Compositions and methods for the treatment of neuromyelitis optica spectrum disorder

Abstract

Methods are provided for the clinical treatment of neuromyelitis optica spectrum disorder (NMOSD) using an anti-C5 antibody or antigen-binding fragment thereof. 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.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 338,410, filed May 4, 2022, the entire contents of which are incorporated herein by reference.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML file format, which is incorporated herein by reference in its entirety. The above XML copy, created on April 26, 2023, is named 0687_WO_SL.xml and is 68,782 bytes in size. [Background technology]

[0003] Neuromyelitis optica spectrum disorder (NMOSD), including neuromyelitis optica (NMO), also known as Devic's disease or Devic's syndrome, is a rare and severely disabling autoimmune inflammatory disease of the central nervous system (CNS) that primarily affects the optic nerve and spinal cord and often leads to blindness, mono-, bilateral-, and quadriplegia, and respiratory failure. NMOSD is characterized by a relapsing disease course, with gradual accumulation of significant neurological disability from which recovery can be poor.

[0004] The clinical hallmarks of NMO are acute optic neuritis and transverse myelitis, frequently affecting more than three vertebral levels, described as longitudinally extensive transverse myelitis (LETM). These clinical events may occur simultaneously or in isolation. Signs and symptoms resulting from lesions beyond the optic nerve and spinal cord may also occur in NMO patients and are reported in approximately 15% of patients. The clinical presentation of NMO is highly variable and the diagnosis may be unclear at the first or even second attack.

[0005] Aquaporin-4 (AQP4) is a water channel protein expressed in the CNS primarily by astrocytes. AQP4 immunoglobulin G (IgG), an antibody present in 65-88% of NMOSD patients, is the first biomarker specific for inflammatory, demyelinating CNS injury. Preclinical data indicate that AQP4-IgG induces the complement cascade, leading to inflammation and the formation of the complement-mediated membrane attack complex (MAC). AQP4-IgG-induced MAC is involved in astrocyte destruction and bystander neuronal 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 potentially disabling disease, the ability to recognize NMO and related disorders and to distinguish them from other demyelinating diseases is important from a clinical perspective. The prognosis of relapsing NMO is poor. The 5-year mortality rate for NMO is reported to be 30%, with 50% remaining permanently severely disabled, visual (blind in one or both eyes) or ambulatory (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. Prevention of relapse is therefore a major therapeutic imperative.

[0007] Although treatment options for NMO have been recently approved (Soliris® (eculizumab) has been shown to reduce relapse frequency in an open-label study of 14 AQP4-IgG positive patients), standard treatment options include steroids and other immunosuppressants. This is empirical and consensus-based supportive care. Acute NMO relapses are generally treated with high-dose intravenous steroids with plasma exchange (PE) often used as rescue therapy for unresponsive patients. Supportive care for relapses currently uses broad-spectrum or selective B-lymphocyte immunosuppressants. Summary of the Invention [Problem to be solved by the invention]

[0008] Of the immunosuppressants, corticosteroids, AZA, mycophenolate mofetil, and rituximab are probably the most commonly used for long-term prevention. Depending on local medical options, supportive care options for NMO may vary. In the United States, options include corticosteroids, AZA, MMF, rituximab, and mitoxantrone, while in Japan, corticosteroids, including oral prednisone or pulsed high-dose steroids (IV), are common treatments. A significant number of patients (>50%) will continue to experience seizures that result in further permanent neurological deficits and disabilities. Given the severity of the disease and limited treatment options, there remains a significant unmet medical need for effective and safe treatments for NMO. [Means for solving the problem]

[0009] Described herein are 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 disclosure relates to 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 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 an amino acid sequence set forth in SEQ ID NO: 13, wherein the amino acid sequence comprises up to four amino acid substitutions in the amino acid sequence set forth in SEQ ID NO: 13, wherein the amino acid substitutions do not include 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 a K D Affinity dissociation constants (K D In certain embodiments, the anti-C5 antibody or antigen-binding fragment thereof binds to human C5 with a K of ≥ 10 nM at pH 6.0 and 25°C. DIn certain embodiments, the subject is aged 18 years or older. In certain embodiments, the subject is positive for anti-AQP4 antibodies. In certain embodiments, the subject has at least one attack or relapse 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, the 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 subject's weight. 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 at a loading dose of 2400 mg on day 1 of the administration cycle; and (b) at a maintenance dose of 3000 mg on day 15 of the administration 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 at a loading dose of 2700 mg on day 1 of the administration cycle; and (b) at a maintenance dose of 3300 mg on day 15 of the administration cycle and every 8 weeks thereafter. In certain embodiments, the subject weighs ≧100 kg, and (a) the anti-C5 antibody is administered at a loading dose of 3000 mg on day 1 of the administration cycle; and (b) at a maintenance dose of 3600 mg on day 15 of the administration cycle and every 8 weeks thereafter. In certain embodiments, the treatment maintains a serum trough concentration of anti-C5 antibody or antigen-binding fragment thereof at 100 μg / mL or more during a dosing cycle. In certain embodiments, the treatment maintains a serum trough concentration of anti-C5 antibody or antigen-binding fragment thereof at 200 μg / mL or more during a dosing cycle. In certain embodiments, the treatment maintains a free C5 concentration of 0.309-0.5 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 administration 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 administration cycle is for 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, for example, 1200-1800 mg of anti-C5 antibody, within 4 hours after PE / PP is completed. In certain embodiments, the human subject experiences a clinically meaningful improvement in one or more clinical markers of NMOSD progression after administration of ravulizumab. In certain embodiments, the clinical marker for NMOSD progression is selected from the group consisting of adjudicated On-Trial ARR, EDSS score, EQ-5D, SF-36, Hauser Ambulation Index (HAI) and OSIS.

[0011] In some embodiments, the subject remains relapse-free for at least 48 weeks, at least 73 weeks, at least 73.5 weeks, at least 96 weeks, or at least 144 weeks.

[0012] In some embodiments, the subject does not experience clinically significant deterioration based on the Hauser Ambulatory Index. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 is a schematic diagram of the overall design of the clinical trial disclosed herein. [Figure 2-1] 1 is a table showing the Schedule of Activities (SoA) for the clinical trials disclosed herein. [Figure 2-2] Same as above. [Figure 2-3] Same as above. [Figure 2-4] Same as above. [Figure 2-5] Same as above. [Figure 2-6] Same as above. [Diagram 2-7] Same as above. [Figure 2-8] Same as above. [Figure 3-1] 1 is a table showing the schedule of activities (SoA) for the recurrence evaluation period for the clinical trials disclosed herein. [Figure 3-2] Same as above. [Figure 4-1] 1 is a table showing the Kurtzke Expanded Disability Status Scale. [Figure 4-2] Same as above. [Figure 4-3] Same as above. [Figure 5-1] Checklist and chart for the EuroQoL 5-dimension (EQ-5D-3L) scale. [Figure 5-2] Same as above. [Figure 6-1] The Short Form Health Survey (SF-36). [Figure 6-2] Same as above. [Figure 6-3] Same as above. [Figure 6-4] Same as above. [Figure 6-5] Same as above. [Figure 6-6] Same as above. [Figure 7] This is the Hauser Ambulatory Index (HAI) checklist. [Figure 8] 1 is a chart of the Optic Myelopathy Score (OSIS). [Figure 9] FIG. 1 is a table showing relapse severity as measured by the Optic Myelopathy Scale. [Figure 10-1] Columbia-Suicide Severity Rating Scale (C-SSRS)-Screening / Baseline Checklist. [Figure 10-2] Same as above. [Figure 10-3] Same as above. [Figure 10-4] Same as above. [Figure 11-1] Columbia-Suicide Severity Rating Scale (C-SSRS) checklist since the last visit. [Figure 11-2] Same as above. [Figure 12A] FIG. 1 is a schematic diagram of the study design. [Figure 12B] 1 is a tabular description of the baseline characteristics of subjects in the placebo and ravulizumab groups. [Figure 13] Tabular description of the annualized relapse rate (ARR), HAI score, EQ-5D index, EQ-5D VAS score, and EDSS score change from baseline to the end of the study in subjects in the placebo group (N=47) and ravulizumab group (N=58). The ARR and HAI endpoints were met. [Figure 14] Tabular description of annually assessed relapse-related hospitalizations, administration of high-dose oral steroids, administration of IV methylprednisolone, and administration of plasmapheresis for subjects in the placebo group (N=47) and ravulizumab group (N=58). [Figure 15A] Tabular description of the incidence of adverse events experienced by subjects in the placebo group (N=47) and the ravulizumab group (N=58). [Figure 15B] Summary of meningococcal infection rates observed with ULTOMIRIS. [Figure 15C] 1 is a tabular description of the efficacy of C5 inhibitors compared with other therapies. [Figure 16] 1 is a tabular description of the target, minimum, and upside criteria for subjects receiving ULTOMIRIS. [Figure 17] 1 is a graphical representation of time to first assessed on-study recurrence over time for subjects in the placebo group (N=47) and the ravulizumab group (N=58). Based on time to first assessed on-study recurrence, ravulizumab was superior to placebo (p<0.0001), with a 98.6% reduction in risk of recurrence. [Figure 18] FIG. 1 is a graphical representation of time over time to first assessment of on-study relapse for subjects in the placebo and ravulizumab groups analyzed taking into account the propensity score, where the propensity score is less than or equal to the median. [Figure 19]1 is a graphical representation of time to first assessment of on-study relapse over time for subjects in the placebo and ravulizumab groups analyzed taking into account the propensity score, where the propensity score is above the median. [Figure 20] FIG. 1 is a graphical representation of time to first assessment of on-study relapse over time for subjects in the placebo and ravulizumab groups analyzed using weighted analysis. [Figure 21] 1 is a graphical representation of time over time to first assessed on-study relapse for subjects in the placebo and ravulizumab groups analyzed by the randomization stratification variables observed in Study ECO-NMO-301, with stratum being baseline EDSS score of ≦2.0. [Figure 22] 1 is a graphical representation of time over time to first assessment of on-study relapse for subjects in the placebo and ravulizumab groups analyzed by the randomization stratification variables observed in Study ECO-NMO-301, with strata being baseline EDSS score ≥ 2.5 and ≤ 7. [Figure 23] Graphical representation of time over time to first assessment of on-study relapse for subjects in the placebo and ravulizumab groups analyzed by randomization stratification variables observed in Study ECO-NMO-301, with strata being baseline EDSS score ≥ 2.5 and ≤ 7, and subjects continuing on the same IST since last relapse. [Figure 24] Graphical representation of time over time to first assessment of on-study relapse for subjects in the placebo and ravulizumab groups analyzed by randomization stratification variables observed in Study ECO-NMO-301, with strata being baseline EDSS score ≥ 2.5 and ≤ 7, and subjects having changed their IST since last relapse. [Diagram 25] FIG. 1 is a graphical representation of time over time to first assessment of on-study relapse in subjects in the placebo group (N=11) and ravulizumab group (N=12), analyzing only subjects using steroid IST. [Figure 26]FIG. 1 is a graphical representation of time over time to first assessment of on-study relapse in subjects in the placebo group (N=13) and ravulizumab group (N=7), analyzing only subjects using azathioprine IST. [Figure 27] FIG. 1 is a graphical representation of time over time to first assessment of on-study relapse in subjects in the placebo group (N=8) and ravulizumab group (N=6), analyzing only subjects using mycophenolate mofetil IST. [Figure 28] FIG. 1 is a graphical representation of time over time to first assessment of on-study relapse in subjects in the placebo group (N=2) and ravulizumab group (N=3), analyzing only subjects using IST other than steroids, azathioprine, and mycophenolate mofetil. [Figure 29] Graphical representation of time over time to first assessment of on-study recurrence in subjects in the placebo (N=13) and ravulizumab (N=30) groups, analyzing only subjects not using IST. In the monotherapy group, ravulizumab (N=30) demonstrated a 97.9% reduction in risk of recurrence, consistent with the results for eculizumab. [Diagram 30] FIG. 1 is a graphical representation of time over time to first assessment of on-study relapse in subjects in the placebo group (N=34) and ravulizumab group (N=28), analyzing only subjects using any IST. [Diagram 31] FIG. 1 is a graphical representation of time over time to first assessment of on-study recurrence in subjects in the placebo group (N=17) and ravulizumab group (N=20), analyzing only subjects who had used rituximab in the previous year. [Diagram 32] Graphical representation of time over time to first assessment of on-study recurrence in subjects in the placebo group (N=30) and ravulizumab group (N=38), analyzing only subjects who had not used rituximab in the previous year. [Diagram 33]Forest plot of time to first assessed on-study relapse by predefined subgroups including propensity score and study ECO-NMO-301 strata. Data for the placebo group were collected as part of the PREVENT trial, study ECU-NMO-301. Vertical dotted lines indicate the overall placebo proportion with relapse and the overall hazard ratio for the full analysis set. Open circles = placebo, closed circles = ravulizumab. (1) Americas: ARG, CAN, and USA; Europe: DEU, DNK, ESP, GBR, HRV, ITA, POL, RUS, and TUR; Asia-Pacific: AUS, HKG, JPN, KOR, and TWN. (2) Unknown race was excluded from the forest plot and interaction effects model. (3) Other ISTs include cyclophosphamide, methotrexate, and tacrolimus. (4) Based on Cox proportional hazards model with treatment covariate. Firth's adjustment using profile likelihood confidence limits was applied when no recurrence was observed for a combination of treatment group and stratum.(5) Based on the Cox proportional hazards model with interaction terms. [Diagram 34] 1 is a forest plot of time to first assessment of on-study relapse by predefined subgroups including EDSS score and region. [Diagram 35] 1 is a forest plot of time to first assessment of on-study relapse by predefined subgroups including age, sex, and race. [Diagram 36] Forest plot of time to first assessment of on-trial relapse by defined subgroups including IST use and rituximab use. [Figure 37] Forest plot of time to first assessed on-study relapse by defined subgroups including time from onset, baseline EDSS score, and past annualized relapse rate. [Figure 38] 1 is a tabular description of the percentage of subjects in the ravulizumab group who experienced adverse events. [Figure 39]Tabular description of age, sex, and ethnicity of subjects in the placebo group (N=47) and ravulizumab group (N=58). [Diagram 40] Tabular description of the race, region, and weight of subjects in the placebo group (N=47) and ravulizumab group (N=58). [Diagram 41] 1 is a tabular description of the height and body mass index (BMI) of subjects in the placebo group (N=47) and the ravulizumab group (N=58). [Diagram 42] Tabular description of median propensity scores by region, age, sex, and use of immunosuppressive therapy for subjects in the placebo group (N=47) and ravulizumab group (N=58). [Diagram 43] Tabular description of median propensity scores by EDSS score and prior annualized relapse rate for subjects in the placebo group (N=47) and ravulizumab group (N=58). [Diagram 44] Tabular description of stabilized inverse probability weights by region, age, sex, and IST use for subjects in the placebo group (N=47) and ravulizumab group (N=58). [Diagram 45] Tabular description of inverse probability of stabilization weighting by baseline EDSS score and prior annualized relapse rate for subjects in the placebo group (N=47) and ravulizumab group (N=58). [Figure 46A] Tabular description of the proportion of subjects using immunosuppressive therapy in the placebo group (N=47) and the ravulizumab group (N=58). [Figure 46B] Tabular description of time to first assessment of on-study relapse for the placebo group (N=47) and ravulizumab group (N=58) over the course of the trial. [Figure 47] Tabular description of the statistical analysis of time to first assessment of on-study relapse in the ravulizumab group (N=58) over the course of the trial. [Figure 48]Tabular description of time to first assessed on-study relapse in the placebo group (N=47) and ravulizumab group (N=58) over the course of the trial, stratified by propensity score. [Figure 49] Tabular description of statistical analysis of time to first assessment of on-study relapse in the ravulizumab group (N=58) over the course of the trial, stratified by propensity score. [Figure 50] 1 is a tabular description of the time to first assessment of on-study relapse for the placebo and ravulizumab groups over the course of the trial using weighted analysis. [Figure 51] Tabular description of the statistical analysis of time to first assessment of on-study relapse in the ravulizumab arms over the course of the trial using weighted analysis. [Figure 52] Tabular description of time to first assessment of on-study relapse in the placebo group (N=34) and ravulizumab group (N=28) over the course of the trial, considering only subjects who had ever used any IST. [Diagram 53] Tabular description of the statistical analysis of time to first assessment of on-study relapse in the ravulizumab group (N=28) over the course of the trial, considering only subjects who used any IST. [Figure 54] Tabular description of time to first assessment of on-study relapse in the placebo group (N=11) and ravulizumab group (N=12) over the course of the trial, considering only subjects who had ever used steroids. [Figure 55] Tabular description of time to first assessment of on-study relapse in the ravulizumab group (N=12) over the course of the trial, considering only subjects who had ever used steroids. [Figure 56] Tabular description of time to first assessment of on-study relapse in the placebo group (N=11) and ravulizumab group (N=12) over the course of the trial, considering only subjects who had ever used azathioprine. [Figure 57]Tabular description of the statistical analysis of time to first assessment of on-study relapse in the ravulizumab group (N=12) over the course of the trial, considering only subjects who had ever used azathioprine. [Figure 58] Tabular description of time to first assessment of on-study relapse in the placebo group (N=8) and ravulizumab group (N=6) over the course of the trial, considering only subjects who had ever used mycophenolate mofetil. [Figure 59] Tabular description of the statistical analysis of time to first assessment of on-study relapse in the ravulizumab group (N=6) over the course of the trial, considering only subjects who had ever used mycophenolate mofetil. [Figure 60] Tabular description of time to first assessment of on-study relapse in the placebo group (N=2) and ravulizumab group (N=3) over the course of the trial, considering only subjects who had used IST other than steroids, azathioprine, and mycophenolate mofetil. [Figure 61] Tabular description of the statistical analysis of time to first assessment of on-study relapse in the ravulizumab group (N=3) over the course of the trial, considering only subjects who had used IST other than steroids, azathioprine, and mycophenolate mofetil. [Figure 62] Tabular description of time to first assessment of on-study relapse in the placebo group (N=13) and ravulizumab group (N=30) over the course of the trial, considering only IST-naive subjects. [Figure 63] Tabular description of the statistical analysis of time to first assessment of on-study relapse in the ravulizumab group (N=30) over the course of the trial, considering only subjects without IST. [Figure 64] Tabular description of time to first on-study relapse in the placebo group (N=47) and ravulizumab group (N=58) over the course of the trial. [Figure 65]Tabular description of the statistical analysis of time to first on-study relapse in the ravulizumab group (N=58) over the course of the trial. [Figure 66] Tabular description of the proportion of subjects in the placebo group (N=47) and the ravulizumab group (N=58) who experienced a relapse during the study and who required hospitalization. [Figure 67] Tabular description of the proportion of subjects in the placebo group (N=47) and ravulizumab group (N=58) who experienced relapse during the study, and the subsequent treatment required. [Figure 68] Tabular description of the proportion of subjects in the placebo group (N=47) and ravulizumab group (N=58) who experienced a relapse during the study, and the number of plasma exchange sessions associated with relapse required. [Figure 69] Tabular description of the proportion of subjects in the placebo group (N=47) and ravulizumab group (N=58) who experienced an on-study assessment of relapse and who required hospitalization. [Figure 70] Tabular description of the proportion of subjects in the placebo group (N=47) and ravulizumab group (N=58) who experienced an on-study assessment of recurrence and subsequent treatment required. [Figure 71] Tabular description of the proportion of subjects in the placebo group (N=47) and ravulizumab group (N=58) who experienced an assessment of recurrence during the study, and the number of plasma exchange sessions related to recurrence required. [Figure 72] 1 is a tabular description of the annualized on-study relapse rates evaluated for subjects in the ravulizumab group (N=58). [Figure 73] Tabular description of the statistical analysis of patient on-study assessed relapse rates for subjects in the ravulizumab group (N=58). [Figure 74] Tabular description of study-assessed relapse rates adjusted for historical annualized relapse rates for subjects in the placebo group (N=47) and ravulizumab group (N=58). [Figure 75]Tabular description of the statistical analysis of on-study assessed relapse rates adjusted for historical annualized relapse rates for subjects in the placebo group (N=47) and ravulizumab group (N=58). [Figure 76] 1 is a tabular description of propensity score-adjusted on-study assessed relapse rates for subjects in the placebo group (N=47) and ravulizumab group (N=58). [Figure 77] Tabular description of the statistical analysis of propensity score-adjusted on-study assessed relapse rates for subjects in the placebo group (N=47) and ravulizumab group (N=58). [Figure 78] 1 is a tabular description of the change in Hauser Ambulation Index (HAI) scores for subjects in the placebo group (N=47) and the ravulizumab group (N=58). [Figure 79] 1 is a tabular description of the clinical worsening of HAI scores for subjects in the placebo group (N=47) and the ravulizumab group (N=58). [Figure 80] 1 is a tabular description of odds ratio analysis of clinical change in HAI scores for subjects in the placebo group (N=47) and the ravulizumab group (N=58). [Figure 81] 1 is a tabular description of clinical worsening of HAI scores of subjects in the placebo group (N=47) and the ravulizumab group (N=58), analyzed based on propensity score. [Figure 82] 1 is a tabular description of the change in EQ-5D index scores for subjects in the placebo group (N=47) and the ravulizumab group (N=58). [Figure 83] 1 is a tabular description of the change in EQ-5D index score of subjects in the placebo group (N=47) and the ravulizumab group (N=58) analyzed based on the propensity score, calculated using ANCOVA and adjusted for the propensity score. [Figure 84] Tabular description of the change in EQ-5D VAS score of subjects in the placebo group (N=47) and the ravulizumab group (N=58), analyzed based on the propensity score. [Figure 85]Tabular description of the change in EQ-5D VAS score of subjects in the placebo group (N=47) and the ravulizumab group (N=58) analyzed based on the propensity score, calculated using ANCOVA and adjusted for the propensity score. [Figure 86] 1 is a tabular description of subjects in the placebo group (N=47) and the ravulizumab group (N=58) experiencing a clinically significant worsening in EDSS score. [Figure 87] Tabular description of the change from baseline in EDSS scores in the placebo group (N=47) and ravulizumab group (N=58). [Figure 88] Tabular description of the change from baseline in EDSS scores in the placebo group (N=47) and ravulizumab group (N=58). [Figure 89] Tabular description of the change from baseline in EDSS scores in the placebo group (N=47) and ravulizumab group (N=58). [Figure 90] Tabular description of the statistical analysis of the change from baseline in EDSS score in the placebo group (N=47) and ravulizumab group (N=58). [Figure 91] 1 is a tabular description of odds ratio analysis of clinical change in EDSS score for subjects in the placebo group (N=47) and the ravulizumab group (N=58). [Figure 92] Tabular description of odds ratio analysis of clinically important worsening in EDSS score for all subjects (N=105), analyzed based on propensity score. [Figure 93] Tabular description of statistical analysis of treatment duration and treatment compliance of subjects in the placebo group (N=47) and ravulizumab group (N=58). [Figure 94] 1 is a tabular description of compliance during the study of subjects in the placebo group (N=47) and the ravulizumab group (N=58). [Figure 95] Tabular description of emergent adverse events experienced by subjects in the placebo group (N=47) and ravulizumab group (N=58). [Figure 96] Tabular description of the analysis of emergent adverse events experienced by subjects in the placebo group (N=47) and ravulizumab group (N=58). [Figure 97] Tabular description of the analysis of emergent adverse events experienced by subjects in the placebo group (N=47) and ravulizumab group (N=58) by preferred term for the event occurring in ≥10% of subjects. [Figure 98] Tabular description of the analysis of emergent adverse infectious events experienced by subjects in the placebo (N=47) and ravulizumab (N=58) groups. SOC = System Organ Class; PT = Preferred Term. Adverse events are coded using the MedDRA Dictionary Version 25.0. Data for the placebo group were collected as part of the PREVENT trial, Study ECU-NMO-301. Treatment-emergent adverse events reported in the placebo group are included in the summary only if the start date of the event was equal to or less than the longest study duration in the ravulizumab group. TEAEs are AEs with start date on or after the first dose of study drug. Percentages are based on the total number of patients in the safety set in a particular treatment group. If a patient had multiple events for a particular SOC or PT, the patient is counted only once for that SOC or PT. SOCs are presented in alphabetical order. PTs are ordered by frequency in the ravulizumab column. Patient-years in treatment arm = sum of study years for all patients in treatment arm; rate per 100 PY = 100 × number of events / patient-year. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present disclosure provides methods of treating neuromyelitis optica spectrum disorder (NMOSD) in a subject in need thereof by administering an antibody that specifically binds complement component 5 (C5). In certain embodiments, the antibody that specifically binds C5 reduces the rate at which C5 is cleaved in vivo into C5a and C5b. In other embodiments, the antibody that specifically binds C5 binds to one or both of the C5a and / or C5b fragments. In any of these embodiments, the antibody that specifically binds C5 reduces the complement cascade at C5, thereby reducing the release of proinflammatory mediators and the formation of cytolytic pores.

[0015] In certain embodiments, the antibody that specifically binds to C5 is ravulizumab or a fragment thereof. Rabulizumab (also known as BNJ441, ALXN1210 or Ultomiris®) is an anti-C5 antibody that includes a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 14 and 11, respectively, or antigen-binding fragments and variants thereof. Rabulizumab is described in PCT / US2015 / 019225 and US9,079,949, the entire teachings of which are incorporated herein by reference. Rabulizumab 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 proinflammatory 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), which are essential for microbial opsonization and immune complex clearance.

[0016] definition As used herein, the term "subject" or "patient" refers to a human patient (e.g., a patient with neuromyelitis optica spectrum disorder (NMOSD)). As used herein, the terms "subject" and "patient" are interchangeable.

[0017] As used herein, the phrase "requiring chronic plasma exchange" to maintain clinical stability refers to the patient's regular use of plasma exchange therapy to manage muscle weakness at least every 3 months over the past 12 months.

[0018] As used herein, "effective treatment" refers to treatment that produces a beneficial effect (e.g., amelioration of at least one symptom of a disease or disorder). The beneficial effect can take the form of an improvement over baseline, i.e., an improvement over a measurement or observation made prior to the initiation of treatment according to the method. Effective treatment can refer to the alleviation of at least one symptom of NMOSD.

[0019] The term "effective amount" refers to an amount of an agent that provides a desired biological, therapeutic and / or prophylactic result. The result may be a reduction, amelioration, alleviation, reduction, delay and / or relief 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 an amount of an anti-C5 antibody or antigen-binding fragment thereof that has been clinically proven to reduce at least one symptom of NMOSD. An effective amount may be administered in one or more administrations.

[0020] As used herein, the terms "induction" and "induction phase" are used interchangeably and refer to the first phase of treatment in a clinical trial.

[0021] As used herein, the terms "maintenance" and "maintenance phase" are used interchangeably and refer to the second phase of treatment in a clinical trial. In certain embodiments, treatment is continued as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs. The maintenance phase of ravulizumab administration can last from 6 weeks to the lifespan of the subject. According to other embodiments, the maintenance phase lasts for 26-52, 26-78, 26-104, 26-130, 26-156, 26-182, 26-208 weeks or more. 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 more. In certain embodiments, the maintenance phase continues for the remainder of the subject's life.

[0022] In certain embodiments, the ravulizumab multiphase dosing regimen includes a third phase. This third phase is used when NMOSD patients must receive rescue therapy to maintain clinical stability and includes administering plasma exchange / plasmapheresis (PE / PP). In this phase after plasma exchange, one dose of ravulizumab is administered to replace the drug lost in plasma exchange / plasmapheresis. According to certain embodiments, if PE / PP rescue therapy is provided on a non-administration day, an additional study drug (or placebo) administration is required. In another embodiment, if PE / PP infusion is provided on an administration day, this must occur before administration of the study drug. In some embodiments, if PE / PP is administered at an unscheduled administration 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 at an unscheduled administration 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 boost dose may or may not vary depending on PE / PP. In other embodiments, if PE / PP is administered at the scheduled administration visit, the regular administration is followed 60 minutes after completion of PE / PP. In certain embodiments, no gap is required between the boost dose and the regular scheduled dose.

[0023] 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 about half of the most recent loading or maintenance dose of ravulizumab. In some embodiments, if the most recent loading dose was 2200 mg-3000 mg of ravulizumab, the additional dose is 1000-1500 mg of ravulizumab. In some embodiments, if the most recent loading dose was about 2400 mg of ravulizumab, the additional dose is about 1200 mg of ravulizumab. In some embodiments, if the most recent loading dose was 2400 mg of ravulizumab, the additional dose is 1200 mg of ravulizumab. In some embodiments, if the most recent loading dose was about 2700 mg of ravulizumab, the additional dose is about 1500 mg of ravulizumab. In some embodiments, if the most recent loading dose is 2700 mg of ravulizumab, the additional dose is 1500 mg of ravulizumab. In some embodiments, if the most recent loading dose is about 3000 mg of ravulizumab, the additional dose is about 1500 mg of ravulizumab. In some embodiments, if the most recent loading dose is 3000 mg of ravulizumab, the additional dose is about 1500 mg of ravulizumab. In some embodiments, if the most recent maintenance dose is about 3000 mg of ravulizumab, the additional dose is about 1500 mg of ravulizumab. In some embodiments, if the maximum maintenance loading dose is 3000 mg of ravulizumab, the additional dose is 1500 mg of ravulizumab. In some embodiments, if the most recent maintenance dose is about 3300 mg of ravulizumab, the additional dose is about 1800 mg of ravulizumab. In some embodiments, if the maximum maintenance loading dose is 3300 mg of ravulizumab, the booster dose is 1800 mg of ravulizumab. In some embodiments, if the most recent maintenance dose is about 3600 mg of ravulizumab, the booster dose is about 1800 mg of ravulizumab. In some embodiments, if the maximum maintenance loading dose is 3600 mg of ravulizumab, the booster dose is 1800 mg of ravulizumab.

[0024] 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 about 2400 mg, about 2700 mg, or about 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 titered based on body weight.

[0025] In some embodiments, patients weighing 40 kg or more but less than 60 kg are administered 2100-2700 mg, 2300-2500 mg, about 2400 mg, or 2400 mg of ravulizumab. In some embodiments, patients weighing 60 kg or more but less than 100 kg are administered 2400-3000 mg, 2600-2800 mg, about 2700 mg, or 2700 mg of ravulizumab. In some embodiments, patients weighing more than 100 kg are administered 2700-3300 mg, 2900-3100 mg, about 3000 mg, or 3000 mg of ravulizumab.

[0026] As used herein, the term "maintenance dose" or "maintenance phase" refers to a 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 titrated based on body weight.

[0027] In some embodiments, patients weighing 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 weighing 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 weighing more than 100 kg are administered 3400-3800 mg, 3500-3700 mg, about 3600 mg, or 3600 mg of ravulizumab.

[0028] As used herein, the term "serum trough level" refers to the lowest level at which a drug (e.g., an anti-C5 antibody or antigen-binding fragment thereof) or medication is present in the serum. In contrast, "peak serum level" refers to the highest level of drug in the serum. "Mean serum level" refers to the average level of drug in the serum over time.

[0029] In one embodiment, the described treatment regimen is sufficient to maintain a particular serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof. In one embodiment, for example, the treatment is for 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, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 8 maintains a serum trough concentration of anti-C5 antibody or antigen-binding fragment thereof of at least 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. In one embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or antigen-binding fragment thereof of at least 100 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or antigen-binding fragment thereof of at least 150 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or antigen-binding fragment thereof of at least 200 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at or above 250 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at or above 300 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at between 100 μg / mL and 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.

[0030] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered 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, 160 μg, 170 μg, 180 μg, 190 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg, 530 μg, 540 μg, 550 μg, 560 μg, 570 μg, 580 μg, 590 μg, 600 μg, 610 μg, 620 μg, 630 μg, 640 μg, 650 μg, 650 The patient is administered an amount and frequency to maintain 50μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg, 200μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, or 260μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain 50μg-250μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain 100μg-200μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains the patient at about 175 μg of antibody per milliliter of blood.

[0031] In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains a minimum free C5 concentration to obtain an effective response. 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 0.309-0.5 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.

[0032] The term "terminal complement inhibition" refers to inhibition of the later stages of the complement cascade. In one embodiment, terminal complement inhibition refers to the inhibition of the cleavage of complement component 5 ("C5") into C5a and C5b by C5 convertase.

[0033] The term "antibody" describes a polypeptide comprising at least one antibody-derived antigen-binding site (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 camelid 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 also 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, conjugation to a non-antibody moiety). An antibody can comprise one or more variant amino acids (compared to a naturally occurring antibody), which, for example, alters the properties (e.g., functional properties) of the antibody. Many such modifications are known in the art which affect the half-life, effector functions and / or immune response to the antibody in a patient. The term antibody also includes artificial or engineered polypeptide constructs which contain at least one antibody-derived antigen-binding site.

[0034] C5-binding protein The term "antibody" describes a polypeptide comprising at least one antibody-derived antigen-binding site (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 camelid 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 also be of any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD or IgE. An antibody can be a naturally occurring antibody or an antibody modified by protein engineering techniques (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). An antibody can comprise one or more variant amino acids (compared to a naturally occurring antibody), which, for example, alters the properties (e.g., functional properties) of the antibody. Such modifications, which affect the half-life, effector functions 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 contain at least one antibody-derived antigen-binding site.

[0035] The anti-C5 antibodies described herein bind to complement component C5 (e.g., human C5) and inhibit cleavage of C5 into 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, art-recognized anti-C5 antibodies can be used. Antibodies that compete with any of these art-recognized antibodies for binding to C5 can also be used.

[0036] Eculizumab (also known as Soliris®) is an anti-C5 antibody comprising a heavy chain and a light chain having the sequences set forth in SEQ ID NOs: 10 and 11, respectively, or antigen-binding fragments and variants thereof. Eculizumab is described in PCT / US2007 / 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 set forth in SEQ ID NO: 7, and the CDR1, CDR2 and CDR3 domains of the VL region of eculizumab having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 1, 2 and 3, respectively, and the light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5 and 6, respectively. In another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences set forth in SEQ ID NOs: 7 and 8, respectively.

[0037] Ravulizumab (also known as BNJ441, ALXN1210, or Ultomiris®) is an anti-C5 antibody comprising a heavy chain and a light chain having the sequences set forth in SEQ ID NOs: 14 and 11, respectively, or antigen-binding fragments and variants thereof. Ravulizumab is described in PCT / US2015 / 019225 and U.S. Pat. Appl. 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 proinflammatory 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), which are essential for microbial opsonization and immune complex clearance.

[0038] 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 set forth in SEQ ID NO: 12 and the CDR1, CDR2 and CDR3 domains of the VL region of ravulizumab having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and the light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5 and 6, respectively. In another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

[0039] Another exemplary anti-C5 antibody is the antibody BNJ421, or antigen-binding fragments and variants thereof, comprising heavy and light chains having the sequences set forth in SEQ ID NOs: 20 and 11, respectively. BNJ421 (also known as ALXN1211) is described in PCT / US2015 / 019225 and U.S. Pat. No. 9,079,949, the teachings of which are incorporated herein by reference.

[0040] 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 set forth in SEQ ID NO: 12 and the CDR1, CDR2 and CDR3 domains of the VL region of BNJ421 having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and the light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5 and 6, respectively. In another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

[0041] The exact boundaries of CDRs are defined differently according to different methods. In some embodiments, the locations of the CDRs or framework regions in a light or heavy chain variable domain may be as defined by Kabat et al. [(1991) "Sequences of Proteins of Immunological Interest." NIH Publication No. 91-3242, USDepartment of Health and Human Services, Bethesda, MD]. In such cases, the CDRs may be referred to as "Kabat CDRs" (e.g., "Kabat LCDR2" or "Kabat HCDR1"). In some embodiments, the locations of the CDRs of a light or heavy chain variable region may be as defined by Chothia et al., Nature, 342:877-83, 1989. Thus, these regions may be referred to as "Chothia CDRs" (e.g., "Chothia LCDR2" or "Chothia HCDR3"). In some embodiments, the locations of the CDRs of light and heavy chain variable regions may be as defined by the Kabat-Chothia combined definition. In such embodiments, these regions can be referred to as “Kabat-Chothia CDR combinations.” Thomas et al. (Mol. Immunol., 33:1389-401, 1996) exemplify the identification of CDR boundaries according to the Kabat and Chothia definitions.

[0042] 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.

[0043] Another exemplary anti-C5 antibody is the 8110 antibody, 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.

[0044] Another exemplary anti-C5 antibody is the 305LO5 antibody described in US Patent 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.

[0045] 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.

[0046] Another exemplary anti-C5 antibody is the H4H12166PP antibody described in PCT / US2017 / 037226 and US2017 / 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.

[0047] In one embodiment, a patient is treated with eculizumab and then switched to treatment with 7086, 8110, 305LO5, SKY59, H4H12166PP, or ravulizumab. In another embodiment, a patient is switched from an anti-C5 antibody (e.g., eculizumab, 7086, 8110, 305LO5, SKY59, or H4H12166PP) to another anti-C5 antibody (e.g., ravulizumab) during the course of treatment. In a particular embodiment, a patient is switched from eculizumab to ravulizumab during the course of treatment.

[0048] In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain CDR1 comprising or consisting of the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19). In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain CDR2 comprising or consisting of the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO: 18). In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain CDR2 comprising or consisting of the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGEILPGSGHTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSSPNWYFDVWGQGTLVTVSS (SEQ ID NO: 12) The heavy chain variable region comprises:

[0049] In some embodiments, the anti-C5 antibody described herein has the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIK (SEQ ID NO: 8) The light chain variable region comprises:

[0050] The anti-C5 antibodies described herein, in some embodiments, may comprise a modified human Fc constant region that binds to the human neonatal Fc receptor (FcRn) with higher affinity than the native human Fc constant region from which it is derived. For example, the Fc constant region may comprise 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 it is derived. The substitutions may 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 exemplified in the working examples (PCT / US2015 / 019225 and U.S. Pat. No. 9,079,949, the disclosures of each of which are incorporated herein by reference in their entireties).

[0051] Substitutions that enhance the binding affinity of antibody Fc constant regions to 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 M428L or T250Q / M428L substitutions described by Petkova, S. et al. (Int. Immunol., 18:1759-69, 2006) Additional substitution pairs have also been described: P257I / Q311I, P257I / N434H, and D376V / N434H (Datta-Mannan, A. et al., J. Biol. Chem., 282:1709-17, 2007, the disclosure of which is incorporated herein by reference in its entirety).

[0052] 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.

[0053] In some embodiments, the modified Fc constant region comprises no more than 30 (e.g., no more than 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) 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 a methionine at position 428 and an asparagine at position 434, each in EU numbering. In some embodiments, the modified Fc constant region comprises a 428L / 434S double substitution, for example, as described in US Pat. No. 8,088,376.

[0054] In some embodiments, the exact positions of these mutations may be shifted from the native human Fc constant region positions due to antibody engineering. The 428L / 434S double substitution, for example, when used in an IgG2 / 4 chimeric Fc, may correspond to 429L and 435S as in the M429L and N435S variant found in BNJ441 (ravulizumab) and described in U.S. Patent No. 9,079,949, the disclosure of which is incorporated herein by reference in its entirety.

[0055] In some embodiments, the modified constant region comprises a substitution at amino acid position 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 a 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 0; 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 (all in EU numbering).

[0056] Suitable anti-C5 antibodies for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 14 and / or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11. Alternatively, suitable anti-C5 antibodies for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 20 and / or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11.

[0057] 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).

[0058] In another embodiment, the K of an antibody against C5 at pH 6.0 at 25° C. D ) / (K of antibody against C5 at pH 7.4 at 25°C D )] is greater than 21 (e.g., 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, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 700, 750, 800, 850, 900, 950, 1000, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 0, 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 greater).

[0059] Methods for determining whether an antibody binds to a protein antigen and / or the affinity with which an antibody binds to a protein antigen are known in the art. For example, binding of an antibody to a protein antigen can be detected and / or quantified using a variety of techniques, such as, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) methods (e.g., the BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ) or enzyme-linked immunosorbent assay (ELISA) (Benny KC 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). Furthermore, methods for measuring affinity (eg, dissociation and association constants) are described in the working examples.

[0060] As used herein, the term "k a " refers to the rate constant for the association of an antibody to an antigen. d " refers to the rate constant for dissociation of an antibody from the antibody / antigen complex. D " refers to the equilibrium dissociation constant of an antibody-antigen interaction. The equilibrium dissociation constant is the ratio of the kinetic rate constants, k D =K a / K d Such determinations are preferably measured at 25° C. or 37° C. (see working examples). For example, the kinetics of antibody binding to human C5 can be determined at pH 8.0, 7.4, 7.0, 6.5 and 6.0 by surface plasmon resonance (SPR) on a BIAcore 3000 instrument, immobilizing the antibody using anti-Fc capture.

[0061] In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof blocks the production or activity of C5a and / or C5b active fragments of a C5 protein (e.g., a human C5 protein). By this blocking effect, the antibody inhibits, for example, the proinflammatory effects of C5a and the generation of the C5b-9 membrane attack complex (MAC) at the cell surface.

[0062] 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 cytolytic ability of complement in a subject's body fluid. Such reduction in the cytolytic ability of complement present in a body fluid can be measured by methods known in the art, such as, for example, a conventional hemolytic assay, such as the hemolytic assay described in Kabat and Mayer (eds.), "Experimental Immunochemistry, 2nd Edition," 135-240, Springfield, IL, CC Thomas (1961), pp. 135-139, or a conventional modification of that assay, such as chicken erythrocyte hemolysis (Hillmen, P. et al., N. Engl. J. Med., 350:552-9, 2004). Methods for determining whether a candidate compound inhibits the cleavage of human C5 into 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 body fluids can be measured, for example, by methods known in the art. For C5b, a hemolytic assay or an assay for soluble C5b-9 can be used, as discussed herein. Other assays known in the art can also be used. These or other suitable types of assays can be used to screen candidate agents capable of inhibiting human complement component C5.

[0063] Immunological techniques, such as, but not limited to, ELISA, can be used to measure the protein concentration of C5 and / or its split products to determine the ability of anti-C5 antibodies or antigen-binding fragments thereof to inhibit the conversion of C5 to 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 terminal complement.

[0064] In some embodiments, C5 activity or its inhibition is quantified using the CH50eq assay. The CH50eq assay is a method for measuring total classical complement activity in serum. This test is a lytic assay that uses antibody-sensitized red blood cells as an activator of the classical complement pathway and uses various dilutions of test serum to determine the amount required to give 50% lysis (CH50). Percent hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measurement of terminal complement complex (TCC) formation, since the TCC itself is directly involved in the hemolysis being measured.

[0065] For example, inhibition relative to terminal complement activity includes a decrease in terminal complement activity of at least 5% (e.g., at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60%) as compared to the effect of a control antibody (or antigen-binding fragment thereof) under similar conditions and at equimolar concentration. Substantial inhibition, as used herein, refers to an inhibition of a given activity (e.g., terminal complement activity) of at least 40% (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% or more). 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.

[0066] 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 39-48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, the anti-C5 antibodies or antigen-binding fragments thereof described herein have 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, e.g., as measured in one of the mouse model systems described in the Working Examples (e.g., a C5-deficient / NOD / scid mouse or an hFcRn transgenic mouse model system).

[0067] In one embodiment, the antibody competes for binding to and / or binds to the same epitope on C5 as the antibodies described herein. The term "binds to the same epitope" with respect to two or more antibodies means that the antibodies bind to the same portion of amino acid residues as determined by a given method. Techniques for determining whether an antibody binds to the "same epitope on C5" as the antibodies described herein include epitope mapping methods such as, for example, x-ray analysis of crystals of antigen:antibody complexes that provide atomic resolution of the epitope and hydrogen / deuterium exchange mass spectrometry (HDX-MS). Other methods monitor the binding of antibodies to peptide antigen fragments or mutants of antigens, where loss of binding due to modification of amino acid residues in the antigen sequence is often considered indicative of epitope components. Additionally, computational combinatorial methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from combinatorial phage display peptide libraries. Antibodies with the same VH and VL or the same CDR1, 2 and 3 sequences are predicted to bind to the same epitope.

[0068] An antibody that "competes with another antibody for binding to a target" refers to an antibody that inhibits (partially or completely) the binding of the other antibody to a target. Whether two antibodies compete with each other for binding to a target, i.e., whether and to what extent one antibody inhibits the binding of the other antibody to a target, can be determined using known competition experiments. In certain embodiments, an antibody competes with and inhibits the binding of another antibody to a 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 evidenced by steric hindrance).

[0069] The anti-C5 antibodies or antigen-binding fragments thereof described herein used in the methods 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 a desired antigen are immortalized, typically by fusion with a myeloma cell (Koehler, G. & Milstein, C., Eur. J. Immunol., 6:511-9, 1976). Alternative methods of immortalization include transformation with Epstein-Barr virus, oncogenes or retroviruses or other methods well known in the art. Colonies arising from a single immortalized cell are screened for production of antibodies of the desired specificity and affinity to 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 binding fragments thereof can be isolated by screening DNA libraries from human B cells (Huse, W. et al., Science, 246:1275-81, 1989).

[0070] composition Pharmaceutical compositions comprising ravulizumab alone or in combination with a prophylactic agent, a therapeutic agent and / or a pharmaceutically acceptable carrier are provided. Pharmaceutical compositions comprising ravulizumab provided herein are for use in, but not limited to, diagnosis, detection or monitoring of a disorder, prevention, treatment, management or amelioration of a disorder or one or more symptoms thereof, and / or research. The formulation of pharmaceutical compositions alone or in combination with a prophylactic agent, a therapeutic agent and / or a pharmaceutically acceptable carrier is known to those skilled in the art.

[0071] In one embodiment, the composition comprises an anti-C5 antibody comprising CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO: 8. In another embodiment, the anti-C5 antibody comprises heavy and light chains having the sequences set forth in SEQ ID NOs: 14 and 11, respectively.

[0072] The composition can be formulated as a pharmaceutical solution for administration to a subject, for example, for the treatment or prevention of NMOSD. Pharmaceutical compositions generally include a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to and includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The composition can include pharmaceutically acceptable salts, such as acid or base addition salts, sugars, carbohydrates, polyols, and / or osmotic adjusters.

[0073] The composition can be formulated according to standard methods. Pharmaceutical formulation is a well-established technique and is 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, for example, in 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 temperatures below 0°C (e.g., -20°C or -80°C). In some embodiments, the compositions may be formulated for storage at 2-8° C. (e.g., 4° C.) for up to 2 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 at 2-8° C. (e.g., 4° C.) for at least 1 year.

[0074] Pharmaceutical compositions can be in a variety of 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, compositions, including compositions intended for systemic or local delivery, can be in the form of an injectable or infusible solution. Compositions can be formulated for administration by parenteral modes (e.g., intravenous, subcutaneous, intraperitoneal or intramuscular injection). As used herein, "parenteral administration," "administered parenterally," and other grammatically equivalent phrases refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid, and intrasternal injection and infusion. In one embodiment, the antibody is formulated for intravenous administration.

[0075] An exemplary non-limiting range for a therapeutically or prophylactically effective amount of ravulizumab or other anti-C5 antibodies, such as eculizumab, BNJ 421, 7086, 8110, SKY59 and H4H12166PP provided herein, is 600-5000 mg, e.g., 900-2000 mg. It should be noted that dosage values ​​may vary depending on the type and severity of the condition to be alleviated. It should be further understood that for any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed methods.

[0076] How to treat 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, a primate, such as a human, a rodent, a lagomorph, a camelid, an ungulate, a dog, and a cat. In certain embodiments, the subject or patient suffering from NMOSD described herein is a human.

[0077] NMOSD is characterized by a relapsing disease course, with gradual accumulation of significant neurological impairment from which recovery may be poor. Neuromyelitis optica (NMO), also known as Devic's disease or Devic's syndrome, is a subset of NMOSD and is a rare and severe autoimmune inflammatory disease of the central nervous system (CNS) that primarily affects the optic nerves and spinal cord, often resulting in blindness, mono-, bi-, or quadriplegia, and respiratory failure.

[0078] In some embodiments, NMO is characterized by NMO-IgG antibodies against aquaporin 4 (anti-AQP4). In some embodiments, a subset of NMO patients has anti-AQP4 + In another embodiment, a subset of NMO patients is + (myelin oligodendrocyte glycoprotein).

[0079] In some embodiments, AQP4 autoantibodies are found in patients with NMO-like symptoms who do not meet the clinical criteria for a diagnosis of NMO, which in some embodiments is relapsing and simultaneous optic nerve and spinal cord inflammation.

[0080] In some embodiments, NMOSD encompasses limited forms of Devic's disease, such as single or relapsing events of longitudinally widespread myelitis and bilateral simultaneous or relapsing optic neuritis. In some embodiments, NMOSD encompasses Asian optic-spinal MS (OSMS) or AQP4 +In some embodiments, NMOSD further includes longitudinally widespread myelitis or optic neuritis associated with systemic autoimmune disease and optic neuritis or myelitis associated with lesions in specific brain regions such as the hypothalamus, periventricular nucleus, and brainstem.

[0081] In certain embodiments, treating NMOSD includes ameliorating or improving one or more symptoms associated with NMOSD, including vision impairment, decreased vision, visual field defects, loss of color vision, spinal cord dysfunction, muscle weakness, decreased sensation, and loss of bladder or bowel control.

[0082] In other embodiments, treating NMOSD includes improving clinical markers of NMOSD progression, including, for example, time to relapse, annualized relapse rate (ARR), Expanded Disability Scale Score (EDSS), modified Rankin Scale (mRS), quality of life (ED-5D), Hauser Ambulatory Index (HAI), change in visual acuity using the Snellen chart, and severity of relapse using the Optic Myelopathy Score (OSIS).

[0083] NMOSD relapse is evidenced by symptoms of NMOSD occurring in subjects whose symptoms have been successfully cured previously. Relapse is indicated by the onset or worsening of symptoms related to vision or sensation. Vision changes associated with NMOSD relapse include rapid onset of eye pain, blurred vision, colors that do not look right, loss of vision, spots or dots in vision, flashing or blinking in vision, difficulty focusing, difficulty reading, and a feeling that the field of vision seems inaccurate. Sensory changes associated with NMOSD relapse include pain, tingling, numbness, arms, legs, or face seeming to fall asleep, loss of sense of position in space, loss of sensation in extremities, slight touch hurts, clothing or bed sheets cause pain, and the subject is unable to detect injury to the subject. Annualized relapse rate (ARR) is the average number of relapses per year.

[0084] In certain embodiments, the subject treated for NMOSD has 3 or more relapses in the 24 months prior to administering ravulizumab. In other embodiments, the subject treated for NMOSD has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more relapses in the 24 months prior to administering ravulizumab. In certain embodiments, the subject treated for NMOSD has an ARR of 1.0 or more in the 24 months prior to administering ravulizumab. In other embodiments, the subject treated for NMOSD has an ARR of at least 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 25, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5.7.0 or more in the 24 months prior to administering ravulizumab.

[0085] Disability can be assessed based on EDSS scores comparing the change from baseline in the two treatment groups. The Kurtzke Expanded Disability Scale score (EDSS) is a method to quantify disability in multiple sclerosis. The EDSS replaced the previous Disability Status Scale used in multiple sclerosis (MS). The EDSS quantifies disability into eight functional systems (FS) and allows neurologists to assign a Functional System Score (FSS) to each of these. The functional systems are pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral, and miscellaneous. 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 impairment. Disability is also assessed based on mRS scores comparing the change from baseline in the two treatment groups. The mRS scores are assessed by the treating physician at time points specified in the study protocol.

[0086] In certain embodiments, the subject treated for NMOSD has an EDSS score of at least 1.0 in the 24 months prior to administration of ravulizumab. In other embodiments, the subject 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 in the 24 months prior to administration of ravulizumab. In other embodiments, the subject treated for NMOSD has an EDSS score of 1.0 to 7.0 in the 24 months prior to administration of ravulizumab. In certain embodiments, the subject treated for NMOSD has an HAI score of at least 2.0 in the 24 months prior to administration of ravulizumab. In other embodiments, a subject 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 in the 24 months prior to administration of ravulizumab. In other embodiments, a subject treated for NMOSD has an HAI score of 0.0 to 8.0 in the 24 months prior to administration of ravulizumab. In certain embodiments, a subject treated for NMOSD has an mRS score of at least 0.0 in the 24 months prior to administration of ravulizumab. In other embodiments, a subject treated for NMOSD has an mRS score of at least 0.0, 1.0, 2.0, 3.0, 4.0, 5.0, or more in the 24 months prior to administration of ravulizumab. In other embodiments, a subject treated for NMOSD has an mRS score of 0.0 to 2.5 in the 24 months prior to administration of ravulizumab.

[0087] Quality of life (QOL) can be assessed by the patient's self-assessment questionnaires EQ-5D and SF-36 at time points specified in the clinical trial protocol. A sample questionnaire for the EQ-5D is shown in Figure 5. The EUROQOL (EQ-5D) is a reliable, validated survey of health status in five domains completed by the subject: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each domain has three levels: level 1 (no problems), level 2 (problems), and level 3 (extreme problems). The EQ-5D is administered at Day 1, Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, and 104 or ET (Visits 2, 6, 8, 10, 16, 22, 28, 34, 40, 46, 52, and 56 or ET). A clinically meaningful improvement in the patient's EQ-5D is reflected as an increase in score after 26 weeks of treatment. A sample SF-36 questionnaire is shown in Figure 5 .

[0088] Ambulatory function can be evaluated, for example, by the HAI scale. Visual acuity can be evaluated, for example, using the Snellen chart. Severity of relapse can be evaluated, for example, using the Optic Spinal Cord Injury Score (OSIS). The OSIS score is summarized in Table 1.

[0089] According to certain embodiments, subjects administered ravulizumab show increased time interval between relapses of NMOSD.In certain embodiments, subjects have a pre-relapse period of more than 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 period before recurrence 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 period before recurrence is greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years. In other embodiments, the period before recurrence is 6-52 weeks, 6-26 weeks, 6-10 weeks, 26-52 weeks, 1-2 years, 1-5 years, 5-10 years, or no recurrence occurs during the subject's lifetime. In other embodiments, the time period before recurrence is greater than 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, 102 months or more.

[0090] According to certain embodiments, the course of treatment with ULTOMIRIS 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 or more weeks. 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.

[0091] According to certain embodiments, during the course of treatment, one or more symptoms or scores associated with NMOSD improve during the course of treatment and are maintained at an improved level throughout treatment. EDSS can improve after, for example, 26 weeks of treatment with a therapeutic antibody that specifically binds to C5, and then remain at an improved level throughout treatment, which can be, for example, 52 weeks of treatment with a therapeutic antibody that specifically binds to C5. One example of a therapeutic antibody that binds to C5 is ravulizumab.

[0092] In certain embodiments, the first signs of improvement occur by 26 weeks of treatment with a therapeutic antibody that specifically binds C5. According to other embodiments, the first signs of improvement occur at 1-26, 26-52, 52-78, 78-104, 104-130, 130-156, 156-182, or 182-208 weeks of treatment with a therapeutic antibody that specifically binds C5. In other embodiments, the first signs of improvement occur at 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 weeks.

[0093] According to certain embodiments, the initial signs of improvement are maintained for several weeks during treatment with a binding protein that specifically binds 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, the 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, if the first sign of improvement is maintained, this means that the metric for the treatment of NMOSD does not fall below the value of the first sign of improvement. The metric can continue to improve, which is still defined as the maintenance of the first sign of improvement.

[0094] In one embodiment, the anti-C5 antibody (e.g., ravulizumab) or antigen-binding fragment thereof is administered once on day 1 of a dosing cycle, once on day 15 of a dosing cycle, and every 8 weeks thereafter. In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered every 8 weeks after the dosing cycle for an extended period of up to 2 years (e.g., at a dose of 3000 mg, 3300 mg, or 3600 mg).

[0095] In another embodiment, the anti-C5 antibody (e.g., ravulizumab) or antigen-binding fragment thereof is administered for one or more administration cycles. In one embodiment, the administration 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 for the life of the human patient.

[0096] In another embodiment, a method of treating a human patient with NMOSD is provided, the method comprising administering to the patient during a dosing cycle an effective amount of an anti-C5 antibody (e.g., ravulizumab) or antigen-binding fragment thereof comprising the CDR1, CDR2 and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and the 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 is The pieces are administered (a) once on day 1 of a dosing cycle at a dose of 2400 mg to patients weighing ≥ 40 to < 60 kg, 2700 mg to patients weighing ≥ 60 to < 100 kg, or 3000 mg to patients weighing ≥ 100 kg; and (b) on day 15 of a dosing cycle and every 8 weeks thereafter at a dose of 3000 mg to patients weighing ≥ 40 to < 60 kg, 3300 mg to patients weighing ≥ 60 to < 100 kg, or 3600 mg to patients weighing ≥ 100 kg.

[0097] In another embodiment, a method of treating a human patient with NMOSD is provided, the method comprising administering to the patient during a dosing 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 set forth in SEQ ID NOs: 19, 18, and 3, respectively, CDR1, CDR2, and CDR3 light chain sequences set forth 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), The CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at 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 a dosing cycle at a dose of 2400 mg to patients weighing ≧40 to <60 kg, 2700 mg to patients weighing ≧60 to <100 kg, or 3000 mg to patients weighing ≧100 kg; and (b) on day 15 of a dosing cycle and every 8 weeks thereafter at a dose of 3000 mg to patients weighing ≧40 to <60 kg, 3300 mg to patients weighing ≧60 to <100 kg, or 3600 mg to patients weighing ≧100 kg.

[0098] In another embodiment, the anti-C5 antibody (e.g., ravulizumab) or antigen-binding fragment thereof is administered to a patient weighing ≧40 to <60 kg at: (a) a dose of 2400 mg once on day 1 of a dosing cycle; and (b) a dose of 3000 mg on day 15 of a dosing cycle and every 8 weeks thereafter.

[0099] In another embodiment, the anti-C5 antibody (e.g., ravulizumab) or antigen-binding fragment thereof is administered to a patient weighing ≧60 to <100 kg at: (a) a dose of 2700 mg once on day 1 of a dosing cycle; and (b) a dose of 3300 mg on day 15 of a dosing cycle and every 8 weeks thereafter.

[0100] In another embodiment, the anti-C5 antibody (e.g., ravulizumab) or antigen-binding fragment thereof is administered to a patient weighing ≧100 kg at: (a) a dose of 3000 mg once on day 1 of a dosing cycle; and (b) a dose of 3600 mg on day 15 of a dosing cycle and every 8 weeks thereafter.

[0101] In another embodiment, the patient switches from receiving 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 is provided for treating a human patient with a complement-related disorder (e.g., NMOSD, e.g., NMO) being treated with eculizumab, comprising stopping treatment with eculizumab and switching the patient to treatment with an alternative complement inhibitor (e.g., ravulizumab). In another embodiment, a method is provided for treating a human patient with a complement-related disorder being treated with ravulizumab, comprising stopping treatment with ravulizumab and switching the patient to treatment with an alternative complement inhibitor.

[0102] Exemplary alternative complement inhibitors include, but are not limited to, antibodies or antigen-binding fragments thereof, small molecules, polypeptides, polypeptide analogs, peptidomimetics, siRNAs, 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 anaphylatoxic activity associated with C5a and / or the assembly of 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.

[0103] In another embodiment, a method is provided for treating a human patient having a complement-associated disorder who is being treated with eculizumab, the method comprising discontinuing treatment with eculizumab and switching the patient to treatment with an alternative anti-C5 antibody.In another embodiment, a method is provided for treating a human patient having a complement-associated disorder who is being treated with ravulizumab, the method comprising discontinuing treatment with ravulizumab and switching the patient to treatment with an alternative anti-C5 antibody.

[0104] Exemplary alternative anti-C5 antibodies include (i) eculizumab, (ii) an antibody or antigen-binding fragment thereof comprising a heavy chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs:21, 22 and 23, respectively, and a 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 a heavy chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs:29, 30 and 31, respectively, and a 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 NO: 37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NO: 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.

[0105] In another embodiment, the patient is treated with ravulizumab and then switched to treatment with 7086, 8110, 305LO5, SKY59, H4H12166PP, or eculizumab. In another embodiment, the patient is switched from an anti-C5 antibody (e.g., eculizumab, 7086, 8110, 305LO5, SKY59, or H4H12166PP) to another anti-C5 antibody (e.g., ravulizumab) during the course of treatment. In a particular embodiment, the patient is switched from eculizumab to ravulizumab during the course of treatment.

[0106] In another aspect, the described treatment regimen is sufficient to maintain a particular serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof. In one embodiment, for example, the treatment is for 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, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 8 maintains a serum trough concentration of anti-C5 antibody or antigen-binding fragment thereof of at least 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. In one embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or antigen-binding fragment thereof of at least 100 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or antigen-binding fragment thereof of at least 150 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or antigen-binding fragment thereof of at least 200 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at or above 250 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at or above 300 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at between 100 μg / mL and 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.

[0107] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered 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, 160 μg, 170 μg, 180 μg, 190 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg, 530 μg, 540 μg, 550 μg, 560 μg, 570 μg, 580 μg, 590 μg, 600 μg, 610 μg, 620 μg, 630 μg, 640 μg, 650 μg, 650 The patient is administered an amount and frequency to maintain 50μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg, 200μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, or 260μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain 50μg-250μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain 100μg-200μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains the patient at about 175 μg of antibody per milliliter of blood.

[0108] In one embodiment, the anti-C5 antibody is administered (or is for administration) according to a particular clinical dosing regimen (eg, at a particular dose and / or according to a particular dosing schedule).

[0109] In another embodiment, the dose of anti-C5 antibody is based on the patient's weight. In one embodiment, the dose of anti-C5 antibody is 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, 950mg, 975mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400mg, 25 00mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg, 42 59 00mg,6000mg,6100mg,6200mg,6300mg,6400mg,6500mg,6600mg,6700mg,6800mg,6900mg,7000mg,7100mg,7200mg,7300mg,7400mg,7500mg,76 00mg, 7700mg, 7800mg, 7900mg, 8000mg, 8100mg, 8200mg, 8300mg, 8400mg, 8500mg, 8600mg, 8700mg, 8800mg, 8900mg, 9000mg, 9100mg, 9200mg, 93 00mg, 9400mg, 9500mg, 9600mg, 9700mg, 9800mg, 9900mg, 10000mg, 10100mg, 10200mg, 10300mg, 10400mg, 10500mg, 10600mg, 10700mg, 10800mg,10,900 mg or 11,000 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧40 to <60 kg.

[0110] In another embodiment, the amount of any of the following may be selected from the group consisting of 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, 97 5mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400mg, 2500mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 4400m g, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000mg, 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6100mg, 62 00mg, 6300mg, 6400mg, 6500mg, 6600mg, 6700mg, 6800mg, 6900mg, 7000mg, 7100mg, 7200mg, 7300mg, 7400mg, 7500mg, 7600mg, 7700mg, 7800mg, 7900mg , 8000mg, 8100mg, 8200mg, 8300mg, 8400mg, 8500mg, 8600mg, 8700mg, 8800mg, 8900mg, 9000mg, 9100mg, 9200mg, 9300mg, 9400mg, 9500mg, 9600mg, 9700mg, 9800mg, 9900mg, 10000mg, 10100mg, 10200mg, 10300mg, 10400mg, 10500mg, 10600mg, 10700mg, 10800mg, 10900mg or 11000mg of an anti-C5 antibody or antigen-binding fragment thereof,It is administered to patients weighing ≥ 60 to < 100 kg.

[0111] In another embodiment, the amount of any of the following may be selected from the group consisting of 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, mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400mg, 2500mg, 2600mg, 2 700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 4400mg ,4500mg,4600mg,4700mg,4800mg,4900mg,5000mg,5100mg,5200mg,5300mg,5400mg,5500mg,5600mg,5700mg,5800mg,5900mg,6000mg,6100mg,620 8 [000mg], 8100mg, 8200mg, 8300mg, 8400mg, 8500mg, 8600mg, 8700mg, 8800mg, 8900mg, 9000mg, 9100mg, 9200mg, 9300mg, 9400mg, 9500mg, 9600mg, 9700mg, 9800mg, 9900mg, 10000mg, 10100mg, 10200mg, 10300mg, 10400mg, 10500mg, 10600mg, 10700mg, 10800mg, 10900mg or 11000mg are administered to patients weighing ≧100kg.In certain embodiments, dosage regimens are adjusted to provide the optimum desired response (eg, an efficacious response).

[0112] In another embodiment, the anti-C5 antibody is administered in a milligram per kilogram (mg / kg) dose. For example, in one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered in a dose of 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, 5.6 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.25 mg / kg, 6.4 mg / kg, 6.6 mg / kg, 6.8 mg / kg, 7.0 mg / kg, 7.25 mg / kg, 7.4 ... kg, 5.50mg / kg, 5.75mg / kg, 6.0mg / kg, 6.25mg / kg, 6.50mg / kg, 6.75mg / kg, 7.0mg / kg, 7.25mg / kg, 7.50mg / kg, 7.75mg / kg, 8.0mg / kg, 8.25mg / kg, 8.50mg / kg, 8.75mg / kg, 9.0mg / kg, 9.25mg / kg, 9.50mg / kg, 9.75mg / kg, 10.0mg / kg, 11.25mg / kg, 11.50mg / kg, 11.75mg / kg, 12.0mg / kg, 12.25mg / kg, 12.50mg / kg, 12.75mg / kg, 13.0mg / kg, 13.25mg / kg, 13.50mg / kg, 13.75mg / kg, 14.0mg / kg, 14.25mg / kg, 14.50mg / kg, 14.75mg / kg, 15.0mg / k g, 15.25mg / kg, 15.50mg / kg, 15.75mg / kg, 16.0mg / kg, 16.25mg / kg, 16.50mg / kg, 16.75mg / kg, 17.0mg / kg, 17.25mg / kg, 17.50mg / kg, 17.75mg / kg , 18.0mg / kg, 18.25mg / kg, 18.50mg / kg, 18.75mg / kg, 19.0mg / kg, 19.25mg / kg, 19.50mg / kg, 19.75mg / kg, 20.0mg / kg, 20.25mg / kg, 20.50mg / kg, 2 0.75mg / kg, 21.0mg / kg, 21.25mg / kg, 21.50mg / kg, 21.75mg / kg, 22.0mg / kg, 22.25mg / kg, 22.50mg / kg, 22.75mg / kg, 23.0mg / kg, 23.25mg / kg, 23.It is administered at doses of 50mg / kg, 23.75mg / kg, 24.0mg / kg, 24.25mg / kg, 24.50mg / kg, 24.75mg / kg or 25.0mg / kg.

[0113] 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 at a loading dose on day 1, followed by a different maintenance dose on day 15 and every eight weeks thereafter.

[0114] In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains a minimum free C5 concentration to obtain an effective response. 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.

[0115] In some embodiments, patients treated according to the methods described herein have been vaccinated against meningococcal infection within three years prior to or at the start of the investigational drug. In one embodiment, patients who begin treatment less than two weeks after receiving a meningococcal vaccine receive appropriate prophylactic antibiotic treatment for up to two weeks after vaccination. In another embodiment, patients treated according to the methods described herein are vaccinated against meningococcal serotypes A, C, Y, W135 and / or B.

[0116] In light of the present disclosure, conventional molecular biology, microbiology, and recombinant DNA techniques are within the skill of the art and are fully explained in the literature. For example, Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (herein referred to as "Sambrook et al., 1989"); DNA Cloning: A Practical Approach, Volumes I and II (DNGlover ed.1985); Oligonucleotide Synthesis (MJGait ed.1984);Nucleic Acid Hybridization[BDHames&S.J.Higgins eds.(1985)];Transcription And Translation[BDHames&S.J.Higgins,eds.(1984)];Animal Cell Culture[RIFreshney,ed.(1986)];Immobilized Cells And Enzymes[IRL Press,(1986)];B.Perbal,A Practical Guide To Molecular Cloning(1984);FMAusubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994). Each of these references is incorporated herein by reference in its entirety.

[0117] Unless otherwise specified, sequence identity / similarity values ​​provided herein refer to values ​​obtained using the BLAST 2.0 suite of programs using default parameters (Altschul, S. et al., Nucleic Acids Res., 25:3389-402, 1997), which is incorporated herein by reference in its entirety.

[0118] As used herein, "sequence identity" or "identity" in the context of two polypeptide sequences includes reference to residues in the two sequences that are the same when aligned for maximum correspondence over a particular comparison window. When percentages of sequence identity are used in the context of proteins, it is recognized that residue positions that are not identical often differ by conservative amino acid substitutions, in which amino acid residues are replaced with other amino acid residues that have similar chemical properties (e.g., charge or hydrophobicity), and thus do not change the functional properties of the molecule. When sequences differ in conservative substitutions, the percent sequence identity may 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 substitutions rather than complete mismatches, thereby increasing the percentage of sequence identity). Thus, for example, where identical amino acids are given a score of 1 and non-conservative substitutions are given a score of 0, conservative substitutions are given a score of 0 to 1. 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), for example, as implemented in the program PC / GENE (Intelligenetics, Mountain View, Calif., USA). Each of these references is incorporated herein by reference in its entirety.

[0119] As used herein, "percentage of sequence identity" refers to a value determined by comparing two optimally aligned sequences over a comparison window, where a portion of the polynucleotide sequence in the comparison window may contain additions or deletions (i.e., gaps) compared to the reference sequence (which does not contain additions or deletions) due to optimal alignment of the two sequences. The percentage is calculated by determining the number of positions where the same nucleic acid base or amino acid residue occurs in both sequences to obtain the number of matched positions, dividing this number of matched positions by the total number of positions in the comparison window, and multiplying the result by 100 to obtain the percentage of sequence identity.

[0120] The term "substantial identity" or "substantially identical" in the context of polynucleotide sequences means that the polynucleotide comprises a sequence having 50-100% sequence identity, e.g., 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 one of the alignment programs described with standard parameters. Those skilled in the art will recognize that these values ​​may be appropriately adjusted to determine the corresponding identity of proteins encoded by two nucleotide sequences by taking into account codon degeneracy, amino acid similarity, reading frame position, etc. Substantial identity of amino acid sequences for these purposes typically means 55-100%, e.g., at least 55%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% sequence identity. EXAMPLES

[0121] Example 1. Efficacy and safety of ravulizumab in treating neuromyelitis optica spectrum disorder (NMOSD) in adult patients 1. Study Design Overall Design This is a Phase 3, external, placebo-controlled, open-label, multicenter study to evaluate the efficacy and safety of ULTOMIRIS in adult patients with NMOSD. Approximately 55 eligible adult patients with NMOSD from North America, Europe, Asia Pacific, and Japan will be enrolled in the study.

[0122] The study has four phases: screening period, primary treatment period, long-term extension period, and 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 and the long-term extension period begins when all patients complete the 26-week visit or discontinue early, followed by the end of primary treatment period (EOPT) visit. All patients will continue to receive ravizumab during the long-term extension period for up to 2 years or until ravizumab is approved and / or available (subject to country-specific regulations), whichever occurs first. Based on the estimated enrollment rate of patients with NMOSD, the total treatment period for each patient will be up to 4 years. Patients will be followed for 8 weeks after the last dose of study drug or early discontinuation (ED).

[0123] If eligible patients enroll in the study, they will receive an intravenous infusion of ULTOMIRIS. Each patient's ULTOMIRIS dose will be based on body weight. The dosing regimen will consist of a loading dose followed by a maintenance dose every 8 weeks (q8w). Maintenance doses should begin 2 weeks after the loading dose.

[0124] For each patient, the total duration of study participation will be up to 4 years and 14 weeks, including the screening period (up to 6 weeks), the first-line treatment period (26 weeks to 2 years), the long-term extension period (up to 2 years), and the safety follow-up period (8 weeks).

[0125] 1.2. Scientific basis for study design This trial was designed to provide data to adequately characterize the benefit-risk profile of ULTOMIRIS for the treatment of patients with NMOSD and uses placebo data from a separate externally controlled trial investigating the use of eculizumab for the treatment of NMOSD.

[0126] The single-arm design, using the placebo arm of NCT01892345 (conducted from 2014 to 2018) as an external placebo control, will allow for a robust evaluation of ravulizumab as a treatment option for NMOSD. To the extent possible, consistency will be maintained between NCT01892345 trials, including inclusion of similar patient populations, allowing for concomitant medications, evaluation procedures, and endpoints to ensure valid comparisons.

[0127] 1.2.1. Rationale for Selected Endpoints 1.2.1.1. Efficacy Endpoints In NMOSD, measurable biological aspects include relapse and disability. Disability in NMOSD is a direct consequence of relapse, supporting the relevance of measuring relapse as an efficacy endpoint.

[0128] In this study, the occurrence of relapse will be evaluated using the primary endpoint TFR and the secondary endpoint ARR. The time to first relapse provides useful information on the efficacy of ULTOMIRIS. Since the efficacy of treatment may be based on delaying and / or reducing relapses, TFR is an appropriate efficacy endpoint for prospectively designed studies in NMOSD. The external placebo arm of the NCT01892345 study will be utilized as an appropriate control group, considering that the primary endpoint of that study is also TFR and the adjudication process and relapse definition are constant between the two studies. Furthermore, the effect of ULTOMIRIS on the frequency of relapse will be measured using the Adjudicated On-Trial ARR. 95% confidence intervals will be calculated around the ARR. The objectives and endpoints of this study are summarized in Table 1 below. [Table 1-1] [Table 1-2]

[0129] 1.2.2. Rationale for duration of first-line treatment The study will end the first-line treatment period when all patients have completed the 26-week visit or discontinued earlier, at which point, based on estimated enrollment rates, it is expected that the first enrolled patients will have been on treatment for approximately 2 years, and the remaining patients will have had time on treatment ranging from 26 weeks to 2 years (inclusive).

[0130] The cutoff of 26 weeks for the last patient is chosen for several reasons. In previous studies of eculizumab, the primary observations were available by that time: 2 of 3 evaluated on-trial relapses observed in the eculizumab group and 12 of 20 evaluated on-trial relapses observed in the placebo group. This design ensures that the number of patients censored in the first 26 weeks is limited in the analysis of time to first evaluated on-trial relapse. It also recognizes that based on the expected enrollment timeline, many patients will have been on treatment for more than a year by the time the last patient completes the 26-week visit, providing efficacy and safety longitudinal data that allow robust comparisons to data collected over a similar time frame in the placebo arm of NCT01892345.

[0131] 1.2.3. Rationale for selected patient population Complement activation is a major determinant of disease pathogenesis in patients with anti-AQP4-positive NMOSD. Therefore, inhibition of terminal complement activation with ULTOMIRIS represents a biologically rational approach to the treatment of patients with anti-AQP4-positive NMOSD. Study inclusion criteria will be carefully selected to reflect an adult patient population consistent with the anti-AQP4-positive NMOSD population likely to be treated with ULTOMIRIS in clinical practice.

[0132] 1.3. Dose Adequacy Ravulizumab Targeting complete terminal complement inhibition as a therapeutic strategy in the treatment of patients with NMOSD has been validated by data from the eculizumab clinical program. The dosing regimen of ULTOMIRIS is designed to target immediate, complete, and sustained inhibition of terminal complement in patients. The weight-based dosing of ULTOMIRIS in the previous PNH program is premised on PK / PD data from early and late-stage clinical development studies in healthy adult volunteers and patients with PNH. The proposed ULTOMIRIS dosing regimen (Section 3.1, Section 5.1.6.1) is the approved regimen for patients with PNH (Ultomiris® United States Prescribing Information (USPI)), and the same dosing regimen is included in the EU initial marketing authorization application (MAA). Therefore, the same dosing regimen will be selected for this study.

[0133] 1.3.2.Additional doses Patients undergoing plasma exchange (PE) / plasmapheresis (PP) (Section 3.5.1.3) as acute treatment following an investigational relapse may receive an additional dose of ULTOMIRIS (Section 5.1.6.2). The additional dose of ULTOMIRIS has been selected based on PK simulations. Consistent with the eculizumab labeling approved to treat adult and pediatric patients with aHUS, adult patients with generalized myasthenia gravis (gMG), and adult patients with NMOSD, an additional dose of 50% of ULTOMIRIS (rounded to the nearest 300 mg if not equal due to vial composition) will be administered in the PP / PE combination setting.

[0134] 1.4. Completion of first-line treatment After all patients have completed the Week 26 visit or discontinued early, patients will return for an End of Primary Treatment (EOPT) visit within 14 days: If the EOPT visit coincides with a future scheduled study visit, patients must complete all assessments at the EOPT visit and may also receive the scheduled dose of ULTOMIRIS. If the patient is in the relapse evaluation period for a first relapse (defined as the first relapse after Day 1), the Week 6 relapse evaluation visit is the patient's EOPT visit.

[0135] The end of the primary treatment period will be defined as the date when all patients have completed the 26-week visit or, if discontinued earlier, the date when they subsequently completed the EOPT visit.

[0136] 1.5. Definition of End of Study Patients were considered to have completed the study if they met any one of the following criteria: The patient completes all phases of the study including the final visit as indicated in the Schedule of Activities. A patient completes a trial early because ULTOMIRIS is enrolled or approved.

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

[0138] 2. Study population Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exceptions, are not permitted.

[0139] 2.1. Selection Criteria A participant is eligible for inclusion in the study only if all criteria in 2.2.1.–2.2.5. apply to him / her.

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

[0141] 2.1.2. Patient types and disease characteristics Patient and disease characteristics for inclusion were as follows: - Diagnosis of NMOSD as defined by anti-AQP4 Ab positivity and the 2015 International Consensus Diagnostic Criteria (Wingerchuk, D. et al., Neurology, 85:177-89, 2015). A previous positive anti-AQP4 Ab test is acceptable if the test was performed using an acceptable validated cell-based assay from an accredited laboratory. In this case, the previous test results and relevant information must be reviewed and approved by the sponsor's medical monitor before initiating study treatment. At least one attack or recurrence in the past 12 months prior to the screening period (Note: Patients with one lifetime attack are considered to meet this inclusion criterion if the attack occurred in the past 12 months.) Expanded Disability Status Scale (EDSS) score ≦7 Patients entering the study 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, must be on a stable dosing regimen of sufficient duration prior to screening with no plans to change the dose during the study as follows: If patients entering the study are receiving AZA, they must have been receiving AZA for ≥6 months and have been on a stable dose for >2 months prior to screening. b. If patients entering the study are receiving other IST (e.g., MMF, MTX, or TAC), patients must have been receiving the IST for ≥3 months and have been on a stable dose for >4 weeks prior to screening. c. If patients entering the study are receiving oral corticosteroids, they must have been receiving a stable dose for >4 weeks prior to screening. d. If a patient is receiving oral corticosteroids with or without other IST entering the study, their daily corticosteroid dose prior to screening must be less than or equal to 20 mg / day of prednisone (or equivalent dose). Vaccination against N. meningitidis within 3 years prior to or at the time of starting ULTOMIRIS. Patients who initiate investigational product treatment less than 2 weeks after receiving meningococcal vaccine must receive appropriate antibiotic prophylaxis until 2 weeks after vaccination.

[0142] 2.1.3. Weight The weight is over 40kg.

[0143] 2.1.4.Gender For both sexes, contraception used by men or women should be consistent with local regulations regarding contraception for clinical trial participants. Male patients must agree to use contraception during treatment and for at least 8 months after the last dose of study drug and must abstain from donating sperm during this period.

[0144] Female patients are eligible to participate if they are not pregnant, not breastfeeding, and meet at least one of the following conditions that apply: - You are not a woman of childbearing potential (WOCBP), or -WOCBP and using highly effective or acceptable contraception during treatment and for at least 8 months after the last dose of study drug. The investigator will evaluate the effectiveness of contraception in relation to the first dose of the investigational product. WOCBP must have a negative high-sensitivity pregnancy test (serum pregnancy test) within 24 hours prior to the first dose of investigational product. The investigator is responsible for reviewing medical history, menstrual history, and recent sexual activity to reduce the risk of selecting women whose pregnancy has not been detected early.

[0145] 2.1.5. Informed consent Be able to give signed informed consent, including compliance with the requirements and limitations listed in the Informed Consent Form (ICF) and this protocol.

[0146] 2.2. Exclusion criteria If any of the criteria in 2.2.1. to 2.2.4 apply, the patient will be excluded from the study.

[0147] 2.2.1. Medical Conditions - History of meningococcal (N. meningitidis) infection. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody titers) - History of unidentified infectious diseases Active systemic bacterial, viral, or fungal infection within 14 days prior to Day 1 administration of study drug Presence of fever of 38°C (100.4°F) or higher within 7 days prior to administration of study drug on Day 1 Hypersensitivity to mouse proteins or one of the excipients in ULTOMIRIS Any medical condition that, in the opinion of the investigator, may interfere with the patient's participation in the study, may place the patient at increased risk, or may confound the evaluation of the patient.

[0148] 2.2.2. Prior / concomitant therapy Previous or current treatment with complement inhibitors. Use of rituximab within 3 months prior to screening. Use of mitoxantrone within 3 months prior to screening. · Use of intravenous immunoglobulin (IVIg) within 3 weeks prior to screening.

[0149] 2.2.3. Prior / Concurrent Clinical Trial Experience and Other Exclusions Participation in any other investigational drug trial or exposure to an investigational drug or device within 30 days of screening or 5 half-lives of the investigational drug, whichever is longer. - Pregnancy, breastfeeding, or intention to become pregnant during the study

[0150] 2.3. Lifestyle Considerations There are no lifestyle restrictions in this study.

[0151] 2.4. Screening failure A screen failure is defined as a patient who consents to participate in the clinical trial but is subsequently not treated with the investigational product. Individuals who do not meet the entry criteria for the study because they are expected to recover or have recovered (screen failure) may be rescreened upon discussion and agreement between the Investigator and the Medical Monitor. Patients who experience a relapse during the screening period that meets the protocol definition of an investigational relapse (section 5.2.3.2) are considered to have failed the screen. Such patients may be rescreened for enrollment in the study if, after receiving treatment for the relapse, the patient is medically stable in the opinion of the Investigator and the Medical Monitor (section 2.1; section 2.2). To be included in the study, patients must meet the entry criteria at rescreening.

[0152] 3. Investigational Drugs An investigational product is defined as any investigational drug, marketed product, placebo, or medical device intended to be administered to study patients in accordance with a clinical trial protocol.

[0153] 3.1. Investigational drug to be administered In this study, patients will receive ULTOMIRIS in an open-label setting during the entire treatment period (Table 2; see Section 5.1.6 for study drug dosage and administration and the SoA (Figure 2) for dosing schedule). [Table 2]

[0154] 3.2. Preparation / Handling / Storage / Accountability When the investigational product arrives at the investigational site, the investigational product kit is removed from the shipping container and stored in the original carton under refrigerated conditions at 2-8°C (35-47°F) and protected from light. ULTOMIRIS will not be frozen. The investigational product will be stored in a secure, limited-access storage area with daily temperature monitoring.

[0155] Investigational drug infusions must be prepared using aseptic technique. ULTOMIRIS is further diluted 1:1 with a compatible diluent. ULTOMIRIS is filtered through a 0.2 micron filter at the time of infusion. In addition, investigational drug infusions comply with the following regulations: The investigator or designee will ensure that proper temperature conditions are maintained during transportation for all investigational product received, and any discrepancies will be reported and resolved prior to use of the investigational product. · Only patients enrolled in the study may receive the investigational product, and only authorized site personnel may supply or administer the investigational product. All investigational products will be stored in a secure, environmentally controlled, and monitored (manual or automated) area, restricting access to the investigator and authorized site personnel, and in accordance with labeled storage conditions. The investigator, institution or head of the institution (if applicable) is responsible for the accountability, reconciliation and record-keeping of the investigational medicinal product (e.g., receipt, reconciliation and final disposition records). Further guidance and information on the final disposal of unused investigational medicinal product is provided in the Pharmacy Manual.

[0156] 3.3. Measures to minimize bias: randomization and blinding This is a single-arm, open-label study. All study patients, site personnel, sponsor designees, and all staff directly associated with the conduct of the study will be unblinded to patient treatment assignment.

[0157] To minimize the potential for bias in this open-label study, operational measures for efficacy endpoints and assessment processes will be employed. The trial database will be monitored according to pre-specified guidelines to ensure that all potential relapses are collected and analyzed. An independent relapse assessment committee will assess each in-study relapse to ensure that it meets the protocol-defined criteria for NMOSD relapse (Section 5.2.3.2). Additionally, EDSS assessors will be aware that all patients are receiving ULTOMIRIS, but EDSS assessors will be blinded to all trial data when performing their assessments.

[0158] 3.4. Compliance with investigational drug Infusions of investigational product to patients will be under the supervision of the Investigator or his / her designee to ensure that patients receive the appropriate dose at the appropriate time during the study.

[0159] The date and time of each dose administered at the clinic will be recorded in the source document and recorded on the case report form (CRF).

[0160] At the time of administration, the dose of the investigational drug and the identity of the study patient are verified by a staff member at the investigational site other than the person administering the investigational drug.

[0161] Combination Therapy Any medications (including over-the-counter or prescription medications, vitamins, minerals, and / or herbal supplements) or vaccinations that patients are receiving at the time of enrollment or during the study will be recorded in the patient's source document / medical record and electronic case report form (eCRF) with the following: ·Reason for use Date of administration, including start and end dates Dosage information, including dose and frequency

[0162] Any changes in concomitant medications will also be recorded in the patient's source document / medical record and eCRF. If possible, concomitant medications will be recorded from the first infusion of ULTOMIRIS until the patient discontinues or completes the study.

[0163] Collect information on use of IST, including steroids. Also record meningococcal vaccination and antibiotics (if applicable) administered for prevention of meningococcal disease.

[0164] Concomitant medications deemed necessary for the patient's care during the study or for the treatment of AEs may be administered at the Investigator's discretion, along with other medications not prohibited in Section 3.5.2, however, the Investigator is responsible for ensuring that all medication details are completely recorded in the patient's source documents / medical record and eCRF.

[0165] If there are any questions regarding concomitant or prior therapy, contact the Medical Monitor.

[0166] 3.5.1. Acceptable Drugs and Therapies The following concomitant medications and treatments are permitted in this study.

[0167] Palliative and supportive care Palliative and supportive care for underlying conditions will be permitted during the course of the trial.

[0168] Immunosuppressants Supportive immunosuppressive therapy (IST) for prevention of relapse, either in combination or as monotherapy, is permitted at the investigator's discretion as follows: Corticosteroids Azathioprine (AZA) Mycophenolate mofetil (MMF) Methotrexate (MTX) Tacrolimus (TAC) Cyclosporine Cyclophosphamide

[0169] If the patient received supportive IST prior to the study and continues on stable maintenance therapy during the study, refer to the inclusion criteria (section 2.1) for requirements regarding IST to ensure that the patient is on a stable dose within the limits required for the study, as described in the study criteria (section 2).

[0170] No adjustments to the IST dose will be made and no new IST will be permitted for each patient during the first 106 weeks, unless the patient experiences a relapse or safety event and the investigator determines a change in IST dose or regimen is necessary to ensure patient safety.

[0171] Changes in immunosuppressive therapy will be recorded on the concomitant medication source documents and eCRF pages.

[0172] Standard treatment for recurrence Treatment of relapse is at the discretion of the treating physician. Following expert opinion, the following standardized treatment regimen (section 5.2.3.2) for confirmed in-study relapse is recommended: One gram (1 g) of intravenous methylprednisolone (IVMP) is administered daily for three to five days, followed by tapering of oral prednisone. If the patient improves, continue study evaluations according to the schedule in this protocol. If there is no or minimal response to IVMP, PE / PP is permitted at the discretion of the treating neurologist. Five cycles of PE, each removing 1.0-1.5 volumes of circulating plasma, are recommended for the treatment of attacks unresponsive to IVMP. If a patient undergoes PE / PP for an ongoing relapse during the treatment period, they should receive a booster dose of the investigational drug after each PE / PP as described in Section 5.1.6.2 Booster Doses. After receiving the booster doses, patients will continue on the protocol-defined dosing schedule in the SoA (Figure 2).

[0173] 3.5.2. Denied Drugs and Treatments The following medications and treatments are prohibited during the study: Mitoxantrone Other biologic agents such as rituximab or tocilizumab · Immunomodulatory therapies including interferon beta-1b; interferon beta-1a, glatiramer acetate, natalizumab, alemtuzumab, dimethyl fumarate, teriflunomide, siponimod and fingolimod. -IVIg for preventing recurrence PE to prevent recurrence

[0174] 3.6. Dose Modification No dose modifications are permitted in this study.

[0175] 3.7. Post-trial intervention Patients will not be offered ULTOMIRIS after their last scheduled dose (Figures 2 and 3). All patients will be followed for safety for an additional 8 weeks after their last dose or early discontinuation of study drug.

[0176] 4.Discontinuation of investigational drug and patient withdrawal or withdrawal 4.1.Discontinuation of investigational drug In rare cases, patients may need to permanently discontinue the investigational product (final discontinuation). If the investigational product is finally discontinued, the patient will remain in the study for safety follow-up evaluations. Please see the SoA (Figures 2 and 3) for data to be collected at the time of discontinuation of the investigational product and at follow-up, as well as further evaluations that need to be completed.

[0177] Patients should consider discontinuing the study drug if any of the following occur during the study: ·Severe hypersensitivity reactions; · Uncontrolled severe infections; Use of prohibited substances as defined in Section 3.5.2 pregnancy or planned pregnancy; or -The sponsor or principal investigator determines it is necessary for the patient.

[0178] 4.2. Patient Withdrawal / Withdrawal from Study Every effort should be made to ensure that the patient is willing to comply with study participation before screening procedures are performed. Study staff should notify the sponsor and site monitors of all study withdrawals as soon as possible. The reason for patient discontinuation should be recorded in the source documents and eCRF. Patients may withdraw from the study at any time at their own request or at the investigator's discretion for safety, behavioral compliance, or administrative reasons. This is expected to be uncommon. At the time of study discontinuation, an Early Discontinuation Visit will be conducted, if possible, as indicated in the SoA (Figure 2). Patients who discontinue early will be followed for safety for an additional 8 weeks and for any further assessments that need to be completed. The patient will then permanently discontinue both the investigational drug and the study. If a patient withdraws consent to future disclosures, the sponsor may store and continue to use data collected before such consent was withdrawn.

[0179] 4.3. Loss to follow-up If a patient does not return or is unavailable for a scheduled visit within an acceptable visit window (Figure 2), study staff at the site will make a reasonable attempt to contact the patient and determine the reason for the missed appointment.

[0180] Patients who do not return for a scheduled visit will be contacted by study staff at the site to determine the reason for the missed appointment. Because obtaining missed patient visit information is important to ensure that a missed visit is not due to an AE or possible relapse, every effort will be made to implement safety follow-up procedures as specified in the protocol.

[0181] In the exceptional circumstance where a patient is unable or will not come to the investigational site for testing, the patient will be instructed to consult a local neurologist or physician. In this case, if possible, the treating physician or designee will contact the local neurologist or physician to obtain as much information as possible about the patient's medical and neurological status and provide clinical guidance as needed. The investigational site will document relevant medical records from the local physician visit and record the relevant data on the Relapse Assessment Visit Form or AE Form as appropriate.

[0182] Patients will be considered lost to follow-up if they repeatedly fail to return for scheduled visits and cannot be contacted by the study site.

[0183] If a patient fails to return to the clinic for a required study visit, the following actions will be taken: The study site will contact the patient to reschedule any missed visits as soon as possible, counsel the patient on the importance of maintaining the assigned visit schedule, and confirm whether the patient wishes to and / or should continue in the study. Before a patient is considered lost to follow-up, the investigator or designee will make every effort to re-establish contact with the patient (three telephone calls, if possible, and, if necessary, certified mail or local equivalent to the patient's last known mailing address). These contact attempts will be documented in the patient's medical record. If a patient remains unreachable, they will be considered lost to follow-up.

[0184] 5. Study Evaluation and Procedures The study procedures and their timing are summarised in the SoA (Figure 2). No protocol exemptions or exclusions will be permitted. Any immediate safety concerns will be discussed with the sponsor immediately upon manifestation or recognition to determine whether the patient should receive the investigational product. Compliance with the study design requirements, including those set out in the SoA, is essential and necessary for the conduct of the study. All screening assessments will be completed and reviewed to ensure that potential patients meet all eligibility criteria. The investigator will maintain a screening log to record details of all patients screened and to confirm eligibility or record reasons for screening failure as appropriate. Procedures performed as part of the routine clinical management of patients (e.g. blood counts) and obtained prior to the signing of the ICF may be utilised for screening or baseline purposes, provided that the procedure meets the criteria set out in the protocol and is performed within the timeframe defined in the SoA.

[0185] 5.1. General assessment and procedures 5.1.1. Informed consent The investigator or qualified designee will obtain signed and dated informed consent from each patient before conducting any study procedures. Every effort will be made to ensure that the patient is willing to comply with study participation before conducting any screening procedures.

[0186] Treating physician The Treating Investigator is the Principal Investigator (PI) / Sub-Investigator for the study who is responsible for overall patient management, including assessment of patient eligibility, oversight of investigational drug administration, recording and treatment of AEs, and monitoring safety evaluations.

[0187] At the time of relapse, the Treating Physician will perform a complete neurological examination to determine whether the patient's symptoms and signs meet the criteria for an investigational relapse (Section 5.2.3.2). The Treating Physician may treat the patient's relapse according to the recommended investigational relapse treatment regimen. Ultimately, the treatment and treatment options for an investigational relapse and changes in IST following an investigational relapse are at the discretion of the Treating Physician.

[0188] 5.1.3. Medical history and NMOSD history The investigator reviewed the patient's medical history and diagnoses and recorded the following at the screening visit: Date of NMOSD diagnosis and a previous magnetic resonance imaging (MRI) contributing to the diagnosis. Confirmation of NMOSD diagnosis as defined by the International Panel for the Diagnosis of NMO (IPND) criteria (section 7.1), including the specific criteria that patients must meet for the diagnosis. Only patients who test positive for anti-AQP4 antibodies and otherwise meet the 2015 IPND criteria are eligible to participate. Record all available information regarding recurrences that occurred prior to screening and meet the protocol definition of a past recurrence (section 5.2.3.1), including: Number of recurrences (onset date) Clinical features of each relapse (e.g., optic neuritis [ON], transverse myelitis [TM], brainstem, area postrema, or other) Acute and maintenance treatment and dosing regimens, and Any measure of disability, such as EDSS score.

[0189] 5.1.4. Vaccine and antibiotic prophylaxis Similar to terminal complement antagonists, use of ULTOMIRIS increases patients' susceptibility to meningococcal infection (N. meningitidis). To reduce the risk of meningococcal infection, all patients will be vaccinated against meningococcal infection within 3 years prior to or at the start of study treatment. Patients who start the investigational product less than two weeks after receiving the meningococcal vaccine will receive appropriate prophylactic antibiotic treatment until two weeks after vaccination. Patients are 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 protect against common pathogenic meningococcal serotypes, vaccines against serotypes A, C, Y, W135, and B are recommended, where available. Vaccination may not be sufficient to prevent meningococcal infection. Appropriate use of antimicrobials should be considered in accordance with official guidance and local practice. Monitor all patients for early signs of meningococcal infection and promptly evaluate any suspected infection and treat with appropriate antibiotics as necessary.

[0190] 5.1.5. Inclusion / Exclusion Criteria All inclusion criteria (Section 2.1) and exclusion criteria (Section 2.2) will be reviewed by the Investigator or a qualified designee to ensure that the patient is eligible to participate in the study. Both the Investigator and Sponsor must approve the patient's eligibility prior to enrollment.

[0191] 5.1.6. Investigational Drug Administration This section describes the dosing regimen of the study drug. Study drug dosing will occur at the scheduled dosing visit (Figure 2) after all other tests and treatments have been completed, except for post-dose blood draws for PK and free C5.

[0192] Ravulizumab Patients will receive a weight-based loading dose of ULTOMIRIS via IV infusion on Day 1, followed by a weight-based maintenance dose on Day 15 (Table 3) and once every 8 weeks (q8w) thereafter. Total treatment duration will be up to 4 years until all patients have completed a 2-year long-term extension period or until ULTOMIRIS is approved and / or available (per country-specific regulations), whichever occurs first.

[0193] Depending on when relapse occurs, scheduled ULTOMIRIS administration visits may or may not overlap with relapse assessment visits and / or follow-up relapse assessment visits. ULTOMIRIS administration visits will continue as scheduled during the relapse assessment period. [Table 3]

[0194] 5.1.6.2.Additional doses During the study, PE / PP will be permitted at the treating physician's discretion for on-study relapses (Section 3.5.1.3). If PE / PP is administered during a non-administration visit as defined in the SoA (Figure 2), an additional dose of ULTOMIRIS will be administered within 4 hours of completion of PE / PP and will be based on the most recently administered dose of ULTOMIRIS (Table 4). If PE / PP is administered during a scheduled administration visit as defined in the SoA (Figure 2), no additional dose of ULTOMIRIS will be administered. Patients will receive a scheduled dose of ULTOMIRIS 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 on-study relapses).

[0195] After receiving the booster dose, patients will continue to receive infusions of the study drug according to the dosing schedule (Figure 2) specified in the protocol.

[0196] [Table 4]

[0197] 5.2.Efficacy evaluation Neurological examination A complete general neurological examination will be performed at scheduled visits throughout the study by the Investigator and a Treating Physician appropriately trained as a clinical assessor (section 5.1.2), preferably the same Treating Physician (Figure 2).

[0198] A complete neurological examination will include evaluation of the following systems: mental status, fundus examination, cranial nerves, deep tendon reflexes, plantar responses, power / strength, sensation, coordination, and gait / balance.

[0199] 5.2.2. NMO Symptom Cards and Assessment At the Day 1 visit, prior to receiving the first dose of study medication, patients will be given an NMOSD symptom card listing potential signs and symptoms of NMOSD relapse and contact information.

[0200] At each visit throughout the study, study staff will ensure that the patient has their NMO symptom card. Treating physicians will review and evaluate the patient for signs or symptoms that may indicate a relapse.

[0201] Relapse 5.2.3.1. Past recurrence A past relapse is any relapse that occurred before the screening visit, including the first NMOSD attack. For the purposes of this protocol, a past relapse is defined as a new onset of a neurological symptom or a worsening of an existing neurological symptom that persists for more than 24 hours and is characterized by objective changes on neurological examination (clinical and / or MRI findings). An event occurring within 30 days will be considered as one relapse.

[0202] 5.2.3.2. Relapse during the study 5.2.3.2.1 Definition of Relapse During the Study An investigational relapse is an acute attack occurring during the study treatment period. For the purposes of this protocol, an "investigational relapse" is defined as a new onset of a neurological symptom or a worsening of an existing neurological symptom, as documented by a treating physician and lasting for more than 24 hours, and characterized by objective changes (clinical signs) on neurological examination (section 5.1.2). The signs and symptoms must be attributable to NMOSD (i.e., not caused by an identifiable cause such as infection, excessive exercise, or excessively high ambient temperature). Isolated changes on MRI or other imaging studies and no associated clinical findings will not be considered an investigational relapse.

[0203] 5.2.3.2.2 Assessment of recurrence during the study Relapse during the study will be monitored throughout the study. The investigator or qualified designee will review signs and symptoms of possible relapse in detail with the patient at each visit.

[0204] Patients will be educated about the potential signs and symptoms of NMOSD relapse and instructed to contact the study site at the first sign or symptom of a possible relapse.

[0205] Patients will be evaluated within 24 hours (and not later than 48 hours) of notification of signs or symptoms suggesting a possible recurrence.

[0206] Assessment of recurrence during the study included: A complete neurological examination to determine whether clinical signs, symptoms, and laboratory findings meet the investigational definition of relapse. Assessment of relapse 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 and sensory subscale scores are used to classify the severity of TM. Assessment of the neurological functional system based on Kurtzke's Functional System Score (FSS) and level of impairment based on the EDSS score (section 5.2.4). Gait assessment using the HAI (section 5.2.7). · Ophthalmological examination including VA, visual field (VF) and colour vision (Section 5.2.9). · MRI + / gadolinium and / or ocular coherence tomography (OCT) studies will be performed to assess for possible recurrence as assessed by the investigator (section 5.2.10). Further testing and follow-up evaluations as specified in the SoA (Figure 3)

[0207] 5.2.3.2.3 Treatment for Relapse During the Study At the time of suspected relapse, the Treating Physician (Section 5.1.2) performed a complete neurological examination to determine if the patient was experiencing an on-study relapse. If determined by the Treating Physician to be an on-study relapse, treatment for the relapse and change in IST following relapse were at the discretion of the Investigator.

[0208] Recommended standard treatments for recurrence during clinical trials are provided in section 3.5.1.

[0209] For administration of additional doses of ULTOMIRIS during on-trial relapse, see Section 5.1.6.

[0210] 5.2.3.2.4 Follow-up for relapse during the study Recurrence assessment visits to monitor the course of recurrence will be conducted according to the schedule defined in the SoA (Figure 3). Additional (unscheduled) follow-up recurrence assessment visits beyond the defined time points will be at the discretion of the investigator or co-investigator.

[0211] After relapse, if the patient and the investigator / subinvestigator determine that it is appropriate for the patient to continue receiving the investigational drug, the patient may continue in the trial.

[0212] All reports of possible recurrence and actions taken regarding possible recurrence will be recorded on the patient's source document and recorded on the eCRF.

[0213] 5.2.3.2.5 Assessment of recurrence during the study Investigational relapses are independently reviewed by a Relapse Adjudication Committee (RAC), comprised of physicians with specific expertise in NMOSD who perform an independent review of investigational relapses. The Committee will determine, by majority vote, whether each reported investigational relapse meets the objective criteria for an investigational relapse. A separate charter describes all of the trial's criteria and procedures.

[0214] 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 EDSS scale ranges from 0 to 10.0 in 0.5 unit increments.

[0215] 5.2.4.1. Expanded Disability Status Scale The total EDSS score is determined by two factors: ambulation and FSS (section 5.2.4.2), as described below: - EDSS scores below 4.0 are determined by the FSS alone. People with an EDSS score of 4.0 or higher are likely to have some degree of walking impairment. An EDSS score of 4.0 to 9.5 is determined by both walking ability and the FSS.

[0216] Functional System Score Functional systems (FS) represent networks of neuronal systems responsible for a specific task / function. The EDSS assigns a severity score to a patient's clinical status using the FSS, which assesses functional impairment in the following eight FS (Section 7.2): FS for functional systems 1-7 are scored on a scale of 0 (low level of problems) to 5 or 6 (high level of problems) to best reflect the level of impairment observed clinically. The "other" category consists of any other neurological findings attributable to NMOSD and is binary, with 0 being absent and 1 being present.

[0217] 5.2.4.3. EDSS and FSS assessors The EDSS and FSS are administered directly by trained assessors. The EDSS assessor performs the complete Kurtzke Neurological Examination and records the FSS and EDSS scores. The following rules apply: The EDSS assessor is not the PI and cannot be directly involved in the management of study patients. If possible, the EDSS assessor should be a physician. If a non-physician EDSS assessor (e.g., a specialist nurse) is used, the assessor must be approved by the sponsor before conducting the assessment. EDSS assessors remained blinded to all other study data and all other patient clinical data. A blinded EDSS assessor will be responsible for conducting EDSS assessments throughout the study, including at the time of relapse. If possible, the same blinded assessor will conduct the EDSS for each patient at the SoA-specified visits. · EDSS assessors performed a complete Kurtzke neurological examination as described in Section 7.2 and recorded the Functional System Score (FSS) and EDSS scores (Kurtzke, 1983).

[0218] Please refer to the sponsor-provided training materials for specific requirements regarding the qualification of EDSS raters. See Table 5 for the roles and responsibilities of investigators and EDSS raters.

[0219] [Table 5]

[0220] EuroQoL 5 Dimension (EQ-5D) The European Quality of Life Scale (EQ-5D) (Figure 5) is a self-assessed standardized instrument for measuring health-related QoL that has been used in a wide range of health conditions, 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 study procedures.

[0221] 5.2.5.1.EQ-5D Descriptive System The descriptive system is a five-item 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 problem in that area.

[0222] EQ visual analog scale The EQ-5D VAS is a global health status scale on which patients select a number from 0 to 100 to describe their health state, with 100 being the "best imaginable health state" and 0 being the "worst imaginable health state."

[0223] This information can be used as a quantitative measure of health outcomes as judged by individual respondents. Previously published studies by members of the EuroQol group have provided preliminary evidence of the feasibility, reliability and validity of this instrument.

[0224] 5.2.6. Short Form Health Survey (SF-36) The SF-36 is a 36-item self-report of health-related quality of life (Stewart, AL, & Ware, JE, Jr. (Eds.). (1992). Measuring functioning and well-being: The medical outcomes study approach. Durham, NC: Duke University Press.; Ware, JE, 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 contains eight subscales that measure different domains of health-related quality of life: physical functioning, role limitations due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitations due to emotional problems, and mental health. The two summary scores are a physical component summary and a mental component summary. There is no single overall score for the SF-36.

[0225] 5.2.7. Hauser Ambulatory Index (HAI) The HAI is a rating scale developed to assess mobility by assessing the time and degree of assistance required to walk 25 feet (Figure 7). The treating physician or an appropriately trained designee will administer the HAI test at protocol-defined visits as briefly described below (Figure 3). Patients are asked to walk a marked 25-foot course as quickly and safely as possible. The examiner records the duration and type of assistance needed (e.g., cane, walker, crutches). The rating scale also has a category for patients who cannot walk.

[0226] Patients' walking will be timed, but this time will not be used directly, but in conjunction with other factors to rate the patients on an 11-point ordinal scale (Bethoux, F. and Bennett, S., Int. J. Care, 13:4-14, 2011). This assessment will be performed on all patients in this study.

[0227] 5.2.8. Optic myelopathy score (OSIS) The OSIS is a scoring system for assessing the severity of relapse (Figure 8). The OSIS VA subscale score is used to classify the severity of ON. The OSIS motor and sensory subscale scores are used to classify the severity of TM. The OSIS is assessed by the treating physician at baseline and at the time of on-study relapse. Further instructions regarding the OSIS assessment of on-study relapses are provided in Section 5.2.3.2.

[0228] Ophthalmological examination 5.2.9.1. Conflict vision The opposing VF is evaluated by the treating physician. It is important to know the baseline ophthalmological status in this evaluation so that changes in the examination can be used to evaluate previous and ongoing ON. Central scotoma is 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).

[0229] Color Vision Color vision will be assessed by the treating physician or any appropriately trained designee using Ishihara plates. Color vision loss may be a marker of ON and is therefore an important evaluation tool in NMOSD.

[0230] 5.2.9.3. Visual acuity Visual acuity is usually affected by ON and progresses over a period of hours to days. The Landolt C-ring chart is used to assess VA.

[0231] The Landolt C consists of a ring with a gap, and therefore looks similar to the letter C. The gap can be in various positions (usually left, right, bottom, top and 45° positions 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 reduced until the patient produces a certain error rate. The smallest perceptible angle of the gap is taken as a measure of visual acuity.

[0232] The treating physician or appropriately trained designee will conduct the VA testing at the protocol-defined visits as described below (Figure 3). · The test is carried out at a standard distance, typically 6 meters or 20 feet. · Landolt charts are typically recorded as acuity ratio distance (6 meters or 20 feet), so for normal VA, it would be recorded as 20 / 20 or 6 / 6. This may be entered as the denominator of a Landolt fraction (US) or as a decimal (outside the US). Testing is always performed with the best possible correction (e.g. wearing glasses) if necessary, and each eye is tested independently.

[0233] 5.2.10 Magnetic Resonance Imaging and Ocular Coherence Tomography Baseline MRI (with optional contrast) and OCT of the brain, cervical and thoracic spine will be performed. Exceptions may be granted (e.g., based on recent medical history results available to the study) if approved by the Alexion medical monitor.

[0234] At the time of recurrence, if deemed clinically significant, MRI (with or without contrast) and / or OCT of the brain, cervical spine, and / or thoracic spine will be performed at the discretion of the investigator to assess for possible recurrence.

[0235] If deemed appropriate by the investigator, a follow-up evaluation will be conducted promptly after an on-study relapse (section 5.2.3).

[0236] 5.3. Safety Assessment The planned time points for all safety assessments are provided in the SoA (Figures 2 and 3).

[0237] 5.3.1. Physical Examination A complete physical examination will include evaluation of at least the following organs / body systems: skin, head, ears, eyes, nose, throat, neck, lymph nodes, pulses, chest, heart, abdomen, extremities, and musculoskeletal. A targeted physical examination will include, at a minimum, examinations relevant to the body systems based on the Investigator's judgment and the patient's symptoms.

[0238] The investigator will pay particular attention to clinical signs associated with previous serious illness. To ensure consistency, every effort will be made to have the same qualified study staff perform the physical examination at each study visit. At the investigator's discretion, additional physical examinations may be performed during the study as medically indicated.

[0239] 5.3.2. Height and weight Weight is measured in pounds or kilograms. Height is measured in inches or centimeters.

[0240] Vital signs Oral temperature (°C or °F), pulse rate, respiratory rate (RR), systolic and diastolic blood pressure (BP) (mm Hg) are assessed. Blood pressure and pulse measurements are assessed using fully automated equipment. Manual techniques are used only if automated equipment is not available. Prior to blood pressure and pulse measurements, allow the patient to rest for at least 5 minutes in a quiet environment without distractions (e.g., television, mobile phone). Ideally, the same group for each patient is used for measurements.

[0241] Electrocardiogram A single 12-lead ECG will be performed at the protocol-defined visit for the SoA (Figures 2 and 3) using an ECG machine to obtain heart rate and measurements of PR, QRS, QT, and QTc intervals. Patients will be in a supine position approximately 5-10 minutes prior to ECG collection and will remain supine but awake during ECG collection. The investigator or qualified designee will be responsible for reviewing the ECG to assess whether it is within normal limits and to determine the clinical significance of the results. These assessments will be recorded in the source documents and in the eCRF.

[0242] 5.3.5. Patient Safety Cards Prior to the first dose of investigational medicinal product, study patients will be given a Patient Safety Card to carry with them at all times. This card will be provided to increase patient awareness of the risk of infectious diseases, particularly meningococcal infection, to facilitate prompt recognition and disclosure of potential signs or symptoms of infection experienced by the study patient during the study, and to inform patients what steps they must take if they are experiencing signs or symptoms of infection.

[0243] At each visit during the study, study staff will ensure that patients have their patient safety cards.

[0244] 5.3.6. Pre- and Concurrent Medical Considerations It is important that the investigator or qualified designee reviews each medication the patient is taking before the start of the study and at each visit.

[0245] 5.3.6.1. Previous Therapeutic Drugs Prior medications and / or vaccines (including vitamins, herbal preparations, and those discussed in Exclusion Criteria section 2.2) and procedures (therapeutic interventions such as surgery / biopsy or physical therapy) that the patient has taken or received within 30 days prior to the start of screening or during the screening period prior to the first dose of ULTOMIRIS will be recorded on the patient's eCRF, as well as any meningococcal vaccines administered within the past 3 years. Additionally, any medications or therapies (including steroids) ever used to prevent relapses or treat the acute phase of NMOSD prior to the first dose of ULTOMIRIS will be collected.

[0246] Concomitant medications Use of concomitant medications and non-pharmacological therapies (section 6.5) will be assessed during the study. At each visit, patients will be asked about any new medications or non-pharmacological therapies or changes to concomitant medications and non-pharmacological therapies since their last visit. Concomitant medications and non-pharmacological therapies will be recorded on source documents and on the patient's eCRF.

[0247] 5.3.7.Clinical Safety Laboratory Assessments The Investigator will review the laboratory reports, document this review, and record any clinically significant changes that occurred during the study in the AE section of the CRF. Laboratory reports will be submitted with the source documents. Clinically significant abnormal laboratory findings are those not related to the underlying disease unless the Investigator determines that they are more severe than would be expected for the patient's condition.

[0248] All laboratory tests with values ​​considered clinically significant abnormal during study participation or within 8 weeks after the last dose of investigational drug will be repeated until the values ​​return to normal or baseline or are no longer considered clinically significant by the investigator or medical monitor. If such values ​​do not return to normal / baseline within a time period deemed reasonable by the investigator, the etiology will be identified and the sponsor will be notified. All protocol-required laboratory evaluations will be performed in accordance with the Laboratory Manual and SoA, as defined in Appendix 2. If a laboratory value from a non-protocol-specified laboratory evaluation performed in the site's local laboratory requires a change in patient management or is considered clinically significant by the investigator (or e.g., AE or dose modification), the result will be recorded on the CRF.

[0249] 5.3.8. Monitoring for risk of suicidal thoughts and behavior Because the investigational product is being evaluated in a neurological indication, patients receiving the investigational product should be appropriately monitored closely for changes in suicidal thoughts or behavior or other abnormal behavior, particularly at the beginning and end of the investigational drug course or at times of dose changes.

[0250] Baseline assessment of suicidal thoughts and behaviors, as well as intervention-emergent suicidal thoughts and behaviors, will be monitored during the study using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0251] There are two types of C-SSRS assessments administered during the study: the baseline C-SSRS (Figure 10) and the C-SSRS from the final visit onwards (Figure 11). The C-SSRS will be administered by the treating physician or an appropriately trained designee at the SoA-specified visit to ensure that patients experiencing suicidal thoughts or behaviours are appropriately recognised and adequately managed or referred for further evaluation. Additional C-SSRS assessments will be permitted if necessary.

[0252] 5.4. Adverse events and serious adverse events Adverse events will be reported by the patient (or, where appropriate, the caregiver, representative or surrogate for the patient) to the investigator.

[0253] The investigator and qualified designee are responsible for detecting, describing, and recording events that meet the definition of an AE or SAE, and for following up on any AEs that are serious, considered to be related to the investigational product or study procedures, or that prompt the patient to discontinue the investigational product (see Section 4).

[0254] In this study, information about recurrences that do not meet the SAE criteria will be recorded in the source documents and eCRF as part of the recurrence assessment visit and will not be reported as AEs.

[0255] 5.4.1. Duration and Frequency of Collecting Adverse Event and Serious Adverse Event Information All AEs and SAEs will be collected from the signature of the ICF until the last visit at the time specified in the SoA (Figures 2 and 3).

[0256] All SAEs will be recorded and reported to the sponsor or designee immediately, and under no circumstances will this last longer than 24 hours, as illustrated in Figures 2 and 3. The investigator will provide updated data on SAEs to the sponsor within 24 hours of learning about them.

[0257] Investigators are under no obligation to actively seek out AEs or SAEs after study participation has ended. However, investigators will promptly notify the sponsor if an SAE, including death, occurs after a subject has discontinued the study and is deemed reasonably related to the investigational product or study participation.

[0258] 5.4.2. Methods for detecting AE and SAE Care should be taken to avoid introducing bias in detecting AEs and / or SAEs. Open-ended, non-leading verbal questioning of the patient is the preferred method for inquiring about the occurrence of AEs.

[0259] 5.4.3. Follow-up of AEs and SAEs After the initial AE / SAE report, Investigators are expected to actively follow up with each patient at subsequent visits / contacts. All SAEs and AEs of Special Interest (AESIs; defined in Section 5.4.6) will be followed up until recovery, stabilization, other explanation for the event, or the patient is lost to follow-up (defined in Section 4.3). Every effort will be made to implement safety follow-up procedures as defined in the protocol.

[0260] 5.4.4. SAE Regulatory Reporting Requirements Prompt notification of an SAE by an investigator to a sponsor is essential to meet legal obligations and ethical responsibilities regarding patient safety and the safety of the investigational product under clinical investigation.

[0261] The sponsor has a legal responsibility to inform both national and other regulatory authorities about the safety of the investigational product under clinical investigation. The sponsor will comply with country-specific regulatory requirements regarding safety reporting to regulatory authorities, Institutional Review Boards (IRBs) / Independent Ethics Committees (IECs) and investigators.

[0262] Suspected unexpected serious adverse reactions (SUSARs) will be reported in accordance with local regulatory requirements and sponsor policy and forwarded to the investigator as appropriate.

[0263] Upon receipt of an Investigator Safety Report from the sponsor containing an SAE or other specific safety information (e.g., a summary or listing of SAEs), the Investigator will review it and submit it with the Investigator Brochure and notify the IRB / IEC, if appropriate, in accordance with local requirements.

[0264] Pregnancy Pregnancy testing will be performed on all WOCBP at protocol-defined time points in the SoA (Figures 2 and 3). Pregnancy testing (urine or serum) may also be performed at any time during the study at the discretion of the investigator.

[0265] A negative pregnancy test is required for WOCBP prior to study drug administration. The following rules apply: Details of all pregnancies of female patients and, where indicated, female partners of male patients will be collected after initiation of investigational drug and until termination of pregnancy. If pregnancy is reported, the investigator will notify the sponsor within 24 hours of learning of the pregnancy. Any 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.

[0266] If a patient becomes pregnant, the study drug will be discontinued immediately and the sponsor will be notified. Each pregnancy will be followed to term and the sponsor will be notified regarding the outcome.

[0267] 5.4.6. Adverse events of particular interest Meningococcal infections are collected as adverse events of special interest (AESI).

[0268] 5.5. Treatment of overdose In this study, administration of investigational drug in amounts greater than those specified in the protocol will be considered an overdose.

[0269] Accidental overdoses that are unrelated to laboratory abnormalities and clinical symptoms are not considered AEs. Overdoses, whether or not an AE is present, will be reported to the sponsor by the investigator within 24 hours.

[0270] The sponsor does not recommend a specific treatment for overdose.

[0271] In the event of an overdose, the investigator will: · Contact the medical monitor immediately. · Closely monitor patients for AEs / SAEs. If requested by the medical monitor, collect plasma samples for PK analysis (determined on a case-by-case basis). · Record the amount of overdose and the timing of the overdose on the CRF.

[0272] The decision to discontinue treatment will be made by the investigator in consultation with the medical monitor based on the patient's clinical evaluation.

[0273] 5.6. Pharmacokinetics and Pharmacodynamics Blood samples for measurement of serum drug concentrations and for PD assessment will be collected before and after study drug administration at the time points specified in the SoA (Figures 2 and 3). Cerebrospinal fluid (CSF) samples for PK and PD assessment are optional at the time points specified in the protocol (Figures 2 and 3) and will be obtained only from patients who consent to CSF ​​collection. Instructions for biological sample collection and handling will be provided by the sponsor. The actual date and time (24-hour clock time) of each sample will be recorded on the eCRF and central test requisition form. Additional information regarding sample collection, including blood volume requirements, is provided in the laboratory manual.

[0274] 5.6.1 Sample collection during the study Baseline (B) and trough (T) PK and PD blood samples will be collected pre-dose within 90 minutes prior to administration of study drug at visits defined in the SoA (section 1.3). Pre-dose blood samples may be collected prior to administration of the dose via the venous access created for the dose infusion. Post-dose (P) PK and PD blood samples will be collected post-dose, within 120 minutes after completion of study drug infusion. Post-dose blood samples will be collected from the patient's contralateral, non-infused arm. Blood samples at non-dose visits may be collected at any time. In the event of unscheduled visits, PK and PD blood samples will be collected as soon as possible.

[0275] 5.6.2 Sample collection during the study Blood samples for PK and PD analyses will be collected at any time during the scheduled relapse assessment visit. However, if the blood sample collection schedule following relapse coincides with the routine sample collections defined in the SoA (Figures 2 and 3), the instructions for routine PK and PD sample collection during the study (Section 5.6.1) must be followed.

[0276] During an on-study relapse, if the patient receives an additional dose of PE / PP and ULTOMIRIS at the relapse evaluation visit, 3 blood samples for PK and PD will be collected at the following intervals: 1. About 5 to 90 minutes before PE / PP 2. After PE / PP and before injection of investigational drug 3. At least 60 minutes after completion of study drug infusion

[0277] If patients receive PE / PP at any visit other than the relapse assessment visit, blood samples for PK and PD will be collected immediately before and after each session of PE / PP. Post-dose samples (e.g., 1 hour after completion of the booster infusion) will also be collected.

[0278] Genetics There were no pre-specified genetic analyses in this study.

[0279] 5.8. Biomarker research 5.8.1. Exploratory biomarker studies Blood samples for biomarker studies will be collected from all patients at the time points defined in the SoA (Figures 2 and 3). CSF samples are optional for biomarker studies and should only be collected from patients who consent to CSF ​​sample collection. Biomarkers will be measured and include, but are not limited to, the following assessments: AQP4-Ab at protocol-defined time points (Section 1.3 SoA), including during the relapse assessment period (see Section 5.2.3.2 for further details). Complement products Markers of neuroinflammation, such as interleukin 6 (IL-6) Markers of neuronal damage, such as neurofilament light chain (NfL)

[0280] 5.8.2. Future biomarker research Collection of DNA and RNA samples is voluntary. DNA and RNA blood samples should only be collected from patients who consent to it. Future DNA and RNA testing on these samples may include, but is not limited to, specific candidate gene / whole genome analysis.

[0281] Residual samples from pharmacokinetic, pharmacodynamic, immunogenicity and biomarker testing will be stored for future biomarker studies. Analysis may be performed for biomarker mutations believed to play a role in NMOSD activity / progression or therapeutic response to ULTOMIRIS. These samples may also be used to develop methods, assays, prognostics and / or companion diagnostics related to the investigational drug target, disease process, pathways associated with the disease state and / or mechanism of action of the investigational drug.

[0282] Samples may be stored for a maximum period following the last patient's final visit for the study at the site selected by the sponsor to allow for further analysis, in accordance with local regulations.

[0283] 5.9. Immunogenicity assessment Anti-drug antibodies (ADA) to ULTOMIRIS will be assessed in serum samples collected pre-dose (within 5–90 min prior to the start of study drug infusion) from all patients according to the SoA (Figures 2 and 3).

[0284] In addition, serum samples should be collected at the final visit from patients who discontinue the investigational drug or withdraw from the study.

[0285] Serum samples will be screened for antibodies that bind ULTOMIRIS and titers of samples that test positive will be reported. Other analyses may be performed to verify the stability of antibodies to ULTOMIRIS and / or to further characterize the immunogenicity of ULTOMIRIS.

[0286] Detection and characterization of antibodies to ULTOMIRIS will be performed by or under the supervision of the Sponsor using validated assay methods. If deemed necessary, samples may be further characterized to determine titer and the presence of neutralizing antibodies. Samples may be stored at a facility selected by the Sponsor for a maximum period following the last patient's final visit for the study, in accordance with local regulations, to allow further analysis of the immune response to ULTOMIRIS.

[0287] 5.10. Health resource utilization and health economics Healthcare resource utilization and health economics data will be collected on CRFs by the investigator and site personnel for all patients throughout the study related to healthcare encounters, excluding protocol-defined procedures, tests, and encounters.

[0288] The data collected can be used to conduct exploratory economic analyses, including: Volume of surgeries and other selected procedures (inpatient and outpatient) Length of hospital stay · Number and type of diagnostic and therapeutic tests and procedures

[0289] 6.Statistical considerations 6.1. Statistical Hypothesis The time to first on-trial relapse was evaluated using the log-rank test, with the null hypothesis being that there is no difference between the survival curves of the ULTOMIRIS-treated and placebo-treated groups. The alternative hypothesis would be that there is a difference between the two survival curves, with ULTOMIRIS-treated patients being superior to placebo.

[0290] We present 95% confidence intervals (CIs) for the assessed ARR to provide estimates of the assessed ARR rate for patients treated with ULTOMIRIS. Although we did not perform formal hypothesis testing of the assessed ARR, patients treated with ULTOMIRIS are expected to have a low ARR, with the upper limit of the 95% CI not exceeding 0.25 relapses / patient-years.

[0291] For HAI, the null hypothesis would be that the odds of a better outcome are the same between the ULTOMIRIS and placebo groups. The alternative hypothesis would be that there is a difference in the odds of a better outcome between the treatment groups, with ULTOMIRIS associated with higher odds of a better clinical outcome.

[0292] For the EQ-5D index and EQ-5D VAS, the null hypothesis is that there is no difference in the distributions of the ULTOMIRIS and placebo groups. The alternative hypothesis is that there is a difference in the distributions of the treatment groups, with ULTOMIRIS being superior to placebo.

[0293] For EDSS, the null hypothesis would be that the odds of a worse outcome are the same between the ULTOMIRIS and placebo groups. The alternative hypothesis would be that the odds of a worse outcome differ between the treatment groups, with the odds of a worse outcome being higher in the placebo group.

[0294] 6.2. Sample size determination This is an open-label, external, placebo-controlled trial evaluating ULTOMIRIS in patients with NMOSD with a primary endpoint of time to first evaluated on-trial relapse. The placebo arm of study NCT01892345 will serve as the external control.

[0295] The sample size and power calculations for this study, using the primary endpoint of time to first recurrence, were based on the following assumptions: Log-rank test for comparing ravulizumab with placebo 47 patients in the placebo group 90% power - Two-sided 5% significance level Dropout rate: 2-10% Relapse-free rate at 12 months was 92% in the ULTOMIRIS arm - 63% of patients in the placebo group were relapse-free at 12 months

[0296] With these assumptions, a maximum sample size of approximately 55 patients in the ravulizumab treatment group would provide at least 90% power to detect a treatment difference in time to first positive recurrence.

[0297] 6.3. Population for analysis For purposes of analysis, the following populations are defined as shown in Table 6: [Table 6]

[0298] 6.4.Statistical analysis The primary analysis will be performed when all patients have completed the primary treatment period. This analysis will include all efficacy, safety, and PK / PD study data intended for regulatory submission and will be the final analysis of the primary treatment period. SAPs supporting the primary analysis will be developed and finalized immediately after the protocol is finalized. If needed, a final SAP will be developed prior to the completion of the long-term extension period to describe additional long-term efficacy and safety analyses. This section summarizes the primary efficacy endpoint, the planned statistical analyses of the secondary endpoints, and the safety analyses.

[0299] Summary statistics will be calculated and displayed by treatment group and by visit when applicable. Descriptive statistics for continuous variables will minimally include number of patients, mean, standard deviation, minimum, median and maximum. For categorical variables, frequencies and percentages will be presented. Graphical displays will be provided where appropriate. All statistical analyses will be performed based on a 5% two-sided type I error unless otherwise stated. Missing data will not be imputed.

[0300] Analyses are performed using SAS® software, version 9.4 or later.

[0301] Efficacy Analysis To account for potential differences in baseline characteristics between ULTOMIRIS and the external placebo comparator, efficacy analyses will include covariate adjustment methodologies, as appropriate; details will be provided in the SAP.

[0302] 6.4.1.1 Primary endpoint The primary efficacy endpoint is time to first assessed on-trial relapse. If there is a statistically significant difference (e.g., p-value <0.05) between the ravulizumab-treated and placebo groups for the primary endpoint of time to first assessed on-trial relapse, the trial will be considered to have met its primary efficacy objective. The log-rank test will be used to compare treatment groups for the primary endpoint. Hazard ratios and risk reductions will be summarized from the Cox proportional hazards model. Confidence intervals (95%) will be presented for the estimated proportion of patients who are relapse-free at various time points (e.g., week 26, week 50) based on complementary log-log transformation. Kaplan-Meier curves will be constructed for both treatment groups.

[0303] Sensitivity analyses of the primary endpoint will be described in the SAP.

[0304] Secondary endpoints 6.4.1.2.1. ARR assessed during the study The on-study ARR assessed is presented, descriptively showing estimates for the ULTOMIRIS treatment groups and 95% CIs from a Poisson regression model with logarithm of time on study as the offset variable and historical ARR as a covariate in the model. This endpoint was considered statistically significant if the upper limit of the 95% CI was ≤0.25 relapses per year.

[0305] EuroQoL 5-dimension (EQ-5D) index score and EQ-5D VAS Changes in EQ-5D index scores from baseline to 6 weeks post-relapse / end of first-line treatment (i.e., for the placebo group, 6 weeks post-relapse for patients who relapsed or end of study NCT01892345 (EOS) for patients who did not relapse; for the ravulizumab group, EQ-5D index scores 6 weeks post-first observed relapse for patients who relapsed and end of first-line treatment for patients who did not relapse) will be analyzed using nonparametric analysis of covariance (ANCOVA) adjusted for baseline EQ-5D index scores. Baseline is defined as the last available assessment before treatment for all patients, regardless of treatment group.

[0306] Changes in EQ-5D VAS from baseline to 6 weeks post-relapse / EOPT period will be analyzed as described for changes in EQ-5D index scores using non-parametric ANCOVA adjusting for baseline EQ-5D VAS.

[0307] Expanded Disability Status Scale (EDSS) Change in EDSS score from baseline to 6 weeks post-relapse / EOPT analysis time point will be calculated as described for EQ-5D endpoints. For EDSS, this change from baseline will be categorized as clinically important worsening (no worsening, clinical worsening). This endpoint will be analyzed using a logistic regression model with treatment group and baseline EDSS as covariates. Details will be provided in SAP.

[0308] Hauser Ambulatory Index (HAI) Change in HAI score from baseline to 6 weeks post-relapse / EOPT analysis time point will be calculated as described for EQ-5D endpoints. For HAI, this change from baseline will be categorized as clinically important change (clinical improvement, stable, clinical deterioration). This 3-tiered endpoint will be analyzed using a proportional odds model including treatment group and baseline HAI as covariates. Details will be provided to SAP.

[0309] 6.4.1.2.5. Explanation of multiple comparisons A closed test procedure will be applied to control type I error for the analysis of the primary and secondary endpoints. If the primary endpoint is statistically significant in favor of ULTOMIRIS, the secondary endpoints will be evaluated according to the following ranking: 1. ARR evaluated during the study 2. Clinically significant change from baseline in walking function measured by the HAI 3. Change from baseline in EQ-5D index score 4. Change from baseline in EQ-5D VAS score 5. Clinically significant worsening from baseline in EDSS score

[0310] Hypothesis testing proceeds from the highest rank of investigational ARR evaluated (#1) to the lowest rank of EDSS score (#5), and if an endpoint does not achieve statistical significance (p>0.05 or upper CI of ARR>0.25), the lower ranked endpoint is considered not statistically significant. Confidence intervals and p-values ​​are presented for all secondary efficacy endpoints for descriptive purposes, regardless of the outcome of closed testing procedures.

[0311] 6.4.1.3. Tertiary / Exploratory Endpoints Summary and analyses of tertiary and exploratory endpoints will be described in the SAP.

[0312] 6.4.2. Safety analysis A safety set will be used to summarize all safety data.

[0313] Analysis of Adverse Events Analysis and reporting of AEs will be based on treatment-emergent adverse events (TEAEs), defined as AEs that occurred at or after the first dose of ULTOMIRIS. Incidence of TEAEs will be summarized by system organ class (SOC) and preferred term, with further summaries of severity, relationship to study drug, TEAEs leading to study drug discontinuation, and TEAEs leading to death. A summary of TESAEs will also be summarized by SOC and preferred term, with an additional summary indicating relationship to study drug. These summaries will be presented by treatment arm (ULTOMIRIS, placebo).

[0314] 6.4.2.2. Analysis of Clinical Laboratory Parameters, Vital Sign Measurements, and Electrocardiogram Parameters Laboratory measurements and their change from baseline at the visit and shift from baseline, if applicable, will be summarised.ECG InterpretationThe ECG will be summarised, including heart rate, PR, QRS, QT and QTc, and vital signs will also be summarised.

[0315] 6.4.2.3. Other Safety Analyses The number and percentage of patients in each category of the C-SSRS and the shift from baseline are presented.

[0316] 6.4.3. Demographics and baseline characteristics The safety set will be used to summarize patient demographics and baseline characteristics by treatment group. Summary statistics will be presented. No formal hypothesis testing will be performed.

[0317] 6.4.4. Patient breakdown The numbers of patients screened, treated, completed the study, discontinued, reasons for discontinuation, and number of patients included in each analysis set will be summarised. Major protocol deviations will be summarised by predefined deviation categories.

[0318] 6.4.5. Medical history, surgical history, and history of neuromyelitis optica spectrum disorder Medical and surgical history will be summarized by Medical Dictionary for Regulatory Affairs (MedDRA) Activities, Version 21.0 or later, SOC, and PT. NMOSD history will also be summarized.

[0319] 6.4.6. Previous and concomitant medications Medications taken before the first dose of the study drug are considered prior medications, and those taken at or after the first dose of the study drug are considered concomitant medications. Prior and concomitant medications will be summarized for all patients in the safety analysis set, including IST for relapse prevention and acute relapse treatment. Medications will be coded using the World Health Organization Drug Dictionary (WHODrug; latest version available at time of analysis).

[0320] 6.4.7. Pharmacokinetic, Pharmacodynamic and Anti-Drug Antibody Analysis PK parameters for ULTOMIRIS will be derived using individual serum concentration data for all patients who received at least one dose of ULTOMIRIS and for whom PK data are evaluable.

[0321] Mean serum concentration-time profile graphs are constructed. Individual patient serum concentration-time profile graphs may also be provided. Actual dose administration and sample collection times are used for all calculations. Descriptive statistics are calculated for serum concentration data at each sample collection, as appropriate. Population-PK assessments may be considered using data from this study or in combination with data from other studies.

[0322] Pharmacodynamic analyses will be performed in all patients who receive at least one dose of ULTOMIRIS and have evaluable PD data.

[0323] Descriptive statistics will be presented for all ULTOMIRIS PD endpoints at each sampling time point (Section 1.3). ULTOMIRIS PD efficacy will be assessed by evaluating absolute free C5 serum concentrations and change over time and percent change from baseline, as appropriate. Evaluation of ULTOMIRIS PK / PD relationships can be explored using data from this study or in combination with data from other studies.

[0324] For the assessment of immunogenicity, the presence of confirmed positive ADA will be summarized. Furthermore, after confirmation of a positive ADA, samples will be evaluated for ADA titer and the presence of neutralizing antibodies.

[0325] 6.5. Interim Analysis The primary analysis will be performed when all patients have completed the primary treatment period. This analysis will include all efficacy, safety, and PK / PD study data intended for regulatory submission and will be the final analysis of the primary treatment period. This analysis will not be considered an interim analysis. Interim analyses, including data collected during the long-term extension, may be performed to support submission requirements.

[0326] 6.6. Data Monitoring Committee (DMC) This study does not include DMC.

[0327] 7. Support for documentation and operational considerations 7.1. Appendix 1: Diagnostic criteria for neuromyelitis optica spectrum disorder International Panel on NMO Diagnostic Criteria for NMOSD using AQP4-IgG (Wingerchuk, D. et al., Neurology, 85:177-89, 2015) - In this study, all three of the following criteria must be met for a diagnosis of NMOSD: 1. At least one core clinical feature: ○Optic neuritis Acute myelitis Area postrema syndrome: Unexplained hiccups or episodes of nausea and vomiting Acute brainstem syndrome Symptomatic narcolepsy or acute diencephalic clinical syndrome with diencephalic MRI lesions typical of NMOSD Symptomatic brain syndrome with brain lesions typical of NMOSD visualized by MRI 2. Anti-AQP4 Ab tests positive using the best detection method available (cell-based assay required for this study) 3. Rule out alternative diagnoses

[0328] 7.2. Appendix 2: Expanded Disability Status Scale (EDSS) The Kurtzke EDSS is a method of quantifying disability in multiple sclerosis (MS). The EDSS replaced the previous Disability Status Scale used in MS. The EDSS quantifies impairment in eight functional systems (FS) and allows the neurologist to assign a Functional System Score (FSS) to each of these. The FS are: Cone ·cerebellum Brain stem ·feelings Intestines and bladder Vision Cerebrum ·others It is.

[0329] As shown in Figure 4, EDSS steps 1.0 to 4.5 refer to fully ambulatory MS patients, while EDSS steps 5.0 to 9.5 are defined by impaired walking. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0330] Example 2. Trial of ravulizumab in adults with NMSOD The study evaluated the efficacy and safety of ULTOMIRIS IV in adult patients with NMOSD. The study was designed as an open-label, multicenter, single-arm study versus placebo in NMOSD as an external comparator to demonstrate the superiority of ULTOMIRIS versus placebo. Patients enrolled in the study received ULTOMIRIS during the first-line treatment period, which ended when the last enrolled patient reached week 50. Patients were then permitted to enter a long-term extension period, during which all patients received ULTOMIRIS.

[0331] The outline of this study is summarized below. ● Strong efficacy was demonstrated in this study - No relapses were observed in treated patients over a median treatment period of 73.5 weeks - 98.6% reduction in risk of relapse compared to placebo Key secondary endpoints were statistically significant (including annualized relapse rate and Hauser ambulation index). - Safety profile is consistent with Soliris and Ultomiris - Two meningococcal infections, but the overall incidence across indications remains similar to Soliris

[0332] The study enrolled 58 adult patients with NMOSD who had a positive serological test for anti-AQP4 antibodies, at least one attack or relapse in the last 12 months before the screening period, and an Expanded Disability Status Scale (EDSS) score ≤7. Prior treatment with prophylactic immunosuppressive therapy (IST) (corticosteroids, azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate mofetil, tacrolimus, or rituximab) was not required for enrollment. However, selected patients receiving IST were allowed to continue treatment throughout the study period. In addition, rescue therapy (including high-dose corticosteroids, PE / PP) was allowed if patients experienced a relapse, as defined by the study protocol.

[0333] A total of 56 (97%) patients completed the first-line treatment period of the study. As shown in Figures 39-46 and Table 8, most of the baseline characteristics of the patients were balanced between the two treatment groups. [Table 8] Abbreviations: ARR = annualized relapse rate; EDSS = Expanded Disability Status Scale; HAI = Hauser Ambulatory Index; IST = immunosuppressive therapy; Max = maximum; Min = minimum; NMOSD = neuromyelitis optica spectrum disorder; SD = standard deviation.

[0334] The primary endpoint of the study was time to first on-trial recurrence as assessed by an independent committee. A significant effect was observed for ULTOMIRIS compared to placebo on time to first assessed on-trial recurrence (p<0.0001) (Figure 17). The hazard ratio (95% confidence interval [CI]) for ULTOMIRIS compared to placebo was 0.014 (0.000, 0.103), representing a 97.9% reduction in risk of recurrence. At week 48, 100% of patients treated with ULTOMIRIS had not recurred (compared to 63.2% of patients treated with placebo). This effect persisted through week 96, at which point 100% of patients treated with ULTOMIRIS had remained recurrence-free (compared to 51.9% of patients treated with placebo). Patients treated with ULTOMIRIS experienced more consistent improvements than patients in the placebo group in terms of time to first assessment of relapse during the study across all predefined subgroups (no IST (monotherapy), steroids only, azathioprine, mycophenolate mofetil, any IST, and rituximab in the year prior to screening).

[0335] In the case of ULTOMIRIS, the annualized relapse rate (ARR) (95% CI) during the evaluated trial was 0 (N / A, N / A), which represents a statistically significantly lower ARR than 0.25 (1 evaluated annualized relapse during the evaluated trial per 4 patient-years) (p<0.0001) (Figure 69).

[0336] The distribution of changes from baseline to the end of the study period (either the end of the primary treatment period or the 6-week recurrence follow-up visit for the first on-study relapse) for functional impairment (HAI [p<0.0122] and EDSS [p<0.0588] shown in Figure 78) and quality of life (EQ-5D index [p<0.0567] and EQ-5D VAS [p<0.0297]) were statistically significant and clinically important for ULTOMIRIS compared to placebo. The results for each of these variables are summarized in Figure 78, Figure 86, Figure 82, and Figure 84, respectively.

[0337] Compared to placebo, treatment with ULTOMIRIS reduced the annual incidence of both relapse-related hospitalizations during the study (14 vs. 0 for placebo, p<0.0001) (shown in Figure 69) and acute relapse treatment (methylprednisolone IV: 115 vs. 0 for placebo, p<0.0001; plasma exchange: 7 vs. 0 for placebo, p<0.0002) (shown in Figures 69 and 70).

[0338] The study shows the surprising observation that all 58 patients who received ULTOMIRIS remained relapse-free over a median treatment period of 73.5 weeks.

[0339] A summary of safety features is provided below in bullet points. Median study duration: Ultomiris: 73.5 weeks (first-line Soliris: 90.93 weeks) vs. 84.1 patient-years - Median study duration exceeds that of PREVENT placebo (43.1 weeks) and is comparable to that of PREVENT eculizumab at the time of the safety update (approximately 99 weeks) ●100% treatment compliance - Safety profile is consistent with Soliris and Ultomiris in other indications (as well as Soliris in NMOSD) - Two meningococcal infections, but the overall incidence across indications remains similar to Soliris. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6]

Claims

1. A composition for treating neuromyelitis optica spectrum disorder (NMOSD) in a human subject in need thereof, comprising an anti-C5 antibody or its antigen-binding fragment, wherein the anti-C5 antibody or its antigen-binding fragment comprises the CDR1, CDR2, and CDR3 heavy chain sequences shown in SEQ ID NOs. 19, 18, and 3, and the CDR1, CDR2, and CDR3 light chain sequences shown in SEQ ID NOs. 4, 5, and 6, respectively, wherein the anti-C5 antibody or its antigen-binding fragment comprises an Fc region including the amino acid sequence shown in SEQ ID NO. 13, wherein the amino acid sequence includes up to four amino acid substitutions in the amino acid sequence shown in SEQ ID NO. 13, and the amino acid substitutions do not include leucine 307 and serine 313, and an effective amount of the anti-C5 antibody or its antigen-binding fragment is administered to the human subject.

2. The composition according to claim 1, wherein the anti-C5 antibody or its antigen-binding fragment comprises a heavy chain variable region shown in SEQ ID NO: 12 and a light chain variable region shown in SEQ ID NO:

8.

3. The composition according to claim 1, wherein the anti-C5 antibody or its antigen-binding fragment comprises the heavy chain constant region shown in SEQ ID NO:

13.

4. The composition according to claim 1, wherein the antibody or its antigen-binding fragment comprises a heavy chain polypeptide having the amino acid sequence of SEQ ID NO: 14 and a light chain polypeptide having the amino acid sequence of SEQ ID NO:

11.

5. The anti-C5 antibody or its antigen-binding fragment has a concentration of 0.1 nM ≤ K at pH 7.4 and 25°C. Ｄ affinity dissociation constant (K) in the range of ≤ 1 nM Ｄ The composition according to claim 1, wherein it binds to human C5.

6. The anti-C5 antibody or its antigen-binding fragment has a K content of ≥10 nM at pH 6.0 and 25°C. Ｄ The composition according to claim 1, wherein it binds to human C5.

7. The composition according to claim 1, wherein the subject is 18 years of age or older.

8. The composition according to claim 1, wherein the subject is positive for anti-AQP4 antibody.

9. The composition according to claim 1, wherein the subject has had at least one seizure or relapse in the past 12 months.

10. The composition according to claim 1, wherein the subject has an Extended Disability Status Scale (EDSS) score of ≤ 7.

11. The composition according to claim 1, characterized in that it is administered without co-administration with additional immunosuppressive therapy (IST).

12. The composition according to claim 1, characterized in that it is administered in combination with at least one IST.

13. The composition according to claim 12, wherein the at least one IST is selected from the group consisting of corticosteroids, azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), and tacrolimus (TAC).

14. The composition according to claim 1, wherein the subject has a body weight of at least 40 kg.

15. The therapeutically effective dose is the composition according to claim 1, based on the body weight of the subject.

16. The composition according to claim 1, wherein the subject exhibits at least one symptom of NMOSD.

17. If the subject has a weight of ≥40 kg and <60 kg, (a) The composition is administered on day 1 of the administration cycle in a loading dose of 2400 mg of the anti-C5 antibody; and (b) The composition according to claim 1, characterized in that it is administered at a maintenance dose of 3,000 mg of the anti-C5 antibody on the 15th day of the administration cycle and every 8 weeks thereafter.

18. If the subject has a weight of ≥60 kg and <100 kg, (a) The composition is administered on day 1 of the administration cycle in a loading dose of 2700 mg of the anti-C5 antibody; and (b) The composition according to claim 1, characterized in that it is administered at a maintenance dose of 3,300 mg of the anti-C5 antibody on the 15th day of the administration cycle and every 8 weeks thereafter.

19. If the subject has a weight of ≥ 100 kg, (a) The composition is administered on day 1 of the administration cycle in a loading dose of 3000 mg of the anti-C5 antibody; and (b) The composition according to claim 1, characterized in that it is administered at a maintenance dose of 3,600 mg of the anti-C5 antibody on the 15th day of the administration cycle and every 8 weeks thereafter.

20. The composition according to claim 1, wherein 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 administration cycle.

21. The composition according to claim 1, wherein 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 administration cycle.

22. The composition according to claim 1, wherein the treatment maintains a free C5 concentration of 0.3 to 0.5 μg / mL or less.

23. The composition according to claim 1, characterized in that the composition is administered at doses of 3,000 mg, 3,300 mg, or 3,600 mg of the anti-C5 antibody or its antigen-binding fragment every eight weeks for up to two years after the administration cycle.

24. The composition according to claim 1, characterized in that it is formulated for intravenous administration.

25. The composition according to claim 1, wherein the patient has not been previously treated with a complement inhibitor.

26. The composition according to any one of claims 17 to 19, wherein the administration cycle comprises a total of 26 weeks of treatment.

27. The composition according to claim 1, wherein the treatment results in terminal complement inhibition.

28. The composition according to claim 1, wherein the subject undergoes plasma exchange (PE) / plasmapheresis (PP).

29. The subject optionally receives an additional dose of ravulizumab within 4 hours after the completion of PE / PP, according to the composition of claim 28.

30. The composition according to claim 29, wherein the additional dose is 1200 to 1800 mg of ravulizumab.

31. The composition according to claim 1, wherein the human subject experiences clinically meaningful improvement in one or more clinical markers related to NMOSD progression after administration of the composition.

32. The composition according to claim 31, wherein the clinical markers for NMOSD progression are selected from the group consisting of the evaluated clinical trial ARR, EDSS score, EQ-5D, SF-36, Hauser gait index (HAI), and OSIS.

33. The composition according to claim 1, wherein the subject remains recurrence-free for at least 48 weeks.

34. The composition according to claim 1, wherein the subject remains recurrence-free for at least 73 weeks.

35. The composition according to claim 1, wherein the subject remains recurrence-free for at least 96 weeks.

36. The composition according to claim 1, wherein the subject remains recurrence-free for at least 144 weeks.

37. The composition according to claim 1, wherein the subject does not experience a clinically significant deterioration based on the Hauser gait index.

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