principal investigator or authorized designee to ensure that the patient is eligible to participate in the trial. Both the principal investigator and the sponsor of the trial must approve the patient's eligibility prior to enrollment.

[0192] 5.1.6. Administration of Investigational Medicinal Product This section describes the dosing regimen of the investigational medicinal product. At the scheduled visit for dosing (Figure 2), after all other tests and treatments have been completed, except for post-dose blood sampling for PK and free C5, the investigational medicinal product is administered.

[0193] 5.1.6.1. Ravulizumab Patients receive a weight-based loading dose of ravulizumab via IV infusion on Day 1, followed by weight-based maintenance doses on Day 15 (Table 3), and then once every 8 weeks (q8w). The total treatment period is up to 4 years, until either all patients have completed a 2-year long-term extension period or ravulizumab is approved and / or available (in accordance with country-specific regulations).

[0194] Depending on the timing of recurrence, the scheduled dosing visit for ravulizumab may or may not coincide with the recurrence assessment visit and / or the follow-up recurrence assessment visit. The dosing visit for ravulizumab continues as scheduled during the recurrence assessment period.

[0195]

Table 3

[0196] 5.1.6.2. Additional Dosage During the trial, PE / PP is permitted at the discretion of the treating physician for recurrence during the trial (Section 3.5.1.3). If PE / PP is administered at the time of a non-scheduled visit as defined in the SoA (Figure 2), an additional dosage shall be administered within 4 hours after completion of PE / PP, based on the dosage of the most recently administered ravulizumab (Table 4). If PE / PP is administered at the time of a scheduled visit as defined in the SoA (Figure 2), no additional dosage of ravulizumab shall be administered. The patient shall receive the regular dosage of ravulizumab 60 - 120 minutes after completion of PE / PP (Section 5.1.6.1) (see Section 5.6.2 for PK and free C5 sample collection during recurrence in the trial).

[0197] After receiving the additional dosage, the patient shall continue the infusion of the investigational medicinal product according to the dosing schedule defined in the trial protocol (Figure 2).

[0198]

Table 4

[0199] 5.2. Efficacy Evaluation 5.2.1. Neurological Examination A complete full-body neurological examination shall be performed by the treating physician who is the principal investigator of the trial and who is appropriately trained as a clinical evaluator, preferably the same treating physician (Section 5.1.2), at the scheduled visits throughout the trial period (Figure 2).

[0200] The complete full-body neurological examination shall include the evaluation of the following systems: mental status, funduscopy, cranial nerves, deep tendon reflexes, plantar responses, power / strength, sensation, coordinated movement, and gait / balance.

[0201] 5.2.2. NMO Symptom Card and Evaluation Before receiving the first dose of the investigational medicinal product at the visit on Day 1, a NMO symptom card listing the potential signs and symptoms of NMOSD recurrence and contact information shall be handed to the patient.

[0202] Throughout the trial period, each time the patient comes to the hospital, the trial staff will confirm that the patient has the NMO symptom card. The treating physician will examine and evaluate the patient for signs or symptoms indicating a relapse.

[0203] 5.2.3. Relapse 5.2.3.1. Past relapses Past relapses are relapses that occurred before screening admission, including the first NMOSD attack. In this trial protocol, past relapses are defined as the new onset of neurological symptoms or the worsening of existing neurological symptoms with objective changes (clinical findings or MRI findings or both) observed by neurological examinations (clinical findings or MRI findings or both) that persist for more than 24 hours. An event occurring within 30 days is considered as one relapse.

[0204] 5.2.3.2. Relapses during the trial 5.2.3.2.1 Definition of relapses during the trial Relapses during the trial are acute attacks that occur during the trial treatment period. In this trial protocol, "relapses during the trial" are defined as the new onset of neurological symptoms or the worsening of existing neurological symptoms with objective changes (clinical signs) observed by neurological examinations that are confirmed by the treating physician and persist for more than 24 hours (section 5.1.2). The signs and symptoms must be attributable to NMOSD (i.e., not caused by identifiable causes such as infections, excessive exercise, or overly high ambient temperatures). If isolated changes are observed by MRI or other imaging examinations without associated clinical findings, they are not considered relapses during the trial.

[0205] 5.2.3.2.2 Evaluation of relapses during the trial Relapses during the trial are monitored throughout the trial period. The principal investigator or a qualified designee will carefully examine the signs and symptoms that may indicate a relapse with the patient each time the patient comes to the hospital.

[0206] The patient will be educated about the potential signs and symptoms of NMOSD relapses and instructed to contact the trial medical institution when the first signs or symptoms that may indicate a relapse appear.

[0207] Evaluate the patient within 24 hours (and not after 48 hours) from notification of signs or symptoms suggesting the possibility of recurrence.

[0208] The evaluation of recurrence during the trial includes the following: · A complete neurological examination to determine whether clinical signs, symptoms, and laboratory findings meet the definition of recurrence during the trial · Evaluation of recurrence severity based on OSIS (Section 5.2.8; Figure 8). The OSIS visual acuity (VA) subscale score is used to classify the severity of ON. The OSIS motor subscale score and sensory subscale score are used to classify the severity of TM. · Evaluation of the neurological function system based on the Kurtzke Functional System Score (FSS) and the level of disability based on the EDSS score (Section 5.2.4). · Evaluation of walking function using HAI (Section 5.2.7). · Ophthalmological examinations including VA, confrontation visual fields (VF), and color vision (Section 5.2.9). · Perform MRI + / gadolinium and / or optical coherence tomography (OCT) examinations to evaluate the likelihood of recurrence as determined by the trial physician in charge (Section 5.2.10). · Additional tests and follow-up evaluations as defined in the SoA (Figure 3)

[0209] 5.2.3.2.3 Treatment for recurrence during the trial When recurrence is suspected, the treating physician (Section 5.1.2) performs a complete neurological examination to determine whether the patient is experiencing recurrence during the trial. If the treating physician determines it to be a recurrence during the trial, the treatment for recurrence and the changes in IST after relapse are at the discretion of the trial physician in charge.

[0210] The recommended standard treatment for recurrence during the trial is provided in Section 3.5.1.

[0211] For the administration of additional doses of lovelizumab during recurrence in the trial, refer to Section 5.1.6.

[0212] 5.2.3.2.4 Follow-up of Recurrence during the Trial Recurrence evaluation visits for monitoring the process of recurrence are conducted according to the schedule specified in the SoA (Figure 3). Additional (unscheduled) follow-up recurrence evaluation visits outside the specified time points are conducted at the discretion of the principal investigator or sub-investigator of the trial.

[0213] After recurrence, if the patient and the principal investigator / sub-investigator of the trial determine that it is appropriate to continue receiving the investigational drug, the patient may continue the trial.

[0214] All reports of possible recurrence and actions taken for possible recurrence are recorded in the patient's source documents and in the eCRF.

[0215] 5.2.3.2.5 Evaluation of Recurrence during the Trial Recurrence during the trial is independently reviewed by a Relapse Adjudication Committee (RAC) composed of physicians with expertise in NMOSD who conduct an independent review of recurrence during the trial. The committee determines, by a majority vote, whether each reported recurrence during the trial meets the objective criteria for recurrence during the trial. Another charter describes all the criteria and procedures for this trial.

[0216] 5.2.4 Expanded Disability Status Scale (EDSS) The 10-point Kurtzke EDSS (Section 7.2) is widely used and accepted as a valid tool for quantifying disability and monitoring changes in disability over time (Kurtzke, J., Neurology, 33:1444-52, 1983). The range of the EDSS scale is 0 to 10.0, in 0.5-unit increments.

[0217] 5.2.4.1 Expanded Disability Status Scale The total EDSS score is determined by two factors: walking and FSS (Section 5.2.4.2) as described below: ·An EDSS score of less than 4.0 is determined by the FSS alone. ·Individuals with an EDSS score of 4.0 or higher may have some degree of walking impairment. ·An EDSS score of 4.0 - 9.5 is determined by both walking ability and the FSS.

[0218] 5.2.4.2. Functional System Score The functional system (FS) represents a network of neuron systems responsible for specific tasks / functions. The EDSS assigns a severity score to a patient's clinical condition using the FSS that evaluates functional impairment in the following eight FSs (Section 7.2). The FSs of functional systems 1 - 7 are scored on a scale of 0 (low - level problems) to 5 or 6 (high - level problems) to best reflect the level of clinically observed impairment. The "Other" category consists of any other neurological findings resulting from NMOSD and is binary, with 0 indicating none and 1 indicating the presence of either.

[0219] 5.2.4.3. Assessors of EDSS and FSS The EDSS and FSS are administered directly by trained assessors. The EDSS assessor conducts a complete Kurtzke neurological examination and records the FSS and EDSS scores. The following rules apply: ·The EDSS assessor cannot be directly involved in the management of trial patients, rather than the PI. If possible, the EDSS assessor should be a physician. When using an EDSS assessor other than a physician (e.g., a specialized nurse), the assessor must be approved by the trial sponsor before the assessment is carried out. ·The EDSS assessor maintains blindness to all other trial data and all other patients' clinical data. ·The blinded EDSS assessor is responsible for conducting EDSS assessments throughout the trial period, including at the time of recurrence. If possible, the same blinded assessor performs the EDSS for each patient at the time of the visit designated in the SoA. · As described in Section 7.2, the EDSS assessors performed a complete Kurtzke neurological examination and recorded the Functional System Score (FSS) and the EDSS score (Kurtzke, 1983).

[0220] For specific requirements regarding the qualification of EDSS assessors, please refer to the training materials provided by the sponsor of the clinical trial. For the roles and responsibilities of the principal investigator of the clinical trial and the EDSS assessors, please refer to Table 5.

[0221]

Table 5

[0222] 5.2.5. EuroQoL 5 Dimensions (EQ-5D) The EuroQol 5 Dimensions (EQ-5D) (Figure 5) is a standardized self-assessment tool for measuring health-related QoL that is used in a wide range of health states, including NMOSD (Schrag, A. et al., J. Neurol. Neurosurg. Psychiatry, 69:67 - 73, 2000). The EQ-5D consists of two pages: the EQ-5D descriptive system and the EQ Visual Analogue Scale (EQ VAS) (Figure 5). The EQ-5D is administered at each visit prior to other test procedures.

[0223] 5.2.5.1. EQ-5D Descriptive System The descriptive system is a five-element scale that includes mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each level is rated on a scale that describes the degree of problems in that area.

[0224] 5.2.5.2. EQ Visual Analogue Scale The EQ-5D VAS is an overall health state scale in which patients select a number from 0 to 100 to describe their health state, where 100 represents "the best imaginable health state" and 0 represents "the worst imaginable health state".

[0225] This information can be used as a quantitative measure of health outcomes judged by individual respondents. Preliminary evidence of the feasibility, reliability, and validity of this instrument has been shown in tests previously published by members of the EuroQol group.

[0226] 5.2.6. Short Form-36 Health Survey (SF-36) The SF-36 is a 36-item self-report of health-related quality of life (Stewart, A. L., & Ware, J. E., Jr. (Eds.). (1992). Measuring functioning and well-being: The medical outcomes study approach. Durham, NC: Duke University Press.; Ware, J. E., Jr. (1988). How to score the revised MOS short-form health scales. Boston: Institute for the Improvement of Medical Care and Health, New England Medical Center.). It includes eight subscales that measure different areas of health-related quality of life: physical function, role limitation due to physical problems, bodily pain, general health perception, vitality, social function, role limitation due to emotional problems, and mental health. Two summary scores are the physical component summary and the mental component summary. There is no single overall score for the SF-36.

[0227] 5.2.7. Hauser Ambulation Index (HAI) The HAI is an assessment scale developed to evaluate mobility by assessing the time and extent of assistance required to walk 25 feet (Figure 7). The treating physician or appropriately trained designee performs the HAI test at the time of the clinic visit as specified in the clinical trial protocol, as briefly described below (Figure 3). · The patient is asked to walk a marked 25-foot course as quickly and safely as possible. ·The examiner records the time and type of assistance required (e.g., cane, walker, crutch). The rating scale also has categories for patients who cannot walk.

[0228] The patient's walking is timed, but this time is not used directly. Instead, it is used in combination with other factors to evaluate the patient on an 11-point ordinal scale (Bethoux, F. and Bennett, S., Int. J. Care, 13:4 - 14, 2011). This evaluation is performed on all patients in this trial.

[0229] 5.2.8. Optic-spinal impairment score (OSIS) OSIS is a scoring system for evaluating the severity of relapses (Figure 8). The OSIS VA subscale score is used to classify the severity of ON. The OSIS motor subscale score and sensory subscale score are used to classify the severity of TM. OSIS is evaluated by the treating physician at baseline and at the time of relapse during the trial. Further instructions regarding the OSIS evaluation of relapses during the trial are provided in Section 5.2.3.2.

[0230] 5.2.9. Ophthalmological examination 5.2.9.1. Confrontation visual field The confrontation VF is evaluated by the treating physician. In this evaluation, it is important to know the baseline ophthalmological status so that changes in the examination can be used to evaluate previous and ongoing ON. Central scotomas are common in patients experiencing ON. However, visual field defects can show a wide spectrum of patterns (Keltner, J. et al., Am. J. Ophthalmol., 128:543 - 53, 1999).

[0231] 5.2.9.2. Color vision Color vision is evaluated using Ishihara plates by the treating physician or any appropriately trained designee. Color vision loss can be a marker of ON and is thus an important evaluation tool in NMOSD.

[0232] 5.2.9.3 Visual acuity Visual acuity is usually affected and progresses over a period of hours to days. The Landolt C Ring Chart is used to evaluate VA.

[0233] The Landolt C consists of a ring with a gap and thus looks like the letter C. The gap can be in various positions (usually left, right, bottom, top and at 45° in between), and the task of the person being tested is to determine on which side the gap is. The size of the C and its gap are decreased until the patient produces a certain error rate. The minimum perceptible angle of the gap is adopted as a measure of visual acuity.

[0234] The treating physician or duly trained designee shall perform the VA test at the visit as specified in the clinical trial protocol as described below (Figure 3). · The test is performed at a standard distance, typically 6 meters or 20 feet. · Since the Landolt chart is typically recorded as the visual acuity ratio distance (6 meters or 20 feet), normal VA is usually recorded as 20 / 20 or 6 / 6. This may be entered as the denominator of the Landolt fraction (in the United States) or the decimal (outside the United States). · The test is always performed with the best possible correction (e.g., wearing glasses) as necessary, and each eye is tested independently.

[0235] 5.2.10 Magnetic resonance imaging and optical coherence tomography of the eye Perform baseline MRI (contrast optional) of the brain, cervical spine and thoracic spine and OCT examination. Exceptions may be granted if approved by the Alexion medical monitor (e.g., based on the most recent medical history results available for the study).

[0236] At recurrence, if clinically important, the responsible investigator may, at his or her discretion, perform MRI (contrast optional) of the brain, cervical spine and / or thoracic spine and / or OCT to assess the likelihood of recurrence.

[0237] If the principal investigator of the clinical trial determines it to be an indication, after recurrence during the clinical trial, conduct a follow-up evaluation promptly (Section 5.2.3).

[0238] 5.3. Safety Evaluation Provide all scheduled time points for safety evaluations to the SoA (Figures 2 and 3).

[0239] 5.3.1. Physical Examination A complete physical examination includes at least the following organ / body system evaluations: skin, head, ears, eyes, nose, throat, neck, lymph nodes, pulse, chest, heart, abdomen, extremities, and musculoskeletal system. Targeted physical examinations include at least examinations related to body systems based on the judgment of the principal investigator of the clinical trial and the patient's symptoms.

[0240] The principal investigator of the clinical trial pays particular attention to clinical signs related to past serious diseases. To maintain consistency, make all efforts to ensure that the same trial staff who are qualified conduct the physical examination each time the patient visits the trial. Based on the judgment of the principal investigator of the clinical trial, additional physical examinations can be conducted as medically indicated during the trial.

[0241] 5.3.2. Height and Weight Weight is measured in pounds or kilograms. Height is measured in inches or centimeters.

[0242] 5.3.3. Vital Signs Evaluate oral temperature (°C or °F), pulse rate, respiratory rate (RR), systolic and diastolic blood pressure (BP) (mm Hg). Measurement values of blood pressure and pulse are evaluated using a fully automated device. Manual techniques are used only when an automated device is not available. Prior to measuring blood pressure and pulse, allow the patient to rest in a quiet environment (e.g., without distractions such as TV, mobile phone) for at least 5 minutes. Ideally, the same group is used for measurement for each patient.

[0243] 5.3.4. Electrocardiogram A single 12 - lead electrocardiogram is performed at the time of hospital visit as specified in the clinical trial protocol of the SoA (Figures 2 and 3) using an ECG device to obtain the heart rate and measurements of the PR, QRS, QT, and QTc intervals. The patient lies in the supine position approximately 5 - 10 minutes before ECG collection and remains in the supine position but awake during ECG collection. The principal investigator of the clinical trial or a qualified designee is responsible for reviewing the electrocardiogram to assess whether it is within the normal range and to determine the clinical significance of the results. These evaluations are recorded in the source documents and eCRF.

[0244] 5.3.5. Patient Safety Card Before the first administration of the investigational drug, the patient safety card is given to the trial patient for constant carrying. This card is provided to enhance the patient's awareness of the risk of infectious diseases, especially meningococcal infection, to facilitate the rapid recognition and disclosure of potential signs or symptoms of infectious diseases that the trial patient may experience during the trial period, and to inform the patient of what measures should be taken if they experience signs or symptoms of an infectious disease.

[0245] At each hospital visit during the trial, the trial staff ensures that the patient has the patient safety card.

[0246] 5.3.6. Pre - and Concomitant Medical Review It is important for the principal investigator of the clinical trial or a qualified designee to review each drug that the patient is taking before the start of the trial and at each hospital visit.

[0247] 5.3.6.1. Pre - treatment Drugs Record in the patient's eCRF the pre - treatment drugs and / or vaccines (including vitamins, herbal preparations, those considered in the exclusion criteria section 2.2), as well as procedures (treatment interventions such as surgery / biopsy or physical therapy), and meningococcal vaccines administered within the past 3 years that the patient took or received within 30 days before the start of screening or during the screening period before the first administration of lulizumabumab. Additionally, collect all drugs or therapies (including steroids) previously used for the prevention of NMOSD recurrence or acute - phase treatment before the first administration of lulizumabumab.

[0248] 5.3.6.2. Concomitant Medications During the trial, evaluate the use of concomitant medications and non-drug therapies (Section 6.5). At each visit, ask the patient about any new medications or non-drug therapies or changes to concomitant medications and non-drug therapies since the last visit. Record concomitant medications and non-drug therapies in the source documents and the patient's eCRF.

[0249] 5.3.7. Clinical Safety Laboratory Assessments The Investigator-in-Charge reviews the laboratory reports, documents this review, and records any clinically important changes that occur during the trial in the AE section of the CRF. The laboratory reports are submitted together with the source documents. Clinically significant abnormal laboratory findings refer to those not related to the underlying disease, unless the Investigator-in-Charge determines that they are more severe than would be expected for the patient's condition.

[0250] Repeat all clinical laboratory tests with values considered clinically significant during the trial or within 8 weeks after the last dose of the investigational medicinal product until the values return to normal or baseline or are determined by the Investigator-in-Charge or the Medical Monitor to be no longer clinically important. If such values do not return to normal / baseline within the period determined by the Investigator-in-Charge to be appropriate, identify the cause and inform the Sponsor. As defined in Appendix 2, all laboratory assessments required by the trial protocol are performed in accordance with the laboratory manual and the SoA. Laboratory values from laboratory assessments performed at the local laboratory of the site that are not specified in the trial protocol are recorded in the CRF if they require a change in patient management or are determined by the Investigator-in-Charge to be clinically important (e.g., for an AE or dose change).

[0251] 5.3.8. Monitoring for Risk of Suicidal Thoughts and Behaviors Since the investigational drug is being evaluated for neurological indications, patients receiving the investigational drug should be appropriately monitored, and in particular, at the start and end of the investigational drug process or at the time of dose change, carefully observed for changes in suicidal thoughts or behaviors or other abnormal behaviors.

[0252] Baseline evaluations of suicidal thoughts and behaviors, as well as suicidal thoughts and behaviors that emerge due to the intervention, are monitored during this trial using the Columbia Suicide Severity Rating Scale (C-SSRS).

[0253] There are two types of C-SSRS evaluations conducted during the trial: the baseline C-SSRS (Figure 10) and the C-SSRS after the final visit (Figure 11). The C-SSRS is administered by the treating physician or an appropriately trained designee at the time of the visit designated in the SoA to ensure that patients experiencing suicidal thoughts or behaviors are appropriately recognized, adequately managed, or referred for further evaluation. Additional C-SSRS evaluations are permitted as necessary.

[0254] 5.4. Adverse Events and Serious Adverse Events Adverse events are reported to the principal investigator of the trial by the patient (or, where appropriate, the caregiver, proxy, or patient's representative).

[0255] The principal investigator of the trial and qualified designees are responsible for detecting, describing, and recording events that meet the definition of an AE or SAE, and also for following up on AEs that are considered severe, related to the investigational drug or the trial procedure, or that prompt the discontinuation of the investigational drug in the patient (see Section 4).

[0256] In this trial, information on recurrences that do not meet the SAE criteria is recorded in the source documents and eCRF as part of the recurrence evaluation visit and not reported as an AE.

[0257] 5.4.1. Period and Frequency for Collecting Adverse Event and Serious Adverse Event Information All AEs and SAEs are collected from the signing of the ICF until the final visit at the time designated in the SoA (Figures 2 and 3).

[0258] Record all SAEs and report them immediately to the sponsor or designee. Under no circumstances shall this exceed 24 hours, as shown in Figures 2 and 3. The principal investigator shall submit the latest SAE data to the sponsor within 24 hours of becoming aware of it.

[0259] The principal investigator has no obligation to actively seek AEs or SAEs after the end of participation in the trial. However, if a SAE, including death, occurs after the subject has withdrawn from the trial and the principal investigator determines that it is reasonably related to the investigational medicinal product or trial participation, the principal investigator shall promptly notify the sponsor.

[0260] 5.4.2. Methods for Detecting AEs and SAEs When detecting AEs and / or SAEs, take care not to introduce bias. Open-ended, non-leading verbal questions to the patient are a preferred method for asking about the occurrence of AEs.

[0261] 5.4.3. Follow-up of AEs and SAEs After the initial AE / SAE report, the principal investigator is required to actively follow up each patient at subsequent visits / contact. For all SAEs and particularly notable AEs (AESIs; defined in section 5.4.6), follow-up shall be conducted until recovery, stabilization, explanation of the event for other reasons, or inability to follow up the patient (defined in section 4.3) is noted. Every effort shall be made to implement the safety follow-up procedures specified in the trial protocol.

[0262] 5.4.4. Regulatory Reporting Requirements for SAEs It is essential for the principal investigator to promptly notify the sponsor of SAEs in order to meet the legal obligations and ethical responsibilities regarding the safety of the patient and the investigational medicinal product under clinical investigation.

[0263] The sponsor has the legal responsibility to notify both national regulatory authorities and other regulatory authorities about the safety of the investigational medicinal product under clinical investigation. The sponsor complies with the country-specific regulatory requirements regarding safety reporting to regulatory authorities, the institutional review board (IRB) / independent ethics committee (IEC), and the responsible investigator of the trial.

[0264] If a serious unexpected adverse reaction (SUSAR) is suspected, report it in accordance with the country-specific regulatory requirements and the sponsor's policy and transfer it to the responsible investigator of the trial if necessary.

[0265] The responsible investigator who receives a safety report from the sponsor that describes a serious adverse event (SAE) or other specific safety information (e.g., summary or list of SAEs) shall, after consideration, submit it together with the investigational medicinal product summary and notify the IRB / IEC if appropriate according to local requirements.

[0266] 5.4.5. Pregnancy Pregnancy tests shall be performed on all women of childbearing potential (WOCBP) at the time points specified in the trial implementation plan of the SoA (Figures 2 and 3). Pregnancy tests (urine or serum) can also be performed at any time during the trial at the discretion of the responsible investigator.

[0267] It is necessary for WOCBP before administration of the investigational medicinal product to have a negative pregnancy test. The following rules apply: · Collect details of all pregnancies of female patients and, if applicable, the female partners of male patients from the start of the investigational medicinal product until the end of the pregnancy. · If a pregnancy is reported, the responsible investigator shall notify the sponsor within 24 hours of learning of the pregnancy. · An abnormal outcome of pregnancy (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomaly, ectopic pregnancy) is considered an SAE. Pregnancy alone is not considered an AE.

[0268] If a patient becomes pregnant, discontinue the investigational medicinal product immediately and notify the sponsor. Each pregnancy shall be followed up until term and the sponsor shall be notified of the outcome.

[0269] 5.4.6. Adverse events of special interest Meningococcal infections are collected as particularly notable adverse events of special interest (AESI).

[0270] 5.5. Treatment of overdose In this trial, administration of the investigational drug exceeding the dose specified in the trial protocol is considered an overdose.

[0271] Accidental overdoses not associated with abnormal clinical laboratory values or clinical symptoms are not considered AEs. Regardless of the presence or absence of an AE, the principal investigator of the trial reports the overdose to the sponsor of the trial within 24 hours.

[0272] The sponsor of the trial does not recommend specific treatment for overdose.

[0273] In case of overdose, the principal investigator of the trial · Immediately contacts the medical monitor. · Closely monitors the patient for AEs / SAEs. · Collects plasma samples for PK analysis if requested by the medical monitor (case-by-case determination). · Records the amount of overdose and the time of overdose in the CRF.

[0274] The decision to interrupt dosing is made by the principal investigator of the trial in consultation with the medical monitor based on the clinical evaluation of the patient.

[0275] 5.6. Pharmacokinetics and pharmacodynamics Blood samples for measuring serum drug concentration and for PD evaluation are collected before and after administration of the investigational drug at the time points specified in the SoA (Figures 2 and 3). Cerebrospinal fluid (CSF) samples for PK and PD evaluation are optional at the time points specified in the trial protocol (Figures 2 and 3) and are obtained only from patients who have consented to CSF collection. Instructions regarding the collection and handling of biological samples are provided by the sponsor of the trial. The actual date and time (24-hour clock time) of each sample is recorded in the eCRF and the central laboratory request form. Additional information regarding sample collection, including blood volume requirements, is provided in the laboratory manual.

[0276] 5.6.1 Sample Collection During the Test Period Blood samples for PK and PD of the baseline (B) and trough (T) are collected before dosing, within 90 minutes before administering the investigational drug upon arrival at the hospital as specified in the SoA (Section 1.3). The pre-dose blood samples can be collected via the venous access created for dose infusion before dosing. Blood samples for PK and PD after dosing (P) are collected within 120 minutes after dosing and after the completion of the infusion of the investigational drug. The post-dose blood samples are collected from the non-infusion arm on the opposite side of the patient. Blood samples at non-dose visits can be collected at any time. In case of unscheduled visits, collect blood samples for PK and PD as soon as possible.

[0277] 5.6.2 Sample Collection During the Test Period Blood samples for PK and PD analysis are collected at any time during the scheduled relapse evaluation visit. However, if the blood sample collection schedule associated with relapse coincides with the regular sample collection as specified in the SoA (Figures 2 and 3), the instructions for regular PK and PD sample collection during the test (Section 5.6.1) must be followed.

[0278] During a relapse during the trial, if the patient receives additional doses of PE / PP and ravulizumab upon arrival for relapse evaluation, collect three blood samples for PK and PD at the following intervals: 1. Approximately 5 to 90 minutes before PE / PP 2. After PE / PP and before infusion of the investigational drug 3. At least 60 minutes after the completion of the infusion of the investigational drug

[0279] If the patient receives PE / PP at any visit other than the relapse evaluation visit, collect blood samples for PK and PD immediately before and after each session of PE / PP. Post-dose samples (e.g., 1 hour after the completion of additional investigational drug infusion) are also collected.

[0280] 5.7. Genetics In this trial, there is no pre-specified genetic analysis.

[0281] 5.8. Biomarker Research 5.8.1. Exploratory Biomarker Research Blood samples for biomarker research are collected from all patients at the time points specified in the SoA (Figures 2 and 3). CSF samples are optional samples for biomarker research and should only be collected from patients who have consented to CSF sample collection. Biomarkers are measured and include, but are not limited to, the following evaluations: · AQP4-Ab at the time points specified in the clinical trial protocol (Section 1.3 SoA), including during the relapse evaluation period (see Section 5.2.3.2 for details). · Complement products · Markers of neuroinflammation such as interleukin 6 (IL-6) · Markers of nerve injury such as neurofilament light chain (NfL)

[0282] 5.8.2. Future Biomarker Research The collection of DNA and RNA samples is optional. Blood samples for DNA and RNA must only be collected from patients who have consented to it. Future DNA and RNA testing on these samples may include, but is not limited to, specific candidate gene / whole genome analysis.

[0283] Residual samples from pharmacokinetics, pharmacodynamics, immunogenicity, and biomarker testing are stored for future biomarker research. Analyses may be performed on biomarker mutations that are thought to play a role in the activity / progression of NMOSD or the treatment response to ravulizumab. These samples may also be used to develop methods, assays, prognoses, and / or companion diagnostics related to the investigational drug target, disease process, pathways related to disease state, and / or the mechanism of action of the investigational drug.

[0284] Samples can be stored for a maximum period in accordance with local regulations after the final visit of the last patient for testing at a facility selected by the sponsor of the trial to enable further analysis.

[0285] 5.9. Immunogenicity Evaluation Antidrug antibodies (ADA) against lulizumab are evaluated in serum samples collected from all patients prior to dosing (within 5 - 90 minutes before the start of infusion of the investigational drug) according to the SoA (Figures 2 and 3).

[0286] Furthermore, serum samples should be collected at the final visit from patients who discontinued the investigational drug or withdrew from the study.

[0287] Serum samples are screened for antibodies that bind to lulizumab, and the titers of samples with confirmed positivity are reported. Other assays may be performed to verify the stability of antibodies against lulizumab and / or to further characterize the immunogenicity of lulizumab.

[0288] Detection and characterization of antibodies against lulizumab are performed using validated assay methods, either under the supervision of or under the control of the sponsor of the clinical trial. If deemed necessary, samples may be further characterized to determine titers and the presence of neutralizing antibodies. Samples may be stored for the longest period in accordance with local regulations after the final visit of the last patient in the study at the facility selected by the sponsor of the clinical trial, to enable further analysis of the immune response against lulizumab.

[0289] 5.10. Medical Resource Utilization and Health Economics Medical resource utilization and health economic data are collected on all patients throughout the study on the CRF by the responsible investigator and the staff of the clinical trial site in relation to medical encounters. Procedures, tests, and encounters defined in the clinical trial protocol are excluded.

[0290] The data collected can be used to conduct exploratory economic analyses, including the following: · Number of surgeries and other selected treatments (inpatients and outpatients) · Length of hospital stay · Number and type of diagnostic and therapeutic tests and procedures

[0291] 6. Statistical Considerations 6.1. Statistical Hypotheses The time to the first evaluated relapse during the trial was evaluated using the log-rank test, and the null hypothesis was that there was no difference in the survival curves between the ravulizumab treatment group and the placebo treatment group. The alternative hypothesis would be that there was a difference between the two survival curves and that ravulizumab was superior to placebo.

[0292] A 95% confidence interval (CI) was presented for the evaluated ARR to provide an estimate of the evaluated ARR rate in patients treated with ravulizumab. A formal hypothesis test for the evaluated ARR was not performed, but it was expected that patients treated with ravulizumab would have a low ARR and that the upper limit of the 95% CI would not exceed 0.25 relapses / patient-year.

[0293] For HAI, the null hypothesis would be that the odds of better performance are the same between the ravulizumab group and the placebo group. The alternative hypothesis would be that there is a difference in the odds of better treatment performance between the treatment groups and that ravulizumab has higher odds of better clinical performance.

[0294] For the EQ-5D index and EQ-5D VAS, the null hypothesis would be that there is no difference in the distribution between the ravulizumab group and the placebo group. The alternative hypothesis would be that there is a difference in the distribution between the treatment groups and that ravulizumab is superior to placebo.

[0295] For EDSS, the null hypothesis would be that the odds of worse performance are the same between the ravulizumab group and the placebo group. The alternative hypothesis would be that there is a difference in the odds of worse treatment performance between the treatment groups and that the odds of worse treatment performance are higher in the placebo group.

[0296] 6.2. Sample Size Determination This trial is an open-label, externally placebo-controlled trial to evaluate ravulizumab in NMOSD patients, with the time to the first evaluated relapse during the trial as the primary endpoint. The placebo treatment group in the NCT01892345 trial serves as an external control.

[0297] The assumptions for the sample size and power calculation of this trial using the time to the first recurrence as the primary endpoint are as follows: · Log-rank test for comparison between Lovastatin and placebo · 47 patients in the placebo treatment group · Power of 90% · Two-sided significance level of 5% · Dropout rate of 2 - 10% · Recurrence-free rate of 92% in the Lovastatin group at 12 months · Relapse-free rate of 63% in the placebo group at 12 months

[0298] Based on these assumptions, a maximum sample size of approximately 55 patients in the Lovastatin treatment group provides at least 90% power to detect a treatment difference in the time to recurrence initially evaluated as positive.

[0299] 6.3. Population for analysis For the purpose of analysis, the following populations are defined as shown in Table 6.

[0300]

Table 6

[0301] 6.4. Statistical analysis The primary analysis is performed when all patients have completed the primary treatment period. This analysis includes all efficacy, safety, PK / PD trial data intended for submission to the regulatory authorities and is the final analysis of the primary treatment period. The SAP to support the primary analysis is developed immediately after the trial implementation plan becomes final and is also final. If necessary, the final SAP is developed before the completion of the long-term extension period to describe additional long-term efficacy and safety analyses. This section provides an overview of the planned statistical analyses of the primary and secondary endpoints of efficacy and safety analyses.

[0302] Summary statistics are calculated and presented for each treatment group and, where applicable, for each visit. Descriptive statistics for continuous variables include, as a minimum, the number of patients, mean, standard deviation, minimum, median, and maximum. For categorical variables, frequencies and percentages are presented. Graphic displays are provided as needed. All statistical analyses are performed based on a two-sided type I error of 5%, unless otherwise specified. Missing data are not imputed.

[0303] Analyses are performed using SAS® software version 9.4 or later.

[0304] 6.4.1. Efficacy Analysis To account for potential differences in baseline characteristics between the Lovirizumab group and the external placebo control, the efficacy analysis includes, as needed, a covariance adjustment methodology. Details are provided in the SAP.

[0305] 6.4.1.1. Primary Endpoint The primary endpoint of efficacy is the period until the first recurrence during the trial is first evaluated. For the period until the first recurrence during the trial that is first evaluated, which is the primary endpoint, if a statistically significant difference (e.g., p-value < 0.05) is observed between the Lovirizumab treatment group and the placebo group, the trial is considered to have met its primary efficacy objective. The log-rank test is used for comparison of treatment groups for the primary endpoint. Hazard ratios and risk reductions are summarized from the Cox proportional hazards model. Confidence intervals (95%) are presented for the estimated proportion of patients who are recurrence-free at various time points (e.g., week 26, week 50) based on complementary log-log transformation. Kaplan-Meier curves are created for both treatment groups.

[0306] A sensitivity analysis for the primary endpoint is described in the SAP.

[0307] 6.4.1.2. Secondary Endpoints 6.4.1.2.1. Evaluated ARR during the Trial Present the evaluated on-treatment ARR, which descriptively shows the estimated value in the ravulizumab treatment group and the 95% CI from a Poisson regression model with the logarithm of time during the study period as an offset variable and the past ARR as a covariate of the model. This endpoint is considered statistically significant if the upper limit of the 95% CI is ≤ 0.25 relapses per year.

[0308] 6.4.1.2.2. EuroQoL 5-Dimension (EQ-5D) Index Score and EQ-5D VAS Analyze the change from baseline in the EQ-5D Index Score to 6 weeks after relapse / end of the primary treatment period (i.e., for the placebo group, 6 weeks after relapse for patients who relapsed or end of the NCT01892345 trial (EOS) for patients who did not relapse; for the ravulizumab group, 6 weeks after the first observed relapse for patients who relapsed and the EQ-5D Index Score at the end of the primary treatment period for patients who did not relapse) using non-parametric analysis of covariance (ANCOVA) adjusted for the baseline EQ-5D metric score. Baseline is defined as the last available pre-treatment assessment for all patients regardless of treatment group.

[0309] Analyze the change from baseline to 6 weeks after relapse / EOPT period timepoint in the EQ-5D VAS using non-parametric ANCOVA adjusted for the baseline EQ-5D VAS as described for the change in the EQ-5D Index Score.

[0310] 6.4.1.2.3. Expanded Disability Status Scale (EDSS) Calculate the change from baseline in the EDSS score to 6 weeks after relapse / EOPT period analysis timepoint as described for the EQ-5D endpoint. For EDSS, this change from baseline is classified as either no worsening or clinically significant worsening. This endpoint is analyzed using a logistic regression model with the treatment group and baseline EDSS as covariates. Details are provided in the SAP.

[0311] 6.4.1.2.4. Hauser Walking Index (HAI) Calculate the change from baseline of the HAI score to 6 weeks after recurrence / at the EOPT period analysis time point as described for the EQ-5D endpoint. For HAI, this change from baseline is classified into clinically important changes (clinical improvement, stability, clinical deterioration). This three-level endpoint is analyzed using a proportional odds model that includes the treatment group and the baseline HAI as covariates. Details will be provided in the SAP.

[0312] 6.4.1.2.5. Explanation of Multiple Comparisons To control the type I error for the analysis of the primary endpoint and secondary endpoints, a closed testing procedure is applied. If the primary endpoint is statistically significant in supporting lovelizumab, the secondary endpoints are evaluated in the following order: 1. ARR during the evaluated trial 2. Clinically important change from baseline in walking function measured by HAI 3. Change from baseline in the EQ-5D index score 4. Change from baseline in the EQ-5D VAS score 5. Clinically important deterioration from baseline in the EDSS score

[0313] Hypothesis testing proceeds from the highest rank (#1) of the ARR during the evaluated trial to the lowest rank (#5) of the EDSS score. If no statistical significance is obtained for the endpoint (p ≥ 0.05 or the upper CI of the ARR > 0.25), the lower-rank endpoints are considered not statistically significant. Confidence intervals and p-values are presented for all secondary efficacy endpoints for descriptive purposes regardless of the results of the closed testing procedure.

[0314] 6.4.1.3. Tertiary / Exploratory Endpoints The summary and analysis of the tertiary and exploratory endpoints are described in the SAP.

[0315] 6.4.2. Safety Analysis Use the safety set to summarize all safety data.

[0316] 6.4.2.1. Analysis of Adverse Events The analysis and reporting of AEs are based on treatment-emergent adverse events (TEAEs) defined as AEs that occurred at the time of the first dose of lulizumab or after the first dose. The incidence of TEAEs is summarized by System Organ Class (SOC) and preferred term, and further summarized by severity, relationship to the investigational medicinal product, TEAEs leading to discontinuation of the investigational medicinal product, and TEAEs leading to death. The summary of TESAE is also summarized by SOC and preferred term, with an additional summary indicating the relationship to the investigational medicinal product. These summaries are presented by treatment group (lulizumab, placebo).

[0317] 6.4.2.2. Analysis of Clinical Laboratory Parameters, Vital Sign Measurements, and Electrocardiogram Parameters Summarize the test measurements and their changes from baseline at the time of the visit, and, where applicable, the shift from baseline. Summarize the ECG including heart rate, PR, QRS, QT, and QTc by ECG interpretation, and also summarize the vital signs.

[0318] 6.4.2.3. Other Safety Analyses Present the number and percentage of patients in each category of the C-SSRS and the shift from baseline.

[0319] 6.4.3. Demographics and Baseline Characteristics Use the safety set to summarize the patient demographics and baseline characteristics for each treatment group. Present summary statistics. Do not perform formal hypothesis testing.

[0320] 6.4.4. Patient Disposition Summarize the number of patients screened, the number of patients treated, the number of patients who completed the study, the number of patients who discontinued the study, the reasons for discontinuation, and the number of patients included in each analysis set. Deviations from the main protocol are summarized by predefined deviation categories.

[0321] 6.4.5. Past medical history, surgical history, and history of neuromyelitis optica spectrum disorder Summarize the past medical history and surgical history by System Organ Class (SOC) and Preferred Term (PT) using the Medical Dictionary for Regulatory Activities, Version 21.0 or later. Also summarize the NMOSD history.

[0322] 6.4.6. Previous medications and concomitant medications Consider the medications taken before the first dose of the investigational drug as previous medications, and those taken at or after the first dose of the investigational drug as concomitant medications. Summarize the previous medications and concomitant medications for all patients in the safety analysis set, including immunosuppressive therapy (IST) for relapse prevention and acute relapse treatment. Drugs are coded using the World Health Organization Drug Dictionary (WHODrug; the latest available version at the time of analysis).

[0323] 6.4.7. Pharmacokinetics, pharmacodynamics, and anti-drug antibody analysis Derive the PK parameters of lebrikizumab using the individual serum concentration data of all patients who received at least one dose of lebrikizumab and for whom PK data are evaluable.

[0324] Construct a graph of the mean serum concentration-time profile. It is also possible to provide graphs of the serum concentration-time profiles of individual patients. Use the actual dose administrations and sample collection times in all calculations. Calculate descriptive statistics as appropriate for the serum concentration data at each sample collection. Population-PK evaluation may be considered using the data from this study or in combination with data from other studies.

[0325] Perform pharmacodynamic analysis for all patients who received at least one dose of lebrikizumab and have evaluable PD data.

[0326] Present descriptive statistics for all lovelizumab PD endpoints at each sampling time point (Section 1.3). The PD effect of lovelizumab is evaluated, as appropriate, by assessing the absolute value of the free C5 serum concentration and the change and rate of change over time from baseline. The evaluation of the PK / PD relationship of lovelizumab can be explored using the data from this trial or in combination with the data from other trials.

[0327] For the evaluation of immunogenicity, summarize the presence of confirmed positive ADA. Further, after confirmation of positive ADA, evaluate the samples for ADA titer and the presence of neutralizing antibodies.

[0328] 6.5. Interim Analysis The primary analysis is conducted when all patients have completed the primary treatment period. This analysis includes all efficacy, safety, PK / PD trial data intended for submission to the regulatory authorities and represents the final analysis of the primary treatment period. This analysis is not considered an interim analysis. An interim analysis that includes data collected during the long-term extension can be conducted to support the submission requirements.

[0329] 6.6. Data Monitoring Committee (DMC) This trial does not include a DMC.

[0330] 7. Support for Documentation and Operational Considerations 7.1. Appendix 1: Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorder International Panel on the Diagnostic Criteria for NMO in NMOSD Using AQP4-IgG (Wingerchuk, D. et al., Neurology, 85: 177-89, 2015) - In this trial, for the diagnosis of NMOSD, all of the following three criteria must be met: 1. At least one central clinical feature: ○ Optic neuritis ○ Acute myelitis ○ Area postrema syndrome: Episodes of unexplained hiccups or nausea and vomiting ○ Acute brainstem syndrome ○ Symptomatic narcolepsy or acute diencephalic clinical syndrome with typical diencephalic MRI lesions in NMOSD ○ Symptomatic brain syndrome with typical brain lesions in NMOSD visualized by MRI 2. Anti-AQP4 Ab positive test using the best available detection method (cell-based assay required for this test) 3. Exclusion of alternative diagnoses

[0331] 7.2. Appendix 2: Expanded Disability Status Scale (EDSS) The Kurtzke EDSS is a method for quantifying disability in multiple sclerosis (MS). The EDSS replaced the previous disability status scale used in MS. The EDSS quantifies disability in eight functional systems (FS) and enables a neurologist to assign a functional system score (FSS) to each of these. The FS are · Pyramids · Cerebellum · Brainstem · Sensory · Bowel and bladder · Visual · Cerebrum · Others as follows.

[0332] As shown in Figure 4, EDSS steps 1.0 to 4.5 refer to MS patients who are fully ambulatory, and EDSS steps 5.0 to 9.5 are defined by walking impairment.

[0333]

Table 7-1

[0334]

Table 7-2

[0335]

Table 7-3

[0336]

Table 7-4

[0337]

Table 8-1

[0338]

Table 8-2

[0339]

Table 8-3

[0340]

Table 8-4

[0341]

Table 8-5

[0342]

Table 8-6

Claims

[Claim 1] The invention described in the specification.

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