Dosage and administration of Anti-c5 antibodies for treatment of generalized myasthenia gravis

Abstract

To provide dosage and administration of anti-C5 antibodies for treatment of generalized myasthenia gravis.SOLUTION: Provided are methods for clinical treatment of generalized myasthenia gravis (gMG) using an anti-C5 antibody or antigen binding fragment thereof. Provided herein are compositions and methods for treating generalized myasthenia gravis (gMG) in a human patient, comprising administering to the patient an anti-C5 antibody or antigen binding fragment thereof, where the anti-C5 antibody or antigen binding fragment thereof is administered (or the anti-C5 antibody or antigen binding fragment thereof is for administration) according to a particular clinical dosage regimen (i.e., at a particular dose amount and according to a prescribed dosing schedule).SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority based on U.S. Provisional Patent Application No. 62 / 805,350, filed on February 14, 2019, and U.S. Provisional Patent Application No. 62 / 814,935, filed on March 7, 2019, the entire contents of which are hereby incorporated by reference for all purposes.

[0002] Reference to Electronically Submitted Sequence Listing The contents of the sequence listing (name: 701828_AX9_0041PC_ST25_Sequence_Listing.txt, size: 55 KB, date of data creation: February 10, 2020) submitted electronically as an ASCII text file are hereby incorporated by reference in their entirety.

Background Art

[0003] The complement system works in cooperation with other immune systems of the body to defend against the invasion of cellular and viral pathogens. There are at least 25 complement proteins, which exist as a complex aggregate of plasma proteins and membrane cofactors. Plasma proteins account for approximately 10% of the globulins in vertebrate serum. The components of the complement system exert their immune defense functions by interacting in a complex but precise series of enzymatic cleavages and membrane-bound events. The resulting complement system cascade leads to the production of products with opsonin function, immunomodulatory function, and lytic function.

[0004] Myasthenia gravis (MG) is a rare, wasting, acquired autoimmune neuropathy of the neuromuscular junction (NMJ) caused by a disorder of neuromuscular transmission, resulting from the binding of autoantibodies (autoAbs) to proteins involved in signal transmission at the NMJ. These proteins include the nicotinic acetylcholine receptor (AChR), or less frequently, muscle-specific tyrosine kinase (MuSK) involved in the clustering of AChR.

[0005] MG can cause life-threatening respiratory failure (myasthenic crisis). In the United States, the prevalence of MG is 14 to 20 per 100,000 people, and approximately 60,000 Americans are affected. The male-to-female ratio of affected individuals is equal, but the peak onset age for women is in their 30s, while the peak onset age for men is in their 60s or 70s. Approximately 15% to 20% of affected individuals experience myasthenic crisis during the course of the disease, and 75% within 2 years of diagnosis require hospitalization and ventilatory support. The mortality rate of MG is approximately 4%, and most of it is due to respiratory failure.

[0006] Clinically, myasthenia gravis is characterized by a decrease in muscle strength and fatigue of voluntary muscles, that is, skeletal muscles. Initially, MG may be accompanied by a decrease in extraocular muscle strength that affects the movement of the eyes and eyelids, and is referred to as ocular myasthenia gravis (oMG). In 10% of affected individuals, the disease is limited to the extraocular muscles. 90% of affected individuals have generalized MG, with a decrease in muscle strength including neck muscles, head muscles, spinal muscles, bulbar muscles, respiratory muscles, or limb muscles. A decrease in bulbar muscle strength refers to the muscles controlled by the nerves emerging from the bulbous part of the brainstem, and manifests as difficulty speaking, chewing, swallowing, and controlling the head.

[0007] Patients with generalized myasthenia gravis (gMG) differ from the population with ocular myasthenia gravis (oMG) in that the neuromuscular inflammation and the resulting clinical findings extend not only to the extraocular muscles but also to all voluntary muscle groups, that is, bulbar muscles, respiratory muscles, head muscles, neck muscles, trunk muscles, or peripheral muscles (regardless of the presence or absence of influence on the extraocular muscles). Severe muscle weakness and serious outcomes (difficulty turning around, dysarthria, dysphagia, disorientation, shortness of breath (both during activity and at rest), muscle weakness in the upper and lower limbs, movement disorders, a significant decrease in the ability to perform activities of daily living (ADL), extreme fatigue, and episodes of pulmonary insufficiency requiring mechanical ventilation) are characteristics of gMG. Patients with gMG have a higher prevalence and a greater disease burden than patients with single oMG. gMG is a rare disorder, with an estimated prevalence of 145 to 278 per 1 million people. Patients with gMG suffer from severe inflammatory neuromuscular disorders and have limited treatment options.

[0008] During the exacerbation of gMG, hospitalization is common due to the need for respiratory support (including mechanical ventilation) after respiratory failure (such as myasthenic crisis), as well as nutritional support and prevention of aspiration related to dysphagia. In patients with more advanced gMG, the mortality rate has been reported to increase up to 40% 10 years after diagnosis.

[0009] There is no cure for MG, but there are therapies that reduce muscle weakness and improve neuromuscular function. Current available treatments for myasthenia gravis aim to regulate neuromuscular transmission, inhibit the production or action of pathogenic antibodies, or inhibit inflammatory cytokines. Specific therapies targeting the underlying pathology of NMJ damage, specifically the condition where when anti - AChR antibodies interact with AChR, complement is activated via the classical pathway, inflammation occurs, and as a result, NMJ is destroyed, do not exist at present. There is also no specific therapy to correct the autoimmune deficiency in MG. The current standard of care, immunosuppressive therapy (IST), usually combines cholinesterase inhibitors, corticosteroids, and immunosuppressive drugs (most commonly azathioprine [AZA], cyclosporine, and mycophenolate mofetil [MMF]). Using this IST, the disease can be reasonably controlled in the majority of subjects with MG. However, these therapies are not the optimal therapies for all patients, and there are groups of subjects who do not respond adequately to IST or cannot tolerate it, as well as groups of subjects who require repeated treatments with plasma exchange (PE) and / or intravenous immunoglobulin (IVIg) to maintain clinical stability.

[0010] In cases where control is difficult, gMG patients experience persistent inflammation, tissue destruction, and associated severe pathologies (including profound muscle weakness, movement disorders, shortness of breath, lung insufficiency, extreme fatigue, risk of aspiration, and significant impairment of ADL). These patients are typically diagnosed in adulthood, and the median age of onset ranges from 36 to 60 years. Due to the pathologies associated with gMG, many patients are unable to work or have reduced work capacity, making it difficult to be self-sufficient and take care of others, and requiring assistance for speech, eating, movement, breathing, and performing ADL.

[0011] In experimental animal models of autoimmune gMG and other forms of autoimmune neuropathy in humans, uncontrolled terminal complement system activation has been associated. Autoantibodies recognize target nerve or muscle tissue, including AChR, thereby activating the terminal complement system uncontrollably on the surface of that nerve or muscle.

[0012] Along with the uncontrolled terminal complement system activation induced by autoantibodies, membrane lytic complex (MAC)-dependent lysis and activation, as well as C5a-dependent inflammation occur at the NMJ, resulting in the loss of AChR and impaired neuromuscular transmission. Consistent with this model, both fragments of complement component C3 (C3a and C3b), as well as MAC C5b-9, have been observed at the NMJ of MG patients.

[0013] Since there is no cure for MG and standard care is not effective for all patients, there is a need to provide improved treatment methods for these patients. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0014] Provided by the present invention are compositions and methods for treating generalized myasthenia gravis (gMG) in a human patient, comprising administering to the patient an anti-C5 antibody or an antigen-binding fragment thereof, and administering the anti-C5 antibody or an antigen-binding fragment thereof according to a specific clinical dosing regimen (i.e., at a specific dosage and according to a predetermined dosing schedule) (or the anti-C5 antibody or an antigen-binding fragment thereof is for administration as described above).

[0015] Ravulizumab (also known as the antibody BNJ441, ALXN1210 or Ultomiris™) comprises a heavy chain having the sequence shown in SEQ ID NO: 14, and a light chain having the sequence shown in SEQ ID NO: 11, or antigen-binding fragments and variants thereof. The terms BNJ441, ALXN1210, ravulizumab and Ultomiris™ can be used interchangeably throughout this document and all refer to the same antibody. Thus, an exemplary antibody for use in the methods described herein is ravulizumab, or an antibody comprising the complementarity-determining regions (CDRs) or variable regions (VRs) of the heavy and light chains of ravulizumab.

[0016] In some embodiments, the antibody comprises the CDR1 domain, CDR2 domain and CDR3 domain of the heavy chain variable (VH) region of ravulizumab having the sequence shown in SEQ ID NO: 12, and the CDR1 domain, CDR2 domain and CDR3 domain of the light chain variable (VL) region of ravulizumab having the sequence shown in SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain CDR1 sequence as shown in SEQ ID NO: 19, a heavy chain CDR2 sequence as shown in SEQ ID NO: 18, and a heavy chain CDR3 sequence as shown in SEQ ID NO: 3, and a light chain CDR1 sequence as shown in SEQ ID NO: 4, a light chain CDR2 sequence as shown in SEQ ID NO: 5, and a light chain CDR3 sequence as shown in SEQ ID NO: 6.

[0017] In some embodiments, the antibody comprises a VH region having the amino acid sequence set forth in SEQ ID NO: 12 and a VL region having the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain constant region as set forth in SEQ ID NO: 13. In some embodiments, the antibody comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises substitutions of Met-429-Leu and Asn-435-Ser at the residues corresponding to methionine at position 428 and asparagine at position 434, respectively, in the EU numbering.

[0018] In some embodiments, the antibody comprises a heavy chain CDR1 sequence as set forth in SEQ ID NO: 19, a heavy chain CDR2 sequence as set forth in SEQ ID NO: 18, and a heavy chain CDR3 sequence as set forth in SEQ ID NO: 3, a light chain CDR1 sequence as set forth in SEQ ID NO: 4, a light chain CDR2 sequence as set forth in SEQ ID NO: 5, and a light chain CDR3 sequence as set forth in SEQ ID NO: 6, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises substitutions of Met-429-Leu and Asn-435-Ser at the residues corresponding to methionine at position 428 and asparagine at position 434, respectively, in the EU numbering.

[0019] In some embodiments, the antibody of the invention competes with the above antibody in binding to the same epitope on C5 and / or binds to the same epitope on C5. In some embodiments, the antibody has at least about 90% amino acid sequence identity with the above antibody in the variable region (e.g., at least about 90%, about 95% or about 99% identity with SEQ ID NO: 12 and SEQ ID NO: 8 in the variable region).

[0020] In some embodiments, the antibody of the invention binds to human C5 with an affinity dissociation constant (KD) in the range of 0.1 nM or more and 1 nM or less at pH 7.4 and 25°C. In some embodiments, the antibody binds to human C5 with a KD of 10 nM or more at pH 6.0 and 25°C. In some embodiments, for the antibody of the invention, [(KD of the antibody or its antigen-binding fragment for human C5 at pH 6.0 and 25°C) / (KD of the antibody or its antigen-binding fragment for human C5 at pH 7.4 and 25°C)] is greater than 25.

[0021] In some embodiments, a patient being treated according to the methods described herein has received a vaccine against Neisseria meningitidis infection within 3 years prior to the start of treatment or at the start of treatment. In some embodiments, for patients being treated less than 2 weeks after receiving the Neisseria meningitidis vaccine, treatment with appropriate prophylactic antibiotics is also carried out until 2 weeks after vaccination. In some embodiments, patients being treated according to the methods described herein are vaccinated against Neisseria meningitidis serogroups A, C, Y, W135, and / or B.

[0022] In some embodiments, the dose of the anti-C5 antibody or its antigen-binding fragment is based on the patient's body weight. For example, in some embodiments, a patient is administered about 2400 mg, about 2700 mg, about 3000 mg, about 3300 mg, and / or about 3600 mg of the anti-C5 antibody or its antigen-binding fragment based on their body weight. In some embodiments, a patient with a body weight of 40 kg or more and less than 60 kg is administered 2400 mg or 3000 mg of the anti-C5 antibody or its antigen-binding fragment. In some embodiments, a patient with a body weight of 60 kg or more and less than 100 kg is administered 2700 mg or 3300 mg of the anti-C5 antibody or its antigen-binding fragment. In some embodiments, a patient with a body weight of 100 kg or more is administered 3000 mg or 3600 mg of the anti-C5 antibody or its antigen-binding fragment. In some embodiments, the dosing regimen is adjusted to provide an optimal desired response (e.g., an effective response).

[0023] In some embodiments, an anti-C5 antibody or an antigen-binding fragment thereof is administered once on the first day of an administration cycle, once on the fifteenth day of the administration cycle, and then every eight weeks thereafter. In some embodiments, after the administration cycle, the anti-C5 antibody or an antigen-binding fragment thereof is administered every eight weeks (e.g., at a dose of 3000 mg, 3300 mg, or 3600 mg) over a maximum extension period of two years.

[0024] In some embodiments, an anti-C5 antibody or an antigen-binding fragment thereof is administered over one or more administration cycles. In some embodiments, the administration cycle is 26 weeks. In some embodiments, the treatment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 cycles. In some embodiments, the treatment continues throughout the life of the human patient.

[0025] In some embodiments, a patient switches from taking one C5 inhibitor to taking another C5 inhibitor during a treatment course. Another anti-C5 antibody may be administered during a separate treatment period. For example, in some embodiments, provided is a method of treating a human patient with a complement-related disorder (such as generalized myasthenia gravis (gMG)) who is being treated with eculizumab, the method comprising discontinuing treatment with eculizumab and switching the patient to treatment with an alternative complement inhibitor. For example, in some embodiments, the patient is treated with eculizumab for a treatment period (such as 26 weeks) and then, during an extension period, with another anti-C5 antibody (such as ravulizumab). In some embodiments, during an induction period, eculizumab is administered to the patient at a dose of 900 mg on days 1, 8, 15, and 22 of a dosing cycle, and then a maintenance dose of 1200 mg of eculizumab is administered on day 19 of the dosing cycle, and thereafter every two weeks (for a total of 26 weeks), and then treatment with ravulizumab is performed over an extension period of up to two years. In some embodiments, provided is a method of treating a human patient with a complement-related disorder who is being treated with ravulizumab, the method comprising discontinuing treatment with ravulizumab and switching the patient to treatment with an alternative complement inhibitor. For example, the patient is treated with ravulizumab for a treatment period (such as 26 weeks) and then, during an extension period, with another anti-C5 antibody (such as eculizumab).

[0026] Exemplary alternative complement inhibitors include, but are not limited to, antibodies or antigen-binding fragments thereof, small molecules, polypeptides, polypeptide analogs, peptidomimetics, siRNA, and aptamers. In some embodiments, 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 bioactive fragments thereof. In some embodiments, the alternative complement inhibitor inhibits one or both of the generation of anaphylatoxin activity associated with C5a and / or the formation of the membrane-damaging complex associated with C5b. In some embodiments, 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.

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

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

[0029] In some embodiments, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains the free C5 concentration at a minimum. For example, in some embodiments, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains the free C5 concentration at 0.2 μg / ml, 0.3 μg / ml, 0.4 μg / ml, 0.5 μg / ml or less. In some embodiments, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains the free C5 concentration at 0.309 - 0.5 μg / ml or less. In some embodiments, the treatments described herein reduce the free C5 concentration by more than 99% over the course of the treatment period. In some embodiments, the treatment reduces the free C5 concentration by more than 99.5% over the course of the treatment period.

[0030] The anti-C5 antibody or antigen-binding fragment thereof can be administered to the patient by any suitable means. In some embodiments, the antibody is formulated for intravenous administration.

[0031] The effectiveness of the treatment methods provided by the present invention can be evaluated using any suitable means. In some embodiments, in gMG patients, the treatment results in at least one therapeutic effect selected from the group consisting of, but not limited to, reduction or cessation of inflammation, tissue destruction, profound muscle weakness, difficulty chewing around the jaw, dysarthria, dysphagia, cognitive impairment, shortness of breath (both during activity and at rest), muscle weakness in the upper and lower extremities, movement disorders, significant decline in the ability to perform activities of daily living (ADL), extreme fatigue, and episodes of pulmonary insufficiency requiring mechanical ventilation. In another embodiment, a clinically significant improvement (decrease) in one or more gMG severity measurements selected from the group consisting of MG-ADL, QMG, MG-QOL15r, Neuro-QOL Fatigue, EQ-5D-5L, MGFA-PIS and / or MGC is seen in the patient.

[0032] In some embodiments, the treatment inhibits terminal complement.

[0033] In some embodiments, the present disclosure provides a method comprising administering to a patient a therapeutically effective amount of ravulizumab, wherein the patient is positive for autoantibodies that bind to nicotinic acetylcholine receptors (anti-AChR), exhibits significant generalized muscle weakness, or has bulbar signs and symptoms of myasthenia gravis, and the method comprises administering ravulizumab to the patient for at least 26 weeks. In some embodiments, the patient has previously received therapy for myasthenia gravis, including inhibitor therapy with anti-cholinesterase and immunosuppressive therapy (IST), and requires long-term plasma exchange or long-term IVIg to maintain clinical stability.

[0034] In some embodiments, in patients treated by the method provided by the present invention, a clinically significant improvement (decrease) in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score is observed after 26 weeks of treatment. In some embodiments, the treatment effect shall be estimated by the mean difference in the change from baseline of the total MG-ADL score at week 26 between the ravulizumab group and the placebo group, regardless of the presence or absence of rescue therapy. The lower the corresponding estimated value, the more beneficial the treatment effect. In some embodiments, rescue therapy shall be permitted if the patient's health is in a critical situation (e.g., in an emergency) or if the patient exhibits a worsening of clinical symptoms as defined herein, in the absence of rescue therapy. In some embodiments, rescue therapy includes high-dose corticosteroids, PP / PE, or IVIg. In some embodiments, a clinically significant improvement observed in the patient is a decrease in the patient's MG-ADL score by at least 3 points after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to the binary endpoint of a 3-point response in MG-ADL at week 26 shall be estimated by the odds ratio (OR), which is the ratio of the corresponding endpoints when the ravulizumab group is compared to the placebo group, regardless of the presence or absence of rescue therapy.

[0035] In some embodiments, in patients being treated by the method provided by the present invention, clinically significant improvement (decrease) in the Quantitative Myasthenia Gravis (QMG) score is seen after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to the change from the baseline continuous endpoint shall be estimated by the mean difference in the change from the baseline of the QMG score at the 26-week time point between the ravulizumab group and the placebo group, regardless of the presence or absence of rescue therapy. The lower the corresponding estimated value, the more beneficial the treatment effect is indicated. In some embodiments, the clinically significant improvement seen in patients is that the QMG score of the patient decreases by at least 5 points after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to the binary endpoint of a 5-point response of QMG at week 26 shall be estimated by the odds ratio (OR), which is the ratio of the corresponding endpoints when the ravulizumab group is compared with the placebo group, regardless of the presence or absence of rescue therapy.

[0036] In some embodiments, in patients being treated by the method provided by the present invention, clinically significant improvement (decrease) in the Myasthenia Gravis Composite (MGC) score is seen after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to the change from the baseline continuous endpoint shall be estimated by the mean difference in the change from the baseline of the MGC score at the 26-week time point between the ravulizumab group and the placebo group, regardless of the presence or absence of rescue therapy. The lower the corresponding estimated value, the more beneficial the treatment effect is indicated.

[0037] In some embodiments, in patients being treated by the methods provided by the present invention, after 26 weeks of treatment, a clinically significant improvement (score reduction) in quality of life as measured by the Revised 15-Component Myasthenia Gravis Quality of Life (MG-QOL15r) score is seen. In some embodiments, the treatment effect corresponding to the change from the baseline continuous endpoint shall be estimated by the mean difference in the change from baseline of the MG-QOL15r score at week 26 between the ravulizumab group and the placebo group, regardless of the presence or absence of rescue therapy. The lower the corresponding estimated value, the more beneficial the treatment effect is indicated.

[0038] In some embodiments, in patients being treated by the methods provided by the present invention, after 26 weeks of treatment, a clinically significant improvement (reduction) in fatigue in neuropathy as measured by the Neuro-QOL Fatigue score is seen. In some embodiments, the treatment effect corresponding to the change from the baseline continuous endpoint shall be estimated by the mean difference in the change from baseline of the Neuro-QOL score at week 26 between the ravulizumab group and the placebo group, regardless of the presence or absence of rescue therapy. The lower the corresponding estimated value, the more beneficial the treatment effect is indicated.

[0039] In some embodiments, in patients treated by the method provided by the present invention, a clinically significant improvement (increase) in health status as measured by the EQ-5D-5L health status score is seen after 26 weeks of treatment. In some embodiments, in patients treated by the method provided by the present invention, a clinically significant improvement (increase) in health status as measured by the EQ-5D-5L index score is seen after 26 weeks of treatment. In some embodiments, in patients treated by the method provided by the present invention, a clinically significant improvement (increase) in health status as measured by the EQ-5D-5L VAS score is seen after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to the change from the baseline continuous endpoint, regardless of the presence or absence of rescue therapy, is estimated by the mean difference in the change from baseline of the EQ-5D-5L health status score (e.g., the EQ-5D-5L index score or EQ-5D-5L VAS score at week 26) between the ravulizumab group and the placebo group. The lower the corresponding estimated value, the more beneficial the treatment effect is indicated.

[0040] In some embodiments, in patients treated by the method provided by the present invention, a clinically significant improvement (increase) in health status as measured by the MGFA-PIS score is seen after 26 weeks of treatment. The treatment effect corresponding to the MGFA-PIS endpoint, regardless of the presence or absence of rescue therapy, is estimated by the proportional odds ratio (OR) of the cumulative proportion across the ordinal categories (starting from the best outcome) of this endpoint when the ravulizumab group is compared to the placebo group at week 26. If the estimated OR exceeds 1, it will indicate that the treatment effect is beneficial.

[0041] In some embodiments, in patients treated by the methods provided by the present invention, after 26 weeks of treatment, a clinically significant improvement (increase) in health status is seen, as measured by a decrease in the incidence of all-cause hospitalizations or deterioration of clinical symptoms as defined herein. In some embodiments, the treatment effect corresponding to the binary endpoint of all-cause hospitalization or deterioration of clinical symptoms as defined herein over 26 weeks is estimated by the odds ratio (OR), which is the ratio of the corresponding endpoint when the Lublizumab group is compared to the placebo group, regardless of the presence or absence of rescue therapy. If the estimated OR corresponding to the composite hospitalization endpoint is less than 1, it indicates that the treatment effect is beneficial. Similarly, if the estimated OR corresponding to the responder endpoint is greater than 1, it indicates that the treatment effect is beneficial.

[0042] In some embodiments, the present disclosure provides a method for treating generalized myasthenia gravis in a patient in need of treatment, comprising administering Lublizumab to the patient, wherein the patient is positive for autoantibodies (anti-AChR) that bind to nicotinic acetylcholine receptors and exhibits marked systemic muscle weakness or bulbar signs and symptoms of myasthenia gravis, and at the same time, is receiving therapy for myasthenia gravis, including inhibitor therapy with an anti-cholinesterase and immunosuppressive therapy (IST), or requires long-term plasma exchange or long-term IVIg to maintain clinical stability, and administering Lublizumab using a stepwise dosing schedule as defined herein, wherein a clinically significant improvement (decrease) in at least one generalized myasthenia gravis severity measurement result selected from the group consisting of MG-ADL, QMG, MG-QOL15r, Neuro-QOL Fatigue, EQ-5D-5L, MGFA-PIS, and / or MGC is seen in the patient.

[0043] In some embodiments, the present disclosure is a method of treating generalized myasthenia gravis in a patient in need of treatment, comprising administering ravulizumab to the patient, wherein the patient is positive for autoantibodies that bind to nicotinic acetylcholine receptors (anti-AChR), and at the same time, significant systemic muscle weakness or bulbar signs and symptoms of myasthenia gravis are observed, and the patient has received therapy for myasthenia gravis, including inhibitor therapy with an anti-cholinesterase and immunosuppressive therapy (IST), and requires long-term plasma exchange or long-term IVIg to maintain clinical stability, and administering ravulizumab using a stepwise dosing schedule as disclosed herein, and in the patient, a clinically significant improvement (decrease) in two generalized myasthenia gravis severity measurement results selected from the group consisting of MG-ADL, QMG, MG-QOL15r, Neuro-QOL Fatigue, EQ-5D-5L, MGFA-PIS, and / or MGC is observed.

[0044] In some embodiments, the present disclosure is a method for treating generalized myasthenia gravis in a patient in need of treatment, comprising administering ravulizumab to the patient, wherein the patient is positive for autoantibodies (anti-AChR) that bind to nicotinic acetylcholine receptors, and at the same time, significant systemic muscle weakness or bulbar signs and symptoms of myasthenia gravis are observed, and the patient has received treatment for myasthenia gravis, including inhibitor therapy with anti-cholinesterase and immunosuppressive therapy (IST), or requires long-term plasma exchange or long-term IVIg to maintain clinical stability. Ravulizumab is administered using a stepwise dosing schedule as disclosed herein, and in the patient, a clinically significant improvement (decrease) in three generalized myasthenia gravis severity measurement results selected from the group consisting of MG-ADL, QMG, MG-QOL15r, Neuro-QOL Fatigue, EQ-5D-5L, MGFA-PIS, and / or MGC is observed. In some embodiments, in the patient, a clinically significant improvement (decrease) in four generalized myasthenia gravis severity measurement results selected from the group consisting of MG-ADL, QMG, MG-QOL15r, Neuro-QOL Fatigue, EQ-5D-5L, MGFA-PIS, and / or MGC is observed. In some embodiments, in the patient, a clinically significant improvement (decrease) in five generalized myasthenia gravis severity measurement results is observed, and the five generalized myasthenia gravis severity measurements are MG-ADL, QMG, MG-QOL15r, Neuro-QOL Fatigue, EQ-5D-5L, MGFA-PIS, and / or MGC. In some embodiments, in the patient, a clinically significant improvement (decrease) in six generalized myasthenia gravis severity measurement results is seen, five of which are MG-ADL, QMG, MG-QOL15r, Neuro-QOL Fatigue, EQ-5D-5L, MGFA-PIS, and / or MGC. In some embodiments, in the patient, a clinically significant improvement (decrease) in seven generalized myasthenia gravis severity measurement results is seen, five of which are MG-ADL, QMG, MG-QOL15r, Neuro-QOL Fatigue, EQ-5D-5L, MGFA-PIS, and / or MGC.

[0045] In some embodiments, the present disclosure provides a method for treating generalized myasthenia gravis in a patient in need of treatment, the method comprising administering ravulizumab by intravenous infusion. In some embodiments, ravulizumab is administered subcutaneously. In some embodiments, the ravulizumab comprises the heavy chain amino acid sequence set forth in SEQ ID NO: 12 and the light chain amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the ravulizumab is a ravulizumab variant comprising the heavy chain amino acid sequence set forth in SEQ ID NO: 14 and the light chain amino acid sequence set forth in SEQ ID NO: 11.

[0046] In some embodiments, the present disclosure provides a method for treating generalized myasthenia gravis in a patient in need of treatment, comprising administering an anti-C5 antibody or an antigen-binding fragment thereof, wherein the antibody is an anti-C5 antibody or an antigen-binding fragment thereof comprising the heavy-chain variable region amino acid sequence set forth in SEQ ID NO: 27 and the light-chain variable region amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the antibody is an anti-C5 antibody or an antigen-binding fragment thereof comprising the heavy-chain variable region amino acid sequence set forth in SEQ ID NO: 35 and the light-chain variable region amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the antibody is an anti-C5 antibody or an antigen-binding fragment thereof comprising the heavy-chain variable region amino acid sequence set forth in SEQ ID NO: 43 and the light-chain variable region amino acid sequence set forth in SEQ ID NO: 44. In some embodiments, the antibody is an anti-C5 antibody or an antigen-binding fragment thereof comprising the heavy-chain variable region amino acid sequence set forth in SEQ ID NO: 45 and the light-chain variable region amino acid sequence set forth in SEQ ID NO: 46.

[0047] In some embodiments, the present disclosure provides a method for treating generalized myasthenia gravis in a patient in need of treatment, comprising administering a therapeutically effective amount of ravulizumab and maintaining the ravulizumab at a concentration of 50 to 100 μg / ml in the serum of the patient.

[0048] In some embodiments, the present disclosure provides a method for treating generalized myasthenia gravis in a patient in need of treatment, comprising administering a therapeutically effective amount of ravulizumab, and after at least 26 weeks of treatment, discontinuing the implementation of IST one or more times in the patient.

[0049] In some embodiments, the present disclosure provides a method for treating generalized myasthenia gravis in a patient in need of treatment, comprising administering a therapeutically effective amount of ravulizumab, and after at least 26 weeks of treatment in the patient, reducing the need for long-term plasma exchange or long-term IVIg to maintain clinical stability.

[0050] In some embodiments, the present disclosure provides a method for treating generalized myasthenia gravis in a patient in need of treatment, the method comprising administering a therapeutically effective amount of ravulizumab, wherein the patient no longer requires long-term plasma exchange or long-term IVIg to maintain clinical stability after at least 26 weeks of treatment.

[0051] In some embodiments, the present disclosure provides a method for treating generalized myasthenia gravis in a patient in need of treatment, the method comprising administering a therapeutically effective amount of ravulizumab, wherein in the patient, the need for long-term plasma exchange or long-term IVIg to maintain clinical stability is reduced after at least 26 weeks of treatment.

[0052] In some embodiments, the present disclosure provides a composition for use in a method of treating myasthenia gravis (MG) in a human patient, the treatment comprising administering to the patient an effective amount of the composition, the composition comprising an antibody or an antigen-binding fragment thereof comprising a heavy-chain CDR1 sequence as set forth in SEQ ID NO: 19, a heavy-chain CDR2 sequence as set forth in SEQ ID NO: 18, and a heavy-chain CDR3 sequence as set forth in SEQ ID NO: 3, and a light-chain CDR1 sequence as set forth in SEQ ID NO: 4, a light-chain CDR2 sequence as set forth in SEQ ID NO: 5, and a light-chain CDR3 sequence as set forth in SEQ ID NO: 6.

[0053] In some embodiments, the antibody or antigen-binding fragment thereof comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises the substitutions Met-429-Leu and Asn-435-Ser at residues corresponding to methionine at position 428 and asparagine at position 434, respectively, in the EU numbering.

[0054] In some embodiments, the composition comprising the antibody or antigen-binding fragment thereof is administered (a) once on the first day of the dosing cycle at a dose of 2400 mg for a patient weighing 40 kg or more and less than 60 kg, 2700 mg for a patient weighing 60 kg or more and less than 100 kg, or 3000 mg for a patient weighing 100 kg or more, and (b) on the 15th day of the dosing cycle and thereafter every 8 weeks at a dose of 3000 mg for a patient weighing 40 kg or more and less than 60 kg, 3300 mg for a patient weighing 60 kg or more and less than 100 kg, or 3600 mg for a patient weighing 100 kg or more.

[0055] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region of SEQ ID NO: 12 and a light chain variable region of SEQ ID NO: 8. In some embodiments, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region of SEQ ID NO: 13.

[0056] In some 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.

[0057] In some embodiments, the antibody or antigen-binding fragment thereof binds to human C5 with an affinity dissociation constant (KD) in the range of 0.1 nM or more and 1 nM or less at pH 7.4 and 25°C. In some embodiments, the antibody or antigen-binding fragment thereof binds to human C5 with a KD of 10 nM or more at pH 6.0 and 25°C.

[0058] In some embodiments, for a patient weighing 40 kg or more and less than 60 kg, the antibody or antigen-binding fragment thereof is administered (a) once on the first day of the dosing cycle at a loading dose of 2400 mg, and (b) on the 15th day of the dosing cycle and thereafter every 8 weeks at a maintenance dose of 3000 mg.

[0059] In some embodiments, for patients with a body weight of 60 kg or more and less than 100 kg, the antibody or its antigen-binding fragment is administered (a) once on the first day of the dosing cycle at a loading dose of 2700 mg, and (b) on the 15th day of the dosing cycle and thereafter every 8 weeks at a maintenance dose of 3300 mg.

[0060] In some embodiments, for patients with a body weight of 100 kg or more, the antibody or its antigen-binding fragment is administered (a) once on the first day of the dosing cycle at a loading dose of 3000 mg, and (b) on the 15th day of the dosing cycle and thereafter every 8 weeks at a maintenance dose of 3600 mg.

[0061] In some embodiments, in the treatment with the antibody or its antigen-binding fragment, the trough concentration of the antibody or its antigen-binding fragment in serum is maintained at 100 μg / ml or more during the dosing cycle. In some embodiments, in the treatment with the antibody or its antigen-binding fragment, the trough concentration of the antibody or its antigen-binding fragment in serum is maintained at 200 μg / ml or more during the dosing cycle.

[0062] In some embodiments, in the treatment with the antibody or its antigen-binding fragment, the concentration of the free antibody or its antigen-binding fragment is maintained at 0.309 - 0.5 μg / mL or less.

[0063] In some embodiments, after the dosing cycle, the antibody or its antigen-binding fragment is administered every 8 weeks at a dose of 3000 mg, 3300 mg or 3600 mg for up to 2 years.

[0064] In some embodiments, the antibody or its antigen-binding fragment is formulated for intravenous administration.

[0065] In some embodiments, the patients treated with the antibody or its antigen-binding fragment have not previously received treatment with a complement inhibitor.

[0066] In some embodiments, the dosing cycle is a total of 26 weeks of treatment.

[0067] In some embodiments, treatment with the antibody or antigen-binding fragment thereof inhibits terminal complement.

[0068] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (decrease) in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score in a patient after 26 weeks of treatment. In some embodiments, the clinically significant improvement seen in the patient is a decrease in the patient's MG-ADL score of at least 3 points after 26 weeks of treatment.

[0069] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (decrease) in the Quantitative Myasthenia Gravis (QMG) score after 26 weeks of treatment. In some embodiments, the clinically significant improvement seen in the patient is a decrease in the patient's QMG of at least 5 points after 26 weeks of treatment.

[0070] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (decrease) in the Myasthenia Gravis Composite (MGC) score after 26 weeks of treatment.

[0071] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (decrease in score) in quality of life as measured by the Myasthenia Gravis Quality of Life (MG-QOL15r) score after 26 weeks of treatment.

[0072] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (reduction) in fatigue in neuropathy as measured by the Neuro-QOL Fatigue score after 26 weeks of treatment.

[0073] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (decrease in score) in health status as measured by the health status score of Euro Quality of Life (EQ-5D-5L) after 26 weeks of treatment.

[0074] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (reduction) in the Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Status (PIS) after 26 weeks of treatment.

[0075] In some embodiments, the myasthenia gravis is generalized myasthenia gravis (gMG). In some embodiments, the gMG patient is anti-AChR antibody positive.

[0076] In some embodiments, the antibody is ravulizumab.

[0077] In some embodiments, provided is a kit for treating myasthenia gravis (MG) in a human patient, the kit comprising: (a) a dose of an antibody or antigen-binding fragment thereof comprising the CDR1 domain, CDR2 domain, and CDR3 domain of the heavy chain variable region having the sequence shown in SEQ ID NO: 12, and the CDR1 domain, CDR2 domain, and CDR3 domain of the light chain variable region having the sequence shown in SEQ ID NO: 8; and (b) instructions for using the antibody or antigen-binding fragment thereof by the method according to any one of the preceding claims.

[0078] In some embodiments, the antibody or antigen-binding fragment thereof of the kit comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), and the variant human Fc CH3 constant region thereof comprises substitutions of Met-429-Leu and Asn-435-Ser at the residues corresponding to methionine at position 428 and asparagine at position 434, respectively, in the EU numbering.

[0079] In some embodiments, the antibody or antigen-binding fragment thereof of the kit is administered to a patient weighing 40 kg or more and less than 60 kg at (a) a loading dose of 2400 mg once on the first day of the administration cycle, and (b) a maintenance dose of 3000 mg on the 15th day of the administration cycle and every 8 weeks thereafter.

[0080] In some embodiments, the antibody or antigen-binding fragment thereof of the kit is administered to a patient weighing 60 kg or more and less than 100 kg at (a) a dose of 2700 mg once on the first day of the administration cycle, and (b) a maintenance dose of 3300 mg on the 15th day of the administration cycle and every 8 weeks thereafter.

[0081] In some embodiments, the antibody or antigen-binding fragment thereof of the kit is administered to a patient weighing 100 kg or more at (a) a dose of 3000 mg once on the first day of the administration cycle, and (b) a maintenance dose of 3600 mg on the 15th day of the administration cycle and every 8 weeks thereafter.

[0082] In some embodiments, the antibody is ravulizumab.

[0083] In some embodiments, the present disclosure provides an antibody comprising the CDR1 domain, CDR2 domain, and CDR3 domain of the heavy chain variable region having the sequence shown in SEQ ID NO: 12, and the CDR1 domain, CDR2 domain, and CDR3 domain of the light chain variable region having the sequence shown in SEQ ID NO: 8, for administration in a treatment cycle.

[0084] In some embodiments, the antibody comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises substitutions of Met-429-Leu and Asn-435-Ser at the residues corresponding to methionine at position 428 and asparagine at position 434, respectively, in the EU numbering.

[0085] In some embodiments, the antibody is administered (a) once on the first day of the dosing cycle at a dose of 2400 mg for patients weighing 40 kg or more and less than 60 kg, 2700 mg for patients weighing 60 kg or more and less than 100 kg, or 3000 mg for patients weighing 100 kg or more, and (b) on the 15th day of the dosing cycle and thereafter every 8 weeks at a dose of 3000 mg for patients weighing 40 kg or more and less than 60 kg, 3300 mg for patients weighing 60 kg or more and less than 100 kg, or 3600 mg for patients weighing 100 kg or more.

[0086] In some embodiments, the antibody has been found to have safety, tolerability, efficacy, and sufficient non-immunogenicity after multiple IV administrations for MG patients.

[0087] In some embodiments, the antibody is ravulizumab.

[0088] In some embodiments, provided is a method for treating a human patient with MG, the method comprising administering to the patient an effective amount of an antibody or an antigen-binding fragment thereof comprising a heavy chain CDR1 sequence as set forth in SEQ ID NO: 19, a heavy chain CDR2 sequence as set forth in SEQ ID NO: 18, and a heavy chain CDR3 sequence as set forth in SEQ ID NO: 3, and a light chain CDR1 sequence as set forth in SEQ ID NO: 4, a light chain CDR2 sequence as set forth in SEQ ID NO: 5, and a light chain CDR3 sequence as set forth in SEQ ID NO: 6.

[0089] In some embodiments, the antibody or antigen-binding fragment thereof comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises substitutions of Met-429-Leu and Asn-435-Ser at residues corresponding to methionine at position 428 and asparagine at position 434, respectively, in the EU numbering.

[0090] In some embodiments, the antibody or antigen-binding fragment thereof is administered (a) once on the first day of a dosing cycle at a dose of 2400 mg to patients weighing 40 kg or more and less than 60 kg, 2700 mg to patients weighing 60 kg or more and less than 100 kg, or 3000 mg to patients weighing 100 kg or more, and (b) on the 15th day of the dosing cycle and every 8 weeks thereafter at a dose of 3000 mg to patients weighing 40 kg or more and less than 60 kg, 3300 mg to patients weighing 60 kg or more and less than 100 kg, or 3600 mg to patients weighing 100 kg or more.

[0091] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region of SEQ ID NO: 12 and a light chain variable region of SEQ ID NO: 8. In some embodiments, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region of SEQ ID NO: 13.

[0092] In some 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.

[0093] In some embodiments, the antibody or antigen-binding fragment thereof has an affinity dissociation constant (K D ) for human C5 in the range of 0.1 nM or more and 1 nM or less at pH 7.4 and 25°C. In some embodiments, the antibody or antigen-binding fragment thereof has a K D of 10 nM or more for human C5 at pH 6.0 and 25°C.

[0094] In some embodiments, for patients with a body weight of 40 kg or more and less than 60 kg, the antibody or its antigen-binding fragment is administered at a dose of 2400 mg once on the first day of the administration cycle, and (b) at a dose of 3000 mg on the 15th day of the administration cycle and every 8 weeks thereafter.

[0095] In some embodiments, for patients with a body weight of 60 kg or more and less than 100 kg, the antibody or its antigen-binding fragment is administered at a dose of 2700 mg once on the first day of the administration cycle, and (b) at a dose of 3300 mg on the 15th day of the administration cycle and every 8 weeks thereafter.

[0096] In some embodiments, for patients with a body weight of 100 kg or more, the antibody or its antigen-binding fragment is administered at a dose of 3000 mg once on the first day of the administration cycle, and (b) at a dose of 3600 mg on the 15th day of the administration cycle and every 8 weeks thereafter.

[0097] In some embodiments, in the treatment with the antibody or its antigen-binding fragment, the trough concentration of the antibody or its antigen-binding fragment in serum is maintained at 100 μg / mL or more during the administration cycle. In some embodiments, in the treatment with the antibody or its antigen-binding fragment, the trough concentration of the antibody or its antigen-binding fragment in serum is maintained at 200 μg / mL or more during the administration cycle.

[0098] In some embodiments, in the treatment with the antibody or its antigen-binding fragment, the concentration of the free antibody or antigen-binding fragment is maintained at 0.309 to 0.5 μg / mL or less.

[0099] In some embodiments, after the administration cycle, the antibody or its antigen-binding fragment is administered at a dose of 3000 mg, 3300 mg or 3600 mg every 8 weeks for up to 2 years.

[0100] In some embodiments, the antibody or its antigen-binding fragment is formulated for intravenous administration.

[0101] In some embodiments, the patient has not previously received treatment with a complement inhibitor.

[0102] In some embodiments, the dosing cycle is a total of 26 weeks of treatment. In some embodiments, terminal complement is inhibited by the treatment.

[0103] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (decrease) in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score in the patient after 26 weeks of treatment. In some embodiments, the clinically significant improvement seen in the patient is a decrease of at least 3 points in the patient's MG-ADL score after 26 weeks of treatment.

[0104] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (decrease) in the Quantitative Myasthenia Gravis (QMG) score after 26 weeks of treatment. In some embodiments, the clinically significant improvement seen in the patient is a decrease of at least 5 points in the patient's QMG after 26 weeks of treatment.

[0105] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (decrease) in the Myasthenia Gravis Composite (MGC) score after 26 weeks of treatment.

[0106] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (decrease in score) in the quality of life as measured by the Myasthenia Gravis Quality of Life (MG-QOL15r) score after 26 weeks of treatment.

[0107] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (reduction) in fatigue in neuropathy as measured by the Neuro-QOL Fatigue score after 26 weeks of treatment.

[0108] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (decrease in score) in health status as measured by the health status score of Euro Quality of Life (EQ-5D-5L) after 26 weeks of treatment.

[0109] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically significant improvement (reduction) in the Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Status (PIS) after 26 weeks of treatment.

[0110] In some embodiments, the myasthenia gravis is generalized myasthenia gravis (gMG). In some embodiments, the gMG patient is anti-AChR antibody positive.

[0111] In some embodiments, the antibody is ravulizumab.

[0112] Furthermore, the present disclosure also includes those that use any of the above embodiments in combination with any other of the above embodiments. The present invention provides, for example, the following items. (Item 1) A composition for use in a method of treating myasthenia gravis (MG) in a human patient, wherein the treatment comprises administering an effective amount of the composition to the patient, The composition contains a heavy-chain CDR1 sequence as shown in SEQ ID NO: 19, a heavy-chain CDR2 sequence as shown in SEQ ID NO: 18, and a heavy-chain CDR3 sequence as shown in SEQ ID NO: 3, and a light-chain CDR1 sequence as shown in SEQ ID NO: 4, a light-chain CDR2 sequence as shown in SEQ ID NO: 5, and a light-chain CDR3 sequence as shown in SEQ ID NO: 6 The composition according to the preceding item, comprising an antibody or an antigen-binding fragment thereof containing the above sequences. (Item 2) The antibody or the antigen-binding fragment thereof contains a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), The variant human Fc CH3 constant region contains substitutions of Met-429-Leu and Asn-435-Ser at the residues corresponding to methionine at position 428 and asparagine at position 434, respectively, in EU numbering, for the composition for use according to item 1. (Item 3) The antibody or the antigen-binding fragment thereof, (a) Once on the first day of the administration cycle, i. For patients weighing 40 kg or more and less than 60 kg, at a loading dose of 2400 mg, ii. For patients weighing 60 kg or more and less than 100 kg, at a loading dose of 2700 mg, or iii. For patients weighing 100 kg or more, at a loading dose of 3000 mg, is administered, (b) On the 15th day of the administration cycle and thereafter every 8 weeks, i. For patients weighing 40 kg or more and less than 60 kg, at a maintenance dose of 3000 mg, ii. For patients weighing 60 kg or more and less than 100 kg, at a maintenance dose of 3300 mg, or iii. For patients weighing 100 kg or more, at a maintenance dose of 3600 mg, is administered, The composition for use according to any one of the preceding items. (Item 4) The composition for use according to any one of the preceding items, wherein the antibody or the antigen-binding fragment thereof comprises a heavy-chain variable region of SEQ ID NO: 12 and a light-chain variable region of SEQ ID NO: 8. (Item 5) The composition for use according to any one of the preceding items, wherein the antibody or the antigen-binding fragment thereof further comprises a heavy-chain constant region of SEQ ID NO: 13. (Item 6) The composition for use according to any one of the preceding items, wherein the antibody or the 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. (Item 7) The composition for use according to any one of the preceding items, wherein the antibody or the antigen-binding fragment thereof binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (K D ) in the range of 0.1 nM or more and 1 nM or less. (Item 8) The composition for use according to any one of the preceding items, wherein the antibody or the antigen-binding fragment thereof binds to human C5 at pH 6.0 and 25°C with a K D of 10 nM or more. (Item 9) The composition for use according to any one of the preceding items, wherein the antibody or the antigen-binding fragment thereof is administered to a patient with a body weight of 40 kg or more and less than 60 kg (a) once on the first day of the administration cycle at a loading dose of 2400 mg, (b) on the 15th day of the administration cycle and thereafter every 8 weeks at a maintenance dose of 3000 mg. The composition for use according to any one of the preceding items. (Item 10) The antibody or the antigen-binding fragment thereof is administered to a patient with a body weight of 60 kg or more and less than 100 kg to (a) once on the first day of the administration cycle at a loading dose of 2700 mg, (b) on the 15th day of the administration cycle and thereafter every 8 weeks at a maintenance dose of 3300 mg. The composition for use according to any one of items 1 to 8. (Item 11) The antibody or the antigen-binding fragment thereof is administered to a patient with a body weight of 100 kg or more (a) on the first day of the administration cycle, once at a loading dose of 3000 mg, (b) on the 15th day of the administration cycle and thereafter every 8 weeks, at a maintenance dose of 3600 mg. The composition for use according to any one of items 1 to 8. (Item 12) In the treatment, during the administration cycle, the trough concentration of the antibody or the antigen-binding fragment thereof in serum is maintained at 100 μg / mL or more. The composition for use according to any one of the preceding items. (Item 13) In the treatment, during the administration cycle, the trough concentration of the antibody or the antigen-binding fragment thereof in serum is maintained at 200 μg / mL or more. The composition for use according to any one of the preceding items. (Item 14) In the treatment, the concentration of the free antibody or the antigen-binding fragment thereof is maintained at 0.309 to 0.5 μg / mL or less. The composition for use according to any one of the preceding items. (Item 15) After the administration cycle, the antibody or the antigen-binding fragment thereof is administered every 8 weeks at a dose of 3000 mg, 3300 mg or 3600 mg for up to 2 years. The composition for use according to any one of the preceding items. (Item 16) The antibody or the antigen-binding fragment thereof is formulated for intravenous administration. The composition for use according to any one of the preceding items. (Item 17) The patient has not previously received treatment with a complement inhibitor. The composition for use according to any one of the preceding items. (Item 18) The administration cycle is a total of 26 weeks of treatment. The composition for use according to any one of the preceding items. (Item 19) A composition for use according to any one of the preceding items, wherein terminal complement is inhibited by said treatment. (Item 20) A composition for use according to any one of the preceding items, wherein clinically significant improvement (decrease) in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score is seen in said patient after 26 weeks of treatment by said treatment. (Item 21) A composition for use according to item 20, wherein said clinically significant improvement seen in said patient is a decrease in the MG-ADL score of said patient by at least 3 points after 26 weeks of treatment. (Item 22) A composition for use according to any one of the preceding items, wherein the Quantitative Myasthenia Gravis (QMG) score improves (decreases) clinically after 26 weeks of treatment by said treatment. A composition for use according to any one of the preceding items, wherein said clinically significant improvement seen in said patient is a decrease in the QMG of said patient by at least 5 points after 26 weeks of treatment. (Item 23) A composition for use according to item 22, wherein said clinically significant improvement seen in said patient is a decrease in the QMG of said patient by at least 5 points after 26 weeks of treatment. (Item 24) A composition for use according to any one of the preceding items, wherein the Myasthenia Gravis Composite (MGC) score improves (decreases) clinically after 26 weeks of treatment by said treatment. (Item 25) A composition for use according to any one of the preceding items, wherein the quality of life as measured by the Myasthenia Gravis Quality of Life (MG-QOL15r) score improves (the score decreases) clinically after 26 weeks of treatment by said treatment. (Item 26) A composition for use according to any one of the preceding items, wherein, by said treatment, after 26 weeks of treatment, neurological fatigue, as measured by the Neuro-QOL Fatigue score, is clinically significantly improved (reduced). (Item 27) A composition for use according to any one of the preceding items, wherein, by said treatment, after 26 weeks of treatment, the health state, as measured by the health state score of Euro Quality of Life (EQ-5D-5L), is clinically significantly improved (the score decreases). (Item 28) A composition for use according to any one of the preceding items, wherein, by said treatment, after 26 weeks of treatment, the Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Status (PIS) is clinically significantly improved (reduced). (Item 29) A composition for use according to any one of Items 1 to 28, wherein the myasthenia gravis is generalized myasthenia gravis (gMG). (Item 30) A composition for use according to Item 29, wherein the gMG patient is positive for anti-AChR antibody. (Item 31) A composition for use according to any one of the preceding items, wherein the antibody is ravulizumab. (Item 32) A kit for treating myasthenia gravis (MG) in a human patient, comprising: (a) A dose of an antibody or an antigen-binding fragment thereof, comprising the CDR1 domain, CDR2 domain, and CDR3 domain of the heavy-chain variable region having the sequence shown in SEQ ID NO: 12, and the CDR1 domain, CDR2 domain, and CDR3 domain of the light-chain variable region having the sequence shown in SEQ ID NO: 8; and (b) Instructions for using the antibody or an antigen-binding fragment thereof according to any one of the preceding items; The kit comprising the above. (Item 33) The antibody or its antigen-binding fragment contains a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), the variant human Fc CH3 constant region has, respectively, in EU numbering, residues corresponding to methionine at position 428 and asparagine at position 434, Met-429- Leu and Asn-435-Ser substitutions, and the kit according to item 32. (Item 34) the antibody or its antigen-binding fragment is administered to a patient weighing 40 kg or more and less than 60 kg, (a) administered once on the first day of the dosing cycle at a loading dose of 2400 mg, (b) on the 15th day of the dosing cycle and thereafter every 8 weeks, administered at a maintenance dose of 3000 mg, and the kit according to item 32. (Item 35) the antibody or its antigen-binding fragment is administered to a patient weighing 60 kg or more and less than 100 kg, (a) administered once on the first day of the dosing cycle at a dose of 2700 mg, (b) on the 15th day of the dosing cycle and thereafter every 8 weeks, administered at a maintenance dose of 3300 mg, and the kit according to item 32. (Item 36) the antibody or its antigen-binding fragment is administered to a patient weighing 100 kg or more, (a) administered once on the first day of the dosing cycle at a dose of 3000 mg, (b) on the 15th day of the dosing cycle and thereafter every 8 weeks, administered at a maintenance dose of 3600 mg, and the kit according to item 32. (Item 37) The antibody is ranizumab, and the kit according to any one of items 32 to 36. (Item 38) An antibody for use in an administration method in a treatment cycle, the antibody comprising a CDR1 domain, a CDR2 domain, and a CDR3 domain of a heavy chain variable region having the sequence shown in SEQ ID NO: 12, and a CDR1 domain, a CDR2 domain, and a CDR3 domain of a light chain variable region having the sequence shown in SEQ ID NO: 8. (Item 39) The antibody or an antigen-binding fragment thereof comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn). The antibody for use according to item 38, wherein the variant human Fc CH3 constant region comprises substitutions of Met-429-Leu and Asn-435-Ser at residues corresponding to methionine at position 428 and asparagine at position 434, respectively, in EU numbering. (Item 40) (a) Once on the first day of an administration cycle, i. For patients weighing 40 kg or more and less than 60 kg, at a loading dose of 2400 mg, ii. For patients weighing 60 kg or more and less than 100 kg, at a loading dose of 2700 mg, or iii. For patients weighing 100 kg or more, at a loading dose of 3000 mg is administered, (b) On the 15th day of the administration cycle and thereafter every 8 weeks, i. For patients weighing 40 kg or more and less than 60 kg, at a maintenance dose of 3000 mg, ii. For patients weighing 60 kg or more and less than 100 kg, at a maintenance dose of 3300 mg, or iii. For patients weighing 100 kg or more, at a maintenance dose of 3600 mg is administered, The antibody for use according to item 38 or item 39. (Item 41) The antibody for use according to item 38, which has been found to have safety, tolerability, efficacy, and sufficient non-immunogenicity after multiple IV administrations for MG patients. (Item 42) The antibody for use according to any one of items 38 to 41, wherein the antibody is ravulizumab. (Item 43) A method for treating a human patient with myasthenia gravis (MG), comprising administering to the patient an effective amount of an antibody or an antigen-binding fragment thereof comprising a heavy-chain CDR1 sequence as set forth in SEQ ID NO: 19, a heavy-chain CDR2 sequence as set forth in SEQ ID NO: 18, and a heavy-chain CDR3 sequence as set forth in SEQ ID NO: 3, and a light-chain CDR1 sequence as set forth in SEQ ID NO: 4, a light-chain CDR2 sequence as set forth in SEQ ID NO: 5, and a light-chain CDR3 sequence as set forth in SEQ ID NO: 6. (Item 44) The method according to item 43, wherein the antibody or the antigen-binding fragment thereof comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn). The method according to item 43, wherein the variant human Fc CH3 constant region comprises substitutions of Met-429-Leu and Asn-435-Ser at the residues corresponding to methionine at position 428 and asparagine at position 434, respectively, in EU numbering. (Item 45) The antibody or the antigen-binding fragment thereof is (a) administered once on the first day of the dosing cycle, i. to a patient weighing 40 kg or more and less than 60 kg at a loading dose of 2400 mg, ii. to a patient weighing 60 kg or more and less than 100 kg at a loading dose of 2700 mg, or iii. to a patient weighing 100 kg or more at a loading dose of 3000 mg, and (b) on the 15th day of the dosing cycle and thereafter every 8 weeks, i. to a patient weighing 40 kg or more and less than 60 kg at a maintenance dose of 3000 mg, ii. to a patient weighing 60 kg or more and less than 100 kg at a maintenance dose of 3300 mg, or iii. to a patient weighing 100 kg or more at a maintenance dose of 3600 mg, and administered according to the method according to item 41 or item 44. The method according to item 41 or item 44. (Item 46) The method according to any one of items 41 to 45, wherein the antibody or the antigen-binding fragment thereof comprises a heavy-chain variable region of SEQ ID NO: 12 and a light-chain variable region of SEQ ID NO: 8. (Item 47) The method according to any one of items 43 to 46, wherein the antibody or the antigen-binding fragment thereof further comprises a heavy-chain constant region of SEQ ID NO: 13. (Item 48) The method according to any one of items 43 to 47, wherein the antibody or the 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. (Item 49) The antibody or the antigen-binding fragment thereof binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (K D ) in the range of 0.1 nM or more and 1 nM or less. The method according to any one of items 43 to 48. (Item 50) The antibody or the antigen-binding fragment thereof binds to human C5 at pH 6.0 and 25°C with a K D of 10 nM or more. The method according to any one of items 43 to 49. (Item 51) The antibody or the antigen-binding fragment thereof is administered to a patient with a body weight of 40 kg or more and less than 60 kg. (a) On the first day of the administration cycle, it is administered once at a loading dose of 2400 mg. (b) On the 15th day of the administration cycle and thereafter every 8 weeks, it is administered at a maintenance dose of 3000 mg. The method according to any one of items 43 to 50. (Item 52) The antibody or the antigen-binding fragment thereof is administered to a patient with a body weight of 60 kg or more and less than 100 kg. (a) On the first day of the administration cycle, it is administered once at a loading dose of 2700 mg. (b) On the 15th day of the administration cycle and thereafter every 8 weeks, it is administered at a maintenance dose of 3300 mg. The method according to any one of items 43 to 50. (Item 53) administering the antibody or antigen-binding fragment thereof to a patient with a body weight of 100 kg or more, (a) administering a loading dose of 3000 mg once on the first day of the administration cycle, (b) administering a maintenance dose of 3600 mg on the 15th day of the administration cycle and every 8 weeks thereafter, The method according to any one of items 43 to 50. (Item 54) The method according to any one of items 43 to 53, wherein in the treatment, the trough concentration of the antibody or antigen-binding fragment thereof in serum is maintained at 100 μg / mL or more during the administration cycle. (Item 55) The method according to any one of items 43 to 54, wherein in the treatment, the trough concentration of the antibody or antigen-binding fragment thereof in serum is maintained at 200 μg / mL or more during the administration cycle. (Item 56) The method according to any one of items 43 to 55, wherein in the treatment, the free antibody concentration is maintained at 0.309 to 0.5 μg / mL or less. (Item 57) After the administration cycle, administering the antibody or antigen-binding fragment thereof at a dose of 3000 mg, 3300 mg or 3600 mg every 8 weeks for up to 2 years, the method according to any one of items 43 to 56. (Item 58) The method according to any one of items 43 to 57, wherein the antibody or antigen-binding fragment thereof is formulated for intravenous administration. (Item 59) The method according to any one of items 43 to 58, wherein the patient has not previously received treatment with a complement inhibitor. (Item 60) The method according to any one of items 43 to 59, wherein the administration cycle is a total of 26 weeks of treatment. (Item 61) The method according to any one of items 43 to 60, wherein terminal complement is inhibited by the treatment. (Item 62) By the treatment, in the patient, after 26 weeks of treatment, a clinically significant improvement (decrease) in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score is observed, as described in any one of items 43 to 61 The method described. (Item 63) The clinically significant improvement observed in the patient is that, after 26 weeks of treatment, the MG-ADL score of the patient decreases by at least 3 points, as described in item 62. (Item 64) By the treatment, after 26 weeks of treatment, the Quantitative Myasthenia Gravis (QMG) score improves (decreases) clinically significantly, as described in any one of items 43 to 63. (Item 65) The clinically significant improvement observed in the patient is that, after 26 weeks of treatment, the QMG of the patient decreases by at least 5 points, as described in item 64. (Item 66) By the treatment, after 26 weeks of treatment, the Myasthenia Gravis Composite (MGC) score improves (decreases) clinically significantly, as described in any one of items 43 to 65. (Item 67) By the treatment, after 26 weeks of treatment, the quality of life as measured by the Myasthenia Gravis Quality of Life (MG-QOL15r) score improves (the score decreases) clinically significantly, as described in any one of items 43 to 65. (Item 68) By the treatment, after 26 weeks of treatment, the neurological fatigue as measured by the Neuro-QOL Fatigue score improves (is reduced) clinically significantly, as described in any one of items 43 to 66. (Item 69) The method according to any one of items 43 to 68, wherein the treatment clinically significantly improves (the score decreases) the health state as measured by the Euro Quality of Life (EQ-5D-5L) health state score after 26 weeks of treatment. (Item 70) The method according to any one of items 43 to 69, wherein the treatment clinically significantly improves (is reduced) the Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Status (PIS) after 26 weeks of treatment. (Item 71) The method according to any one of items 43 to 70, wherein the myasthenia gravis is generalized myasthenia gravis (gMG). (Item 72) The method according to item 71, wherein the gMG patient is positive for anti-AChR antibody. (Item 73) The method according to any one of items 43 to 72, wherein the antibody is ravulizumab.

Brief Description of Drawings

[0113]

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Mode for Carrying Out the Invention

[0114] As used herein, the terms "subject" or "patient" refer to a human patient (e.g., a patient with generalized myasthenia gravis (gMG)). As used herein, the terms "subject" and "patient" are synonymous.

[0115] As used herein, the phrase "requiring long-term plasma exchange" refers to regularly using plasma exchange therapy for a patient at least every three months over the most recent 12 months to manage muscle weakness.

[0116] As used herein, the phrase "requiring long-term IVIg" refers to regularly using IVIg therapy for a patient at least every three months over the most recent 12 months to manage muscle weakness.

[0117] As used herein, the phrase "worsening of clinical symptoms" refers to a patient in whom MG crisis is observed, which is defined as muscle weakness due to MG that is severe enough to require intubation or delay extubation after surgery, where respiratory failure is due to muscle weakness of the respiratory muscles, accompanied by muscle weakness of the severe bulbar muscles (oropharyngeal muscles), or where severe bulbar (oropharyngeal) muscle weakness is a prominent feature in the patient, and there is a significant worsening of symptoms with a score of 3 in any one of the individual items of MG-Activities of Daily Living (MG-ADL) excluding diplopia or ptosis, or a 2-point worsening from baseline, or when, in the judgment of the treating physician or a physician designated by the treating physician, rescue therapy is to be implemented for a patient whose health status would otherwise be in a critical situation (e.g., an emergency situation).

[0118] As used herein, "effective treatment" refers to a treatment that provides a beneficial effect, such as improvement of at least one symptom of a disease or disorder. The beneficial effect can take the form of an improvement from a baseline, i.e., an improvement from a measurement or observation made prior to initiation of therapy by the methods of the present invention. Effective treatment may refer to, for example, alleviation of at least one symptom of MG.

[0119] The term "effective amount" refers to that amount of an agent that provides a desired biological, therapeutic, and / or prophylactic result. The result can be a reduction, improvement, palliation, suppression, delay, and / or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired modification of a biological system. In one example, an "effective amount" is that amount of an anti-C5 antibody or antigen-binding fragment thereof that is useful for alleviating at least one symptom of MG, e.g., an amount that has been clinically demonstrated to provide alleviation. The effective amount can be administered in one or more administrations.

[0120] As used herein, the terms "induction" and "induction phase" are used synonymously and refer to the first stage of a dosing regimen.

[0121] As used herein, the terms "maintenance" and "maintenance period" are used synonymously and refer to the second stage of the dosing regimen. In some embodiments, treatment is continued as long as clinical benefits are observed or until untreatable toxicity or disease progression is recognized. The maintenance period of the administration of Lublizumab can range from 6 weeks to persist throughout the life of the subject. According to some embodiments, the maintenance period persists for 26 to 52 weeks, 26 to 78 weeks, 26 to 104 weeks, 26 to 130 weeks, 26 to 156 weeks, 26 to 182 weeks, 26 to 208 weeks or longer. In some embodiments, the maintenance period persists for more than 26 weeks, more than 27 weeks, more than 28 weeks, more than 29 weeks, more than 30 weeks, more than 31 weeks, more than 32 weeks, more than 33 weeks, more than 34 weeks, more than 35 weeks, more than 36 weeks, more than 37 weeks, more than 38 weeks, more than 39 weeks, more than 40 weeks, more than 41 weeks, more than 42 weeks, more than 43 weeks, more than 44 weeks, more than 45 weeks, more than 46 weeks, more than 47 weeks, more than 48 weeks, more than 49 weeks, more than 50 weeks, more than 51 weeks, more than 52 weeks, more than 78 weeks, more than 104 weeks, more than 130 weeks, more than 156 weeks or more than 182 weeks. According to some embodiments, the maintenance period persists for a period of more than 1 year, more than 2 years, more than 3 years, more than 4 years, more than 5 years, more than 10 years, more than 15 years, more than 20 years, more than 25 years, more than 30 years, more than 35 years, more than 40 years, more than 45 years, more than 50 years, more than 55 years, more than 60 years, more than 65 years, more than 70 years, more than 75 years, more than 80 years or longer. In some embodiments, the maintenance period persists throughout the remaining life of the subject.

[0122] In some embodiments, the multi - step dosing regimen of ravulizumab includes a third step. This third step is used when relief measures must be taken for MG patients for the purpose of maintaining clinical stability and includes administering plasma exchange / plasmapheresis (PE / PP) and / or IVIg. In this step, after plasma exchange, a certain dose of ravulizumab is administered to replenish the ravulizumab lost during plasma exchange / plasmapheresis. According to some embodiments, when performing PE / PP or IVIg rescue therapy on a non - dosing day, an additional investigational agent, such as ravulizumab, needs to be administered. In another embodiment, when performing an infusion of PE / PP or IVIg on a dosing day, it must be done before administering the investigational agent. According to some embodiments, when performing PE / PP or IVIg during an unscheduled visit for dosing purposes, an additional dose is administered to the patient who has received PE / PP 4 hours after the completion of that PE / PP session. In another embodiment, an additional dose is administered to the patient who has received IVIg 4 hours after the completion of the last continuous session(s) of IVIg. In some embodiments, the additional dose may or may not vary depending on PE / PP or IVIg (Tables 1 and 2). In some embodiments, when performing PE / PP or IVIg during a scheduled visit for dosing purposes, regular dosing will be done 60 minutes after the completion of PE / PP or IVIg. In some embodiments, there is no need to provide an interval between the additional dose and the regular dose as scheduled. Table 1: Additional dose when PE / PP is used as rescue therapy during an unscheduled visit for dosing purposes

Table 1

Table 2

[0123] As used herein, the term "loading dose" refers to the initial dose administered to a patient. The loading dose may be, for example, 2400 mg, 2700 mg, or 3000 mg. The loading dose may be increased or decreased based on body weight.

[0124] As used herein, the term "maintenance dose" or "maintenance period" refers to the dose administered to a patient after the loading dose. For example, the maintenance dose may be 3000 mg, 3300 mg, or 3600 mg. The maintenance dose may be increased or decreased based on body weight.

[0125] As used herein, the term "serum trough level" refers to the lowest concentration of a drug (e.g., an anti-C5 antibody or an antigen-binding fragment thereof) or a medicament when present in serum. In contrast, "serum peak level" refers to the highest concentration of the drug in serum. "Average serum level" refers to the average concentration of the drug in serum over a period of time.

[0126] In one embodiment, the described treatment regimen is a regimen sufficient to maintain a specific trough concentration in serum of an anti-C5 antibody or an antigen-binding fragment thereof. In one embodiment, for example, in such treatment, the trough concentration in serum of the anti-C5 antibody or an antigen-binding fragment thereof is maintained at 50 μg / mL, 55 μg / mL, 60 μg / mL, 65 μg / mL, 70 μg / mL, 75 μg / mL, 80 μg / mL, 85 μg / mL, 90 μg / mL, 95 μg / mL, 100 μg / mL, 105 μg / mL, 110 μg / mL, 115 μg / mL, 120 μg / mL, 125 μg / mL, 130 μg / mL, 135 μg / mL, 140 μg / mL, 145 μg / mL, 150 μg / mL, 155 μg / mL, 160 μg / mL, 165 μg / mL, 170 μg / mL, 175 μg / mL, 180 μg / mL, 185 μg / mL, 190 μg / mL, 200 μg / mL, 205 μg / mL, 210 μg / mL, 215 μg / mL, 220 μg / mL, 225 μg / mL, 230 μg / mL, 240 μg / mL, 245 μg / mL, 250 μg / mL, 255 μg / mL, 260 μg / mL, 265 μg / mL, 270 μg / mL, 280 μg / mL, 290 μg / mL, 300 μg / mL, 305 μg / mL, 310 μg / mL, 315 μg / mL, 320 μg / mL, 325 μg / mL, 330 μg / mL, 335 μg / mL, 340 μg / mL, 345 μg / mL, 350 μg / mL, 355 μg / mL, 360 μg / mL, 365 μg / mL, 370 μg / mL, 375 μg / mL, 380 μg / mL, 385 μg / mL, 390 μg / mL, 395 μg / mL or 400 μg / mL or more. In one embodiment, in such treatment, the trough concentration in serum of the anti-C5 antibody or an antigen-binding fragment thereof is maintained at 100 μg / mL or more. In another embodiment, in such treatment, the trough concentration in serum of the anti-C5 antibody or an antigen-binding fragment thereof is maintained at 150 μg / mL or more. In another embodiment, in such treatment, the trough concentration in serum of the anti-C5 antibody or an antigen-binding fragment thereof is maintained at 200 μg / mL or more. In another embodiment, in such treatment, the trough concentration in serum of the anti-C5 antibody or an antigen-binding fragment thereof is maintained at 250 μg / mL or more. In another embodiment, in such treatment, the trough concentration in serum of the anti-C5 antibody or an antigen-binding fragment thereof is maintained at 300 μg / mL or more.In another embodiment, in the treatment, the trough concentration of the anti-C5 antibody or its antigen-binding fragment in serum is maintained at 100 μg / mL to 200 μg / mL. In another embodiment, in the treatment, the trough concentration of the anti-C5 antibody or its antigen-binding fragment in serum is maintained at about 175 μg / mL.

[0127] In another embodiment, to obtain an effective response, the anti-C5 antibody or its antigen-binding fragment is administered to the patient in an amount and frequency that maintains the desired minimum free C5 concentration. In one embodiment, for example, the anti-C5 antibody or its antigen-binding fragment is administered to the patient in an amount and frequency that maintains the free C5 concentration at 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 or its antigen-binding fragment is administered to the patient in an amount and frequency that maintains the free C5 concentration at 0.309 to 0.5 μg / mL or less. In another embodiment, in the treatment described herein, the free C5 concentration decreases by more than 99% throughout the treatment period. In another embodiment, in the treatment, the free C5 concentration decreases by more than 99.5% throughout the treatment period.

[0128] The term "antibody" describes a polypeptide that includes at least one antigen-binding site derived from an antibody (e.g., VH / VL region, Fv or CDR). Antibodies include known forms of antibodies. The antibody can be, for example, a human antibody, a humanized antibody, a bispecific antibody, a chimeric antibody or a camel antibody. The antibody can also be a Fab, Fab’2, scFv, SMIP, Affibody®, nanobody or single domain antibody. The antibody can be an antibody of any of the isotypes IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD and IgE, as well as a hybrid isotype, for example an IgG2 / 4 antibody. The antibody can be a natural antibody or an antibody modified by protein engineering techniques (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). The antibody may include, for example, one or more variant amino acids that change the properties (e.g., functional properties) of the antibody (compared to a natural antibody). In such modifications, many modifications that affect, for example, the half-life, effector function and / or immune response of the antibody in a patient are well known in the art. The term "antibody" also includes an artificial polypeptide construct or engineered polypeptide construct that includes at least one antigen-binding site derived from an antibody.

[0129] Anti-C5 antibody The anti-C5 antibodies described herein bind to complement component C5 (e.g., human complement system C5) and inhibit the cleavage of C5 into fragments C5a and C5b. Anti-C5 antibodies (or VH / VL domains or other antigen-binding fragments derived from such antibodies) suitable for use in the present invention can be prepared using methods known in the art. Anti-C5 antibodies recognized in the art can also be used. Antibodies that compete with any of these antibodies recognized in the art for binding to C5 can also be used.

[0130] Eculizumab (also known as Soliris®) is an anti-C5 antibody, or an antigen-binding fragment and variant thereof, comprising a heavy chain having the sequence shown in SEQ ID NO: 10 and a light chain having the sequence shown in SEQ ID NO: 11. 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 domain, CDR2 domain, and CDR3 domain of the VH region of eculizumab having the sequence shown in SEQ ID NO: 7, and the CDR1 domain, CDR2 domain, and CDR3 domain of the VL region of eculizumab having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises a heavy chain CDR1 domain having the sequence shown in SEQ ID NO: 1, a heavy chain CDR2 domain having the sequence shown in SEQ ID NO: 2, and a heavy chain CDR3 domain having the sequence shown in SEQ ID NO: 3, and a light chain CDR1 domain having the sequence shown in SEQ ID NO: 4, a light chain CDR2 domain having the sequence shown in SEQ ID NO: 5, and a light chain CDR3 domain having the sequence shown in SEQ ID NO: 6. In another embodiment, the antibody comprises a VH region having the amino acid sequence shown in SEQ ID NO: 7 and a VL region having the amino acid sequence shown in SEQ ID NO: 8.

[0131] Ravulizumab (also known as BNJ441, ALXN1210 or Ultomiris®) is an anti-C5 antibody comprising a heavy chain having the sequence set forth in SEQ ID NO: 14 and a light chain having the sequence set forth in SEQ ID NO: 11, or an antigen-binding fragment and variants thereof. Ravulizumab is described in PCT / US2015 / 019225 and U.S. Patent No. 9,079,949, the teachings of which are incorporated herein by reference. Ravulizumab selectively binds to human complement protein C5 and inhibits the cleavage of C5 into C5a and C5b upon complement activation. This inhibition blocks the release of the inflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC) C5b-9, while simultaneously blocking adjacent components of complement activation, namely early components (e.g., C3 and C3b), which are essential for microbial opsonization and immune complex clearance.

[0132] In one embodiment, the antibody comprises the CDRs or variable regions of the heavy and light chains of ravulizumab. Thus, in one embodiment, the antibody comprises the CDR1 domain, CDR2 domain and CDR3 domain of the VH region of ravulizumab having the sequence set forth in SEQ ID NO: 12, and the CDR1 domain, CDR2 domain and CDR3 domain of the VL region of ravulizumab having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises a heavy chain CDR1 domain having the sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 domain having the sequence set forth in SEQ ID NO: 18, and a heavy chain CDR3 domain having the sequence set forth in SEQ ID NO: 3, and a light chain CDR1 domain having the sequence set forth in SEQ ID NO: 4, a light chain CDR2 domain having the sequence set forth in SEQ ID NO: 5, and a light chain CDR3 domain having the sequence set forth in SEQ ID NO: 6. In another embodiment, the antibody comprises a VH region having the amino acid sequence set forth in SEQ ID NO: 12 and a VL region having the amino acid sequence set forth in SEQ ID NO: 8.

[0133] Another exemplary anti-C5 antibody is antibody BNJ421, or an antigen-binding fragment and variant thereof, comprising a heavy chain having the sequence set forth in SEQ ID NO: 20 and a light chain having the sequence set forth in SEQ ID NO: 11. BNJ421 is described in PCT / US2015 / 019225 and U.S. Patent No. 9,079,949, the entire teachings of which are incorporated herein by reference.

[0134] In some embodiments, the antibody comprises the CDRs or variable regions of the heavy and light chains of BNJ421. Thus, in one embodiment, the antibody comprises the CDR1 domain, CDR2 domain, and CDR3 domain of the VH region of BNJ421 having the sequence set forth in SEQ ID NO: 12, and the CDR1 domain, CDR2 domain, and CDR3 domain of the VL region of BNJ421 having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises a heavy chain CDR1 domain having the sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 domain having the sequence set forth in SEQ ID NO: 18, and a heavy chain CDR3 domain having the sequence set forth in SEQ ID NO: 3, and a light chain CDR1 domain having the sequence set forth in SEQ ID NO: 4, a light chain CDR2 domain having the sequence set forth in SEQ ID NO: 5, and a light chain CDR3 domain having the sequence set forth in SEQ ID NO: 6. In another embodiment, the antibody comprises a VH region having the amino acid sequence set forth in SEQ ID NO: 12 and a VL region having the amino acid sequence set forth in SEQ ID NO: 8.

[0135] The exact boundaries of CDRs have been defined in different ways and in different forms. In some embodiments, the positions of CDRs or framework regions within the variable domains of the light or heavy chains can be defined by the literature of Kabat et al. [(1991) “Sequences of Proteins of Immunological Interest.” NIH Publication No. 91-3242, U.S. Department of Health and Human Services, Bethesda, MD]. In such cases, the CDRs can be referred to as “Kabat CDRs” (e.g., “Kabat LCDR2” or “Kabat HCDR1”). In some embodiments, the positions of CDRs in the variable regions of the light or heavy chains can be defined by the literature of Chothia et al. (Nature, 342:877-83, 1989). Therefore, these regions can be referred to as “Chothia CDRs” (e.g., “Chothia LCDR2” or “Chothia HCDR3”). In some embodiments, the positions of CDRs in the variable regions of the light and heavy chains can be defined by a combined Kabat-Chothia definition. In such embodiments, these regions can be referred to as “Kabat-Chothia combined type CDRs” (Thomas, T. et al., Mol. Immunol., 33:1389-401, 1996).

[0136] 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 CDRs or variable regions of the heavy and light chains 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 a heavy chain CDR1 domain having the sequence shown in SEQ ID NO: 21, a heavy chain CDR2 domain having the sequence shown in SEQ ID NO: 22, and a heavy chain CDR3 domain having the sequence shown in SEQ ID NO: 23, as well as a light chain CDR1 domain having the sequence shown in SEQ ID NO: 24, a light chain CDR2 domain having the sequence shown in SEQ ID NO: 25, and a light chain CDR3 domain having the sequence shown in SEQ ID NO: 26. In another embodiment, the antibody or antigen-binding fragment thereof comprises the VH region of the 7086 antibody having the sequence shown in SEQ ID NO: 27 and the VL region of the 7086 antibody having the sequence shown in SEQ ID NO: 28.

[0137] 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 CDRs or variable regions of the heavy and light chains of the 8110 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain CDR1 domain having the sequence shown in SEQ ID NO: 29, a heavy chain CDR2 domain having the sequence shown in SEQ ID NO: 30, and a heavy chain CDR3 domain having the sequence shown in SEQ ID NO: 31, as well as a light chain CDR1 domain having the sequence shown in SEQ ID NO: 32, a light chain CDR2 domain having the sequence shown in SEQ ID NO: 33, and a light chain CDR3 domain having the sequence shown in SEQ ID NO: 34. In another embodiment, the antibody comprises the VH region of the 8110 antibody having the sequence shown in SEQ ID NO: 35 and the VL region of the 8110 antibody having the sequence shown in SEQ ID NO: 36.

[0138] Another exemplary anti-C5 antibody is the 305LO5 antibody described in US2016 / 0176954A1. In one embodiment, the antibody comprises the CDRs or variable regions of the heavy and light chains of the 305LO5 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain CDR1 domain having the sequence shown in SEQ ID NO: 37, a heavy chain CDR2 domain having the sequence shown in SEQ ID NO: 38, and a heavy chain CDR3 domain having the sequence shown in SEQ ID NO: 39, as well as a light chain CDR1 domain having the sequence shown in SEQ ID NO: 40, a light chain CDR2 domain having the sequence shown in SEQ ID NO: 41, and a light chain CDR3 domain having the sequence shown in SEQ ID NO: 42. In another embodiment, the antibody comprises the VH region of the 305LO5 antibody having the sequence shown in SEQ ID NO: 43 and the VL region of the 305LO5 antibody having the sequence shown in SEQ ID NO: 44.

[0139] Another exemplary anti-C5 antibody is the SKY59 antibody (Fukuzawa T.et al., Sci.Rep., 7:1080, 2017). In one embodiment, the antibody comprises the CDRs or variable regions of the heavy and light chains 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.

[0140] Another exemplary anti-C5 antibody is the H4H12166PP antibody described in PCT / US2017 / 037226 and US2017 / 0355757A1. In one embodiment, the antibody comprises the CDRs or variable regions of the heavy and light chains 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 shown in SEQ ID NO: 47 and the VL region of the H4H12166PP antibody having the sequence shown 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.

[0141] In one embodiment, a patient is treated with eculizumab and then switched to treatment with 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, H4H12166PP antibody or ravulizumab. In another embodiment, the patient switches from an anti-C5 antibody (e.g., eculizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody or H4H12166PP antibody) to another anti-C5 antibody (e.g., ravulizumab) during a treatment cycle. In certain embodiments, the patient switches from eculizumab to ravulizumab during a treatment cycle.

[0142] In some embodiments, the anti-C5 antibodies described herein include a heavy chain CDR1 having the amino acid sequence GHIFSNYWIQ (SEQ ID NO: 19) or consisting of that amino acid sequence. In some embodiments, the anti-C5 antibodies described herein include a heavy chain CDR2 having the amino acid sequence EILPGSGHTEYTENFKD (SEQ ID NO: 18) or consisting of that amino acid sequence. In some embodiments, the anti-C5 antibodies described herein include a heavy chain variable region having the amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGEILPGSGHTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSSPNWYFDVWGQGTLVTVSS (SEQ ID NO: 12).

[0143] In some embodiments, the anti-C5 antibodies described herein include a light chain variable region having the amino acid sequence DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIK (SEQ ID NO: 8).

[0144] In some embodiments, the anti-C5 antibodies described herein can include a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn) with a higher affinity than the native human Fc constant region from which the variant human Fc constant region is derived. The Fc constant region can include, for example, one or more (e.g., 2, 3, 4, 5, 6, 7, or 8 or more) amino acid substitutions relative to the native human Fc constant region from which the variant human Fc constant region is derived. The substitutions can improve the binding affinity of an IgG antibody comprising the variant Fc constant region to FcRn at pH 6.0 while maintaining the pH-dependence of the interaction. Methods for testing whether one or more of the substitutions in the Fc constant region of an antibody improve the affinity of the Fc constant region for FcRn at pH 6.0 (while maintaining the pH-dependence of the interaction) are known in the art and are exemplified in the Examples (see, for example, PCT / US2015 / 019225 and U.S. Patent No. 9,079,949, the entire disclosures of each of which are incorporated herein by reference in their entirety).

[0145] Substitutions that enhance the binding affinity of the Fc constant region of an antibody to FcRn are known in the art, and examples of such substitutions include, for example, (1) the M252Y / S254T / T256E triple substitution (Dall’Acqua, W. et al., J. Biol. Chem., 281:23514-24, 2006), (2) the M428L or T250Q / M428L substitution (Hinton, P. et al., J. Biol. Chem., 279:6213-6, 2004, Hinton, P. et al., J. Immunol., 176:346-56, 2006) and (3) the N434A or T307 / E380A / N434A substitution (Petkova, S. et al., Int. Immunol., 18:1759-69, 2006). In the present invention, additional substitution pairs, such as P257I / Q311I, P257I / N434H and D376V / N434H (Datta-Mannan, A. et al., J. Biol. Chem., 282:1709-17, 2007) are also contemplated.

[0146] In some embodiments, the variant constant region has a substitution for valine at the EU amino acid residue at position 255. In some embodiments, the variant constant region has a substitution for asparagine at the EU amino acid residue at position 309. In some embodiments, the variant constant region has a substitution for isoleucine at the EU amino acid residue at position 312. In some embodiments, the variant constant region has a substitution at the EU amino acid residue at position 386.

[0147] In some embodiments, the variant Fc constant region comprises 30 or fewer (e.g., 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2) amino acid substitutions, insertions, or deletions relative to the native constant region from which the variant Fc constant region is derived. In some embodiments, the variant 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 variant human Fc constant region comprises methionine at position 428 and asparagine at position 434 in EU numbering, respectively. In some embodiments, the variant Fc constant region comprises the 428L / 434S double substitution as described, for example, in U.S. Patent No. 8,088,376.

[0148] In some embodiments, the exact positions of these mutations can be shifted from the positions of the native human Fc constant region by antibody engineering. The 428L / 434S double substitution when used with IgG2 / 4 chimeric Fc can correspond to 429L and 435S, as seen in the M429L and N435S variants of BNJ441 (ruplizumab) described, for example, in U.S. Patent No. 9,079,949, the disclosure of which is incorporated herein by reference in its entirety.

[0149] In some embodiments, the variant constant region comprises substitutions at amino acid positions 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, 384, 385, 386, 387, 389, 424, 428, 433, 434 or 436 (EU numbering) relative to the native human Fc constant region. In some embodiments, the substitutions are a substitution of glycine at position 237 with methionine, a substitution of proline at position 238 with alanine, a substitution of serine at position 239 with lysine, a substitution of lysine at position 248 with isoleucine, a substitution of threonine at position 250 with alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan or tyrosine, a substitution of methionine at position 252 with phenylalanine, tryptophan or tyrosine, a substitution of serine at position 254 with threonine, a substitution of arginine at position 255 with glutamic acid, a substitution of threonine at position 256 with aspartic acid, glutamic acid or glutamine, a substitution of proline at position 257 with alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine or valine, a substitution of glutamic acid at position 258 with histidine, a substitution of aspartic acid at position 265 with alanine, a substitution of aspartic acid at position 270 with phenylalanine, a substitution of asparagine at position 286 with alanine or glutamic acid, a substitution of threonine at position 289 with histidine, a substitution of asparagine at position 297 with alanine, a substitution of serine at position 298 with glycine, a substitution of valine at position 303 with alanine, a substitution of valine at position 305 with alanine, a substitution of threonine at position 307 with alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan or tyrosine,Substitutions of valine at positions 308 with alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine or threonine; substitutions of leucine or valine at position 309 with alanine, aspartic acid, glutamic acid, proline or arginine; substitutions of glutamine at position 311 with alanine, histidine or isoleucine; substitutions of aspartic acid at position 312 with alanine or histidine; substitutions of leucine at position 314 with lysine or arginine; substitutions of asparagine at position 315 with alanine or histidine; substitutions of lysine at position 317 with alanine; substitutions of asparagine at position 325 with glycine; substitutions of isoleucine at position 332 with valine; substitutions of lysine at position 334 with leucine; substitutions of lysine at position 360 with histidine; substitutions of aspartic acid at position 376 with alanine; substitutions of glutamic acid at position 380 with alanine; substitutions of glutamic acid at position 382 with alanine; substitutions of asparagine or serine at position 384 with alanine; substitutions of glycine at position 385 with aspartic acid or histidine; substitutions of glutamine at position 386 with proline; substitutions of proline at position 387 with glutamic acid; substitutions of asparagine at position 389 with alanine or serine; substitutions of serine at position 424 with alanine; substitutions of methionine at position 428 with alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan or tyrosine; substitutions of histidine at position 433 with lysine; substitutions of asparagine at position 434 with alanine, phenylalanine, histidine, serine, tryptophan or tyrosine; and substitutions of tyrosine or phenylalanine at position 436 with histidine (all according to EU numbering), and are selected from the group consisting of.

[0150] Anti-C5 antibodies suitable for use in the methods described herein can comprise a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 14, and / or a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 11. Alternatively, anti-C5 antibodies suitable for use in the methods described herein can comprise a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 20, and / or a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 11.

[0151] In one embodiment, the antibody binds to C5 with an affinity dissociation constant (K D ) of at least 0.1 nM (e.g., at least 0.15 nM, 0.175 nM, 0.2 nM, 0.25 nM, 0.275 nM, 0.3 nM, 0.325 nM, 0.35 nM, 0.375 nM, 0.4 nM, 0.425 nM, 0.45 nM, 0.475 nM, 0.5 nM, 0.525 nM, 0.55 nM, 0.575 nM, 0.6 nM, 0.625 nM, 0.65 nM, 0.675 nM, 0.7 nM, 0.725 nM, 0.75 nM, 0.775 nM, 0.8 nM, 0.825 nM, 0.85 nM, 0.875 nM, 0.9 nM, 0.925 nM, 0.95 nM or 0.975 nM) at pH 7.4 and 25 °C (or under physiological conditions if otherwise indicated). In some embodiments, the K D of the anti-C5 antibody or antigen-binding fragment thereof is 1 nM or less (e.g., 0.9 nM or less, 0.8 nM or less, 0.7 nM or less, 0.6 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less or 0.2 nM or less).

[0152] In some embodiments, [(K D of the antibody for C5 at pH 6.0 and 25 °C) / (K D)] is greater than 21 (for example, greater than 22, greater than 23, greater than 24, greater than 25, greater than 26, greater than 27, greater than 28, greater than 29, greater than 30, greater than 35, greater than 40, greater than 45, greater than 50, greater than 55, greater than 60, greater than 65, greater than 70, greater than 75, greater than 80, greater than 85, greater than 90, greater than 95, greater than 100, greater than 110, greater than 120, greater than 130, greater than 140, greater than 150, greater than 160, greater than 170, greater than 180, greater than 190, greater than 200, greater than 210, greater than 220, greater than 230, greater than 240, greater than 250, greater than 260, greater than 270, greater than 280, greater than 290, greater than 300, greater than 350, greater than 400, greater than 450, greater than 500, greater than 600, greater than 700, greater than 800, greater than 900, greater than 1000, greater than 1500, greater than 2000, greater than 2500, greater than 3000, greater than 3500, greater than 4000, greater than 4500, greater than 5000, greater than 5500, greater than 6000, greater than 6500, greater than 7000, greater than 7500 or greater than 8000).

[0153] Methods for determining whether an antibody binds to a protein antigen and / or for determining the affinity of an antibody for a protein antigen are known in the art. Binding of an antibody to a protein antigen can be detected and / or quantified using various techniques such as, for example, Western blot, dot blot, surface plasmon resonance (SPR) methods (e.g., BIAcore system, Pharmacia Biosensor AB (Uppsala, Sweden and Piscataway, N.J.)), or enzyme-linked immunosorbent assay (ELISA) (see, for example, Benny K.C. Lo (2004) “Antibody Engineering: Methods and Protocols,” Humana Press (ISBN: 1588290921), Johne, B. et al., J. Immunol. Meth., 160:191-8, 1993, Jonsson, U. et al., Ann. Biol. Clin., 51:19-26, 1993, Jonsson, U. et al., Biotechniques, 11:620-7, 1991, but not limited thereto). For example, additional methods for measuring affinity (e.g., dissociation constant and association constant) are shown in the examples.

[0154] As used herein, “k aThe term "___" refers to the rate constant at which an antibody associates with an antigen. "k d " refers to the rate constant at which an antibody dissociates from an antibody / antigen complex. And the term "K D " refers to the equilibrium dissociation constant of the antibody-antigen interaction. The equilibrium dissociation constant is estimated from the ratio of the kinetic rate constants, i.e., K D = k a / k d . Such determined values are preferably measured at 25 °C or 37 °C. The kinetics of antibodies binding to human C5 can be determined by surface plasmon resonance (SPR) using an anti-Fc capture method for immobilizing the antibody with an instrument called BIAcore 3000, for example, at pH 8.0, pH 7.4, pH 7.0, pH 6.5, and pH 6.0.

[0155] Methods for determining whether a particular antibody described herein inhibits the cleavage of C5 are known in the art. Inhibition of human complement component C5 can reduce the cytolytic ability of complement in the body fluid of a subject. Such a reduction in the cytolytic ability of complement present in the body fluid(s) can be achieved by methods known in the art, for example, Kabat and Mayer (eds.), "Experimental Immunochemistry, 2 ndEdition,” 135-240, Springfield, IL, CC Thomas (1961), pages 135-139, or by conventional variants of such assays, such as the chicken erythrocyte hemolysis method (Hillmen, P. et al., N. Engl. J. Med., 350: 552-9, 2004). Methods for determining whether a candidate compound inhibits the cleavage of human C5 into the forms of C5a and C5b are known in the art (Evans, M. et al., Mol. Immunol., 32: 1183-95, 1995). For example, the concentrations and / or biological activities of C5a and C5b in body fluids can be measured by methods known in the art. For C5b, a hemolysis assay or an assay for soluble C5b-9 as discussed herein can be used. Other assays known in the art can also be used. These assays or other suitable assays can be used to screen for drug candidates that can inhibit human complement component C5.

[0156] Using immunological techniques such as, but not limited to, ELISA, the protein concentration of C5 and / or its cleavage products can be measured to determine the ability of an anti-C5 antibody or its antigen-binding fragment to inhibit the conversion of C5 into biologically active products. In some embodiments, the generation of C5a is measured. In some embodiments, an antibody specific for the C5b-9 neoepitope is used to detect the formation of the terminal complement.

[0157] Using a hemolysis assay, the inhibitory activity of an anti-C5 antibody or an antigen-binding fragment thereof against complement activation can be determined. To determine the effect of an anti-C5 antibody or an antigen-binding fragment thereof on hemolysis mediated by the classical pathway of complement in an in vitro serum test solution, for example, sheep red blood cells coated with hemolysin or chicken red blood cells sensitized with an anti-chicken red blood cell antibody are used as target cells. The percentage of lysis is normalized by considering the lysis that occurs in the absence of the inhibitor as 100% lysis. In some embodiments, for example, the classical pathway of complement is activated by a human IgM antibody as used in the Wieslab® Classical Pathway Complement Kit (Wieslab® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with the anti-C5 antibody or an antigen-binding fragment thereof in the presence of a human IgM antibody. The amount of C5b-9 produced is measured by contacting the mixture with an anti-C5b-9 antibody conjugated to an enzyme and a fluorescent substrate and measuring the absorbance at an appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody or an antigen-binding fragment thereof. In some embodiments, the test serum is a C5-deficient serum reconstituted with C5 polypeptide.

[0158] To determine the effect of an anti-C5 antibody or an antigen-binding fragment thereof on complement-mediated hemolysis in the alternative pathway, non-sensitized rabbit erythrocytes or non-sensitized guinea pig erythrocytes can be used as target cells. In some embodiments, the serum test solution is C5-deficient serum reconstituted with C5 polypeptide. The percentage of lysis is normalized by considering the lysis that occurs in the absence of the inhibitor as 100% lysis. In some embodiments, the alternative pathway of complement is activated by a lipopolysaccharide molecule, such as that used in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with the anti-C5 antibody or an antigen-binding fragment thereof in the presence of lipopolysaccharide. The amount of C5b-9 produced is measured by contacting the mixture with an anti-C5b-9 antibody conjugated to an enzyme and a fluorescent substrate and measuring the fluorescence at an appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody or an antigen-binding fragment thereof.

[0159] In some embodiments, the CH50eq assay is used to quantify C5 activity or its inhibition. The CH50eq assay is a method for measuring the total activity of classical complement in serum. This test is a lysis assay that determines the amount (CH50) required to lyse 50% using antibody-sensitized red blood cells as an activator of the classical complement pathway and various dilutions of the test serum. The hemolysis rate (%) can be determined using, for example, a spectrophotometer. In the CH50eq assay, the formation of the terminal complement complex (TCC) is indirectly measured. This is because the TCC itself is directly involved in the measured hemolysis. Briefly, to activate the classical complement pathway, a TCC is generated by adding an undiluted serum sample (e.g., a reconstituted human serum sample) to a microassay well containing antibody-sensitized red blood cells. Next, the activated serum sample is diluted in a microassay well coated with a capture reagent (e.g., an antibody that binds to one or more components of the TCC). The TCC present in the activated sample binds to the monoclonal antibody coating the surface of the microassay well. The well is washed, and a detection reagent that is detectably labeled and recognizes the bound TCC is added to each well. The detectable label can be, for example, a fluorescent label or an enzyme label. The result of the assay is expressed in CH50 unit equivalents per milliliter (CH50 U Eq / mL).

[0160] For example, in the case of terminal complement activity, inhibition includes, for example, in a hemolysis assay or a CH50eq assay, the activity of the terminal complement being reduced by at least 5% (e.g., at least 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60%) compared to the action of a control antibody (or its antigen-binding fragment) under the same conditions and at equimolar concentrations. Substantial inhibition, as used herein, refers to a given activity (e.g., terminal complement activity) being inhibited by 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 include one or more amino acid substitutions relative to the CDRs of eculizumab (i.e., SEQ ID NOs: 1-6) in a hemolysis assay or a CH50eq assay, 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.

[0161] 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 approximately 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%, 500%) longer than the serum half-life of eculizumab when measured in, for example, one of the mouse model systems described in the Examples (e.g., C5-deficient / NOD / scid mice or hFcRn transgenic mouse model systems).

[0162] In one embodiment, the antibody competes with the antibodies described herein in binding to the same epitope on C5 and / or binds to the same epitope on C5. The term "binds to the same epitope" with respect to two or more antibodies means that, when determined by a given method, those antibodies bind to the same segment of amino acid residues. Techniques for determining whether an antibody binds to the "same epitope on C5" as the antibodies described herein include, for example, epitope mapping methods such as X-ray analysis of crystals of the antigen:antibody complex (which provides atomic resolution of the epitope), and hydrogen / deuterium exchange mass spectrometry (HDX-MS). In other methods, the binding of an antibody to peptide antigen fragments or mutant variant forms of the antigen is monitored, and in so doing, loss of binding due to modification of amino acid residues within the antigen sequence is often regarded as an indicator of the epitope component. Computer-based combinatorial epitope mapping methods can also be used. These methods rely on the ability of the antibody of interest to affinity isolate a given short peptide from a combinatorial phage display peptide library. Antibodies having the same VH and VL, or the same CDR1 sequence, CDR2 sequence, and CDR3 sequence, are expected to bind to the same epitope.

[0163] An antibody that "competes with another antibody in binding to the target" refers to an antibody that (partially or completely) inhibits the binding of the other antibody to its target. Whether two antibodies compete with each other in binding to the target, i.e., whether one antibody inhibits the binding of the other antibody to its target, and the degree to which it inhibits that binding, can be determined using known competition assays. In some embodiments, the antibody competes with another antibody and inhibits the binding of that other antibody to its target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%. The level of inhibition or competition may vary depending on which antibody is the "blocking antibody" (i.e., the cold antibody that is first incubated with the target). Competing antibodies can bind, for example, to the same epitope, overlapping epitopes, or adjacent epitopes (such as those demonstrated by steric hindrance).

[0164] The anti-C5 antibodies or antigen-binding fragments thereof described in this specification, which are used in the methods described in this specification, can be prepared using various techniques recognized in the art. Monoclonal antibodies can be obtained by various techniques well known to those skilled in the art. Briefly, spleen cells derived from an animal immunized with the desired antigen are immortalized, generally by fusion with myeloma cells (Kohler, G. & Milstein, C., Eur. J. Immunol., 6: 511-9, 1976). Alternative immortalization methods include transformation by Epstein-Barr virus, oncogenes or retroviruses, or other methods well known in the art. In colonies arising from a single immortalized cell, screening is performed for the production of antibodies having the desired specificity and affinity for the antigen, and various techniques including injection into the peritoneal cavity of a vertebrate host can enhance the yield of monoclonal antibodies produced by such cells. Alternatively, by screening a DNA library derived from human B cells, a DNA sequence encoding a monoclonal antibody or its binding fragment can be isolated (Huse, W. et al., Science, 246: 1275-81, 1989).

[0165] Composition A pharmaceutical composition containing ravulizumab is provided alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier. The pharmaceutical composition containing ravulizumab provided by the present invention is for use, for example, in the diagnosis, detection or monitoring of a disorder, the prevention, treatment, management or improvement of one or more of a disorder or its symptoms, and / or research. The formulation of the pharmaceutical composition (the formulation alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier) is known in the art.

[0166] Also provided by the present invention is a composition comprising an anti-C5 antibody or an antigen-binding fragment thereof for use in the treatment methods described herein, wherein the patient switches from one anti-C5 antibody (e.g., eculizumab) to another anti-C5 antibody (e.g., ravulizumab) in the treatment cycle.

[0167] The composition can be formulated, for example, as a pharmaceutical solution for administration to a subject for the purpose of treating or preventing MG. The pharmaceutical composition can contain a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to and includes any solvent, dispersion medium, coating agent, antibacterial agent, antifungal agent, isotonic agent, absorption delaying agent, etc. that is physiologically compatible. The composition of the present invention can contain pharmaceutically acceptable salts, such as acid addition salts or base addition salts, sugars, carbohydrates, polyols, and / or isotonic agents.

[0168] The composition of the present invention can be prepared by known methods (Gennaro (2000) “Remington: The Science and Practice of Pharmacy,” 20 th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472), Ansel et al. (1999) “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 7 th Edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727) and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association,” 3 rdIt can be formulated according to the Edition (ISBN: 091733096X). In some embodiments, the composition can be formulated as a buffered solution at a suitable concentration and suitable for storage at 2 - 8°C (e.g., 4°C). In some embodiments, the composition can be formulated for storage at a temperature below 0°C (e.g., -20°C or -80°C). In some embodiments, the composition of the present invention can 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). That is, in some embodiments, the composition described herein is stable even when stored at 2 - 8°C (e.g., 4°C) for at least 1 year.

[0169] The pharmaceutical composition of the present invention can be in various forms. These forms include, for example, liquid solutions (e.g., injection solutions and infusion solutions), dispersants or suspensions, tablets, pills, powders, liposomes, and liquid, semi-solid and solid dosage forms such as suppositories. The preferred form depends in part on the intended mode of administration and therapeutic use. Compositions including those intended for systemic or local delivery can be, for example, in the form of an injection solution or infusion solution. The composition can be formulated for administration by parenteral methods (e.g., intravenous injection, subcutaneous injection, intraperitoneal injection or intramuscular injection). "Parenteral administration", "administer parenterally" and other grammatically equivalent phrases, as used herein, refer to modes of administration other than enteral and topical administration (usually modes of administration by injection), and such methods include, but are not limited to, injection and infusion into the vein, nose, eye, lung, muscle, artery, intrathecal space, capsule, eye socket, heart, skin, lung, abdomen, trachea, subcutaneous, subepidermal, joint, subcapsular, subarachnoid, spinal cord, epidural, intracerebral, intracranial, internal carotid and intrasternal. In one embodiment, the antibody is formulated for intravenous administration.

[0170] Exemplary non-limiting ranges of a therapeutically effective or prophylactically effective amount of lovelizumab or other anti-C5 antibodies (such as eculizumab, BNJ421, 7086, 8110, SKY59, and H4H12166PP) shown in this specification are 600 to 5000 mg, for example 900 to 2000 mg. It should be noted that the dosage values may vary depending on the type and severity of the condition to be alleviated. In any particular subject, over time, the predetermined dosing regimen may be adjusted according to the individual needs and the professional judgment of the person administering the composition or giving instructions for the administration of the composition, and it should be further understood that the dosage ranges shown in this specification are merely exemplary and are not intended to limit the scope or practice of the claimed method.

[0171] Combination therapy The anti-C5 antibodies provided by the present invention can also be administered together with one or more additional pharmaceuticals or therapeutic agents useful for the treatment of MG. The additional agent can be, for example, a therapeutic agent recognized in the art as being useful for the treatment of MG. The combination can also include two or more additional agents, for example, two or three additional agents. The binder in various embodiments is administered together with an agent that is a protein, peptide, carbohydrate, drug, small molecule, or genetic material (e.g., DNA or RNA). In various embodiments, the agent is one or more cholinesterase inhibitors, one or more corticosteroids, and / or one or more immunosuppressive drugs (most commonly azathioprine [AZA], cyclosporine, and / or mycophenolate mofetil [MMF]).

[0172] Method Provided by the present invention is a method for treating complement-related disorder(s) (e.g., MG, e.g., gMG, e.g., gMG when the patient is positive for anti-AChR antibody) in a human patient, comprising administering to the patient an anti-C5 antibody or an antigen-binding fragment thereof, and administering the anti-C5 antibody or an antigen-binding fragment thereof according to a specific clinical administration regimen (i.e., at a specific dosage and according to a predetermined administration schedule).

[0173] In some embodiments, MG includes gMG. In some embodiments, gMG is a subject or patient who is positive for autoantibodies that bind to AChR, and who shows significant systemic muscle weakness or continuous signs and symptoms of bulbar MG, while at the same time receiving up-to-date standard care for MG (such as cholinesterase inhibitor therapy and IST), or who requires long-term plasma exchange or long-term IVIg to maintain clinical stability.

[0174] In one embodiment, the anti-C5 antibody or an antigen-binding fragment thereof is administered once on the first day of an administration cycle, once on the 15th day of the administration cycle, and then every 8 weeks thereafter. In one embodiment, the anti-C5 antibody or an antigen-binding fragment thereof is administered every 8 weeks for a maximum extension period of 2 years after the administration cycle (e.g., at a dose of 3000 mg, 3300 mg or 3600 mg).

[0175] In another embodiment, the anti-C5 antibody or an antigen-binding fragment thereof is administered over one or more administration cycles. In one embodiment, the administration cycle is 26 weeks. In another embodiment, the treatment comprises at least 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles or 11 cycles. In another embodiment, the treatment is continued throughout the lifetime of the human patient.

[0176] In another embodiment, the patient switches from taking one C5 inhibitor to taking another C5 inhibitor during the treatment cool. Another anti-C5 antibody can be administered during a separate treatment period. In one embodiment, for example, a method of treating a human patient with a complement-related disorder (such as MG) who is being treated with eculizumab, the method comprising discontinuing the treatment with eculizumab and switching the patient to treatment with an alternative complement inhibitor. In another embodiment, a method of treating a human patient with a complement-related disorder who is being treated with ravulizumab, the method comprising discontinuing the treatment with ravulizumab and switching the patient to treatment with an alternative complement inhibitor.

[0177] Exemplary alternative complement inhibitors include, but are not limited to, antibodies or antigen-binding fragments thereof, small molecules, polypeptides, polypeptide analogs, peptidomimetics, siRNA, and aptamers. In one embodiment, the alternative complement inhibitor inhibits one or more of complement components C1, C2, C3, C4, C5, C6, C7, C8, C9, factor D, factor B, properdin, MBL, MASP-1, MASP-2, or bioactive fragments thereof. In another embodiment, the alternative complement inhibitor inhibits the anaphylatoxin activity associated with C5a and / or the formation of the cytolytic 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.

[0178] Exemplary alternative anti-C5 antibodies include: (i) eculizumab; (ii) an antibody or antigen-binding fragment thereof comprising a heavy chain CDR1 domain comprising SEQ ID NO: 21, a heavy chain CDR2 domain comprising SEQ ID NO: 22, and a heavy chain CDR3 domain comprising SEQ ID NO: 23, and a light chain CDR1 domain comprising SEQ ID NO: 24, a light chain CDR2 domain comprising SEQ ID NO: 25, and a light chain CDR3 domain comprising SEQ ID NO: 26; (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 domain comprising SEQ ID NO: 29, a heavy chain CDR2 domain comprising SEQ ID NO: 30, and a heavy chain CDR3 domain comprising SEQ ID NO: 31, and a light chain CDR1 domain comprising SEQ ID NO: 32, a light chain CDR2 domain comprising SEQ ID NO: 33, and a light chain CDR3 domain comprising SEQ ID NO: 34; (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 a heavy chain CDR1 domain comprising SEQ ID NO: 37, a heavy chain CDR2 domain comprising SEQ ID NO: 38, and a heavy chain CDR3 domain comprising SEQ ID NO: 39, and a light chain CDR1 domain comprising SEQ ID NO: 40, a light chain CDR2 domain comprising SEQ ID NO: 41, and a light chain CDR3 domain comprising SEQ ID NO: 42; (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, but are not limited thereto.

[0179] In another embodiment, the patient is treated with ravulizumab and then switched to treatment with the 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, H4H12166PP antibody, or eculizumab. In another embodiment, the patient switches from an anti-C5 antibody (e.g., eculizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or H4H12166PP antibody) to another anti-C5 antibody (e.g., ravulizumab) during the treatment course. In certain embodiments, the patient switches from eculizumab to ravulizumab during the treatment course.

[0180] In one embodiment, an anti-C5 antibody is administered (or is for administration) according to a specific clinical dosing regimen (e.g., at a specific dose and / or according to a predetermined dosing schedule). In one embodiment, the anti-C5 antibody is administered at a fixed dose that is constant regardless of the patient's weight. As used herein, the terms "fixed dose", "uniform dose" and "uniform fixed dose" are used synonymously and refer to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). Thus, a fixed dose or uniform dose is not expressed as a dose in mg / kg, but rather as an absolute amount of the anti-C5 antibody or antigen-binding fragment thereof.

[0181] In one embodiment, the anti-C5 antibody is administered at a fixed dose 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, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 mg, 5600 mg, 5700 mg, 5800 mg, 5900 mg, 6000 mg, 6100 mg, 6200 mg, 6300 mg, 6400 mg, 6500 mg, 6600 mg, 6700 mg, 6800 mg, 6900 mg, 7000 mg, 7100 mg, 7200 mg, 7300 mg, 7400 mg, 7500 mg, 7600 mg, 7700 mg, 7800 mg, 7900 mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg, 10900 mg or 11000 mg, regardless of the patient's weight.

[0182] In another embodiment, the dosage of the anti-C5 antibody is based on the patient's body weight. In one embodiment, for a patient with a body weight of 40 kg or more and less than 60 kg, the anti-C5 antibody or its antigen-binding fragment is administered at a dose 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, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 mg, 5600 mg, 5700 mg, 5800 mg, 5900 mg, 6000 mg, 6100 mg, 6200 mg, 6300 mg, 6400 mg, 6500 mg, 6600 mg, 6700 mg, 6800 mg, 6900 mg, 7000 mg, 7100 mg, 7200 mg, 7300 mg, 7400 mg, 7500 mg, 7600 mg, 7700 mg, 7800 mg, 7900 mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg,Administer 10600 mg, 10700 mg, 10800 mg, 10900 mg or 11000 mg.

[0183] In another embodiment, for patients with a body weight of 60 kg or more and less than 100 kg, the anti-C5 antibody or its antigen-binding fragment is administered at a dose 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, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 mg, 5600 mg, 5700 mg, 5800 mg, 5900 mg, 6000 mg, 6100 mg, 6200 mg, 6300 mg, 6400 mg, 6500 mg, 6600 mg, 6700 mg, 6800 mg, 6900 mg, 7000 mg, 7100 mg, 7200 mg, 7300 mg, 7400 mg, 7500 mg, 7600 mg, 7700 mg, 7800 mg, 7900 mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg,Administer 10900 mg or 11000 mg.

[0184] In another embodiment, a patient with a body weight of 100 kg or more is administered 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 mg, 5600 mg, 5700 mg, 5800 mg, 5900 mg, 6000 mg, 6100 mg, 6200 mg, 6300 mg, 6400 mg, 6500 mg, 6600 mg, 6700 mg, 6800 mg, 6900 mg, 7000 mg, 7100 mg, 7200 mg, 7300 mg, 7400 mg, 7500 mg, 7600 mg, 7700 mg, 7800 mg, 7900 mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg, 10900 mg or 11000 mg.In some embodiments, the dosing regimen is adjusted to obtain an optimal desired response (e.g., an effective response).

[0185] In another embodiment, the anti-C5 antibody is administered at a dose of milligrams per kilogram (mg / kg). In one embodiment, the anti-C5 antibody or an antigen-binding fragment thereof is 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1.0 mg / kg, 1.25 mg / kg, 1.50 mg / kg, 1.75 mg / kg, 2.0 mg / kg, 2.25 mg / kg, 2.50 mg / kg, 2.75 mg / kg, 3.0 mg / kg, 3.25 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.0 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.0 mg / kg, 5.25 mg / kg, 5.50 mg / kg, 5.75 mg / kg, 6.0 mg / kg, 6.25 mg / kg, 6.50 mg / kg, 6.75 mg / kg, 7.0 mg / kg, 7.25 mg / kg, 7.50 mg / kg, 7.75 mg / kg, 8.0 mg / kg, 8.25 mg / kg, 8.50 mg / kg, 8.75 mg / kg, 9.0 mg / kg, 9.25 mg / kg, 9.50 mg / kg, 9.75 mg / kg, 10.0 mg / kg, 11.25 mg / kg, 11.50 mg / kg, 11.75 mg / kg, 12.0 mg / kg, 12.25 mg / kg, 12.50 mg / kg, 12.75 mg / kg, 13.0 mg / kg, 13.25 mg / kg, 13.50 mg / kg, 13.75 mg / kg, 14.0 mg / kg, 14.25 mg / kg, 14.50 mg / kg, 14.75 mg / kg, 15.0 mg / kg, 15.25 mg / kg, 15.50 mg / kg, 15.75 mg / kg, 16.0 mg / kg, 16.25 mg / kg, 16.50 mg / kg, 16.75 mg / kg, 17.0 mg / kg, 17.25 mg / kg, 17.50 mg / kg, 17.75 mg / kg, 18.0 mg / kg, 18.25 mg / kg, 18.50 mg / kg, 18.75 mg / kg, 19.0 mg / kg, 19.25 mg / kg, 19.50 mg / kg, 19.75 mg / kg, 20.0 mg / kg, 20.25 mg / kg, 20.50 mg / kg, 20.75 mg / kg, 21.0 mg / kg, 21.25 mg / kg, 21.50 mg / kg, 21.75 mg / kg, 22.0 mg / kg, 22.25 mg / kg, 22.50 mg / kg, 22.75 mg / kg, 23.0 mg / kg, 23.Administer at a dose of 25 mg / kg, 23.50 mg / kg, 23.75 mg / kg, 24.0 mg / kg, 24.25 mg / kg, 24.50 mg / kg, 24.75 mg / kg or 25.0 mg / kg.

[0186] 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 the first day, then at a different maintenance dose on the 15th day, and thereafter at eight-week intervals.

[0187] In another embodiment, the anti-C5 antibody is administered to a patient in an amount and frequency that maintains the free C5 concentration at a minimum to obtain an effective response. In one embodiment, the anti-C5 antibody is administered to a patient in an amount and frequency that maintains the free C5 concentration at 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 a patient in an amount and frequency that maintains the free C5 concentration at 0.309 - 0.5 μg / mL or less.

[0188] In some embodiments, a patient being treated according to the methods described herein has been vaccinated against Neisseria meningitidis infection within three years prior to starting the test drug, or at the time of starting the test drug. In one embodiment, patients who start treatment less than two weeks after receiving the Neisseria meningitidis vaccine are treated with appropriate prophylactic antibiotics until two weeks after vaccination. In another embodiment, patients being treated according to the methods described herein are vaccinated against Neisseria meningitidis serogroups A, C, Y, W135 and / or B.

[0189] Outcome In some embodiments, the treatment of MG includes ameliorating or improving one or more of the symptoms associated with MG. Symptoms associated with MG include muscle weakness and fatigue. Muscles primarily affected by MG include those that control eye and eyelid movement, facial expression, chewing, speech, swallowing, breathing, neck movement, and limb movement.

[0190] In some embodiments, the treatment of MG includes improving clinical markers related to the progression of MG. These markers include the MG-ADL score, the QMG score related to disease severity, MGC, NIF, forced vital capacity, MGFA Post-Intervention Status, and other quality of life measurements. In some embodiments, MG-ADL is the primary score for measuring improvement in MG.

[0191] MG-ADL is an 8-item questionnaire that focuses on the symptoms and functional performance of activities of daily living (ADL) in subjects with MG (Table 3). The 8 items of MG-ADL are derived from the symptom-based components of the original 13-item QMG to assess the physical impairments secondary to ocular myopathy (2 items), bulbar myopathy (3 items), respiratory impairment (1 item), and gross motor or limb impairment (2 items) related to the effects of MG. In this functional status tool, each response is graded from 0 (normal) to 3 (most severe). The total score range of MG-ADL is 0 - 24. A clinically significant improvement in a patient's MG-ADL, in one embodiment, is, for example, a decrease in score by 3 points or more after 26 weeks of treatment.

[0192] The latest QMG scoring system consists of 13 items including extraocular muscles (2 items), face (1 item), medulla oblongata (2 items), gross motor (6 items), axial body (1 item), and respiration (1 item), each graded from 0 to 3, with 3 indicating the most severe (Table 4). The range of the total QMG score is 0 to 39. The QMG scoring system is an objective assessment of therapy for MG and is based on a quantitative test of sentinel muscle groups. The MGFA Task Force recommends using the QMG score in prospective studies of therapy for MG (Benatar, M. et al., Muscle Nerve, 45:909-17, 2012). Clinically significant improvement in a patient's QMG is, in one embodiment, for example, a decrease in score by 5 points or more after 26 weeks of treatment. Table 3: MG-ADL Profile

Table 3

Table 4

[0193] MGC is a validated assessment tool for measuring the clinical state of subjects with MG (16). In MGC, 10 important functional areas that are particularly affected by MG are evaluated, and the scale is weighted with respect to the clinical significance in which the reported outcomes of the subject are incorporated (Table 5, Burns, T. et al., Muscle Nerve, 54:1015-22, 2016). MGC is performed at screening, day 1, weeks 1 to 4, 8, 12, 16, 20, and 26, or at ET (also at the 1st to 6th, 8th, 10th, 12th, 14th, and 17th visits or at ET). Clinically significant improvement in a patient's MGC is, in one embodiment, for example, a decrease in score by 3 points or more after 26 weeks of treatment. Table 5: MG Composite Scale

Table 5

[0194] The Revised Myasthenia Gravis Qualify of Life 15-Item Scale (MG-QOL15r) is a QoL assessment tool related to health status and is a QoL assessment tool specialized for MG patients (Table 6). The MG-QOL15r provides information on the patient's perception of functional and physical impairments, determines the degree to which the symptoms of the disease are tolerated, and is designed to be easily administered and interpreted. In the MG-QOL15r, patients fill it out. The higher the score, the greater the degree of MG-related impairment and the discomfort caused by that impairment. A clinically significant improvement in the patient's MG-QOL15 is a decrease in score after 26 weeks of treatment. Table 6: Revised MG-QOL15r Scale

Table 6

[0195] Neuro-QOL Fatigue is a reliable, validated, concise 19-item fatigue survey tool that is filled out by the subject or patient. The higher the score, the greater the fatigue and the greater the impact of MG on activities (Table 7, Gershon, R. et al., Qual. Life Res., 21:475-86, 2012). A clinically significant improvement in the patient's Neuro-QQL Fatigue score is reflected by a decrease in score after 26 weeks of treatment. Table 7: Neuro-QOL Fatigue

Table 7-1

Table 7-2

[0196] The Euro Quality of Life-5L (EQ-5D-5L) is a self-administered questionnaire on health state-related QoL (Figs. 3A, 3B, and 3C). The EQ-5D-5L essentially consists of two pages, namely the EQ-5D descriptive scale (Fig. 3B) system and the EQ Visual Analogue Scale (EQ VAS) (Fig. 3C). This scale measures QoL with a five-item scale that includes the level of mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each level is rated on a scale that describes the degree of problems in that area (e.g., no problems walking around, some problems, moderate problems, significant problems, or unable to walk around). For each of these five items, patients are asked to indicate their health status by checking the box next to the most appropriate description. This judgment yields a single-digit number representing the level selected for that area. The five single-digit numbers can be arranged to form a five-digit number that describes the patient's health status. A clinically meaningful improvement in the patient's EQ 5D is reflected by a decrease in the score for each category after 26 weeks of treatment. This tool also has a scale for overall health status (EQ VAS), where the assessor selects a number from 1 to 100 (100 = the best possible state) to describe the health status. The EQ VAS is a vertical visual analogue scale on which patients record their health status based on their own assessment, and the endpoints are referred to as the "best imaginable health state" and the "worst imaginable health state". The VAS can be used as a quantitative scale of health outcomes that reflects the patient's own judgment. A clinically meaningful improvement in the patient's EQ VAS is reflected by an increase in the score after 26 weeks of treatment. Convergent validity was sought by examining the correlation between the items of the EQ-5D-5L and the World Health Organization 5 Well-being questionnaire (r = 0.43, p < 0.001) (see Janssen, M. et al., Qual. Life Res., 22:1717-27, 2013).The EQ-5D-5L approach is the mean of reliable test-retest reliability using intra-class coefficients, with means of 0.78 and 0.73 (Brooks, R., Health Policy, 37:53-72, 1996, Chaudhury, C. et al., Biochemistry, 45:4983-90, 2006).

[0197] In patients with MG where the condition deteriorates, life-threatening respiratory complications (including severe muscle weakness of the respiratory muscles) may occur. In patients with MG, the presence or absence of signs of respiratory failure should be carefully monitored for respiratory function. If serial measurements of forced vital capacity (FVC) or negative inspiratory force (NIF) consistently decrease, if the integrity of the upper airway is lost (difficulty in handling oral secretions, swallowing, or speaking), or if respiratory failure has occurred, ventilatory support is recommended. FVC, which is one of the test items in QMG, is performed when QMG is carried out. NIF is performed using a NIF meter.

[0198] The clinical status of MG is evaluated using the MGFA Post-Intervention Status (MGFA-PIS). Changes in the state categories of improvement, no change, deterioration, worsening, death due to MG, and minimal manifestations (MM) can be evaluated (Table 8). Table 8: MGFA-PIS

Table 8

[0199] In patients administered with lovelizumab, a decrease in MG-ADL is observed. In some embodiments, the subject has an initial MG-ADL score of more than 6 points. In some embodiments, the subject has an initial MG-ADL score of more than 0 point, more than 1 point, more than 2 points, more than 3 points, more than 4 points, more than 5 points, more than 6 points, more than 7 points, more than 8 points, more than 9 points, more than 10 points, more than 11 points, more than 12 points, more than 13 points, more than 14 points, more than 15 points, more than 16 points, more than 17 points, more than 18 points, more than 19 points, more than 20 points, more than 21 points, more than 22 points or more than 23 points. In some embodiments, after the treatment cycle with lovelizumab, the subject's MG-ADL score decreases to less than 6 points. In some embodiments, the MG-ADL score decreases by at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 16 points, at least 17 points, at least 18 points, at least 19 points, at least 20 points, at least 21 points, at least 22 points, at least 23 points or at least 24 points after treatment with lovelizumab. In some embodiments, the subject's MG-ADL score decreases by at least 1 point after the treatment cycle with lovelizumab. In some embodiments, the subject's MG-ADL decreases by 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, 11 points, 12 points, 13 points, 14 points, 15 points, 16 points, 17 points, 18 points, 19 points, 20 points, 21 points, 22 points, 23 points or 24 points after treatment with lovelizumab.

[0200] According to some embodiments, the treatment course with ravulizumab continues for 26 weeks. According to some embodiments, the treatment course continues for 26 to 52 weeks, 26 to 78 weeks, 26 to 104 weeks, 26 to 130 weeks, 26 to 156 weeks, 26 to 182 weeks, 26 to 208 weeks or more. In some embodiments, the treatment course continues for more than 26 weeks, more than 27 weeks, more than 28 weeks, more than 29 weeks, more than 30 weeks, more than 31 weeks, more than 32 weeks, more than 33 weeks, more than 34 weeks, more than 35 weeks, more than 36 weeks, more than 37 weeks, more than 38 weeks, more than 39 weeks, more than 40 weeks, more than 41 weeks, more than 42 weeks, more than 43 weeks, more than 44 weeks, more than 45 weeks, more than 46 weeks, more than 47 weeks, more than 48 weeks, more than 49 weeks, more than 50 weeks, more than 51 weeks, more than 52 weeks, more than 78 weeks, more than 104 weeks, more than 130 weeks, more than 156 weeks or more than 182 weeks. According to some embodiments, the treatment course continues for more than 1 year, more than 2 years, more than 3 years, more than 4 years, more than 5 years, more than 10 years, more than 15 years, more than 20 years, more than 25 years, more than 30 years, more than 35 years, more than 40 years, more than 45 years, more than 50 years, more than 55 years, more than 60 years, more than 65 years, more than 70 years, more than 75 years, more than 80 years, or a period exceeding this. In some embodiments, the treatment course continues for the remainder of the subject's life.

[0201] According to some embodiments, in the treatment course, one or more of the symptoms or scores associated with MG improve in the treatment course and are maintained at that improved level throughout the treatment. MG-ADL can be maintained at that improved level, for example, after improvement after 26 weeks of treatment with a therapeutic antibody that specifically binds to C5, over the period of that treatment (52 weeks of treatment with a therapeutic antibody that specifically binds to C5). An example of a therapeutic antibody that binds to C5 is ravulizumab.

[0202] In some embodiments, the first signs of improvement appear after 26 weeks of treatment with a therapeutic antibody that specifically binds C5. According to some embodiments, the first signs of improvement appear between weeks 1 - 26, 26 - 52, 52 - 78, 78 - 104, 104 - 130, 130 - 156, 156 - 182, or 182 - 208 of treatment with a therapeutic antibody that specifically binds C5. In some embodiments, the first signs of improvement appear at week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 78, 104, 130, 156, or 182.

[0203] In some embodiments, MG includes refractory gMG. In some embodiments, refractory gMG is a subject or patient who is positive for autoantibodies that bind to AChR and in whom marked generalized muscle weakness or bulbar signs and symptoms of MG persist, and who is receiving up - to - date standard care for myasthenia gravis (such as cholinesterase inhibitor therapy and IST) or requires long - term plasma exchange or long - term IVIg to maintain clinical stability. In some embodiments, refractory gMG is characterized as including a subject or patient in whom marked generalized muscle weakness or bulbar signs and symptoms of myasthenia gravis persist while receiving up - to - date standard care for MG (such as cholinesterase inhibitor therapy and IST) or requiring long - term plasma exchange or long - term IVIg to maintain clinical stability.

[0204] Kits and Unit Dosage Forms The present invention also provides a kit comprising a pharmaceutical composition containing an anti-C5 antibody or an antigen-binding fragment thereof (such as ravulizumab) and a pharmaceutically acceptable carrier, in a therapeutically effective amount adapted for use in the above method. For administering the composition to a patient with MG, the kit may optionally also include, for example, instructions including an administration schedule so that an administration person (e.g., a doctor, a nurse or a patient) can administer the composition contained in the kit. The kit can also include a syringe.

[0205] Optionally, the kit can include a plurality of single-dose pharmaceutical composition packages each containing an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof for single administration by the above method. Devices or instruments necessary for administering the pharmaceutical composition(s) may also be included in the kit. The kit may supply one or more prefilled syringes containing an anti-C5 antibody or an antigen-binding fragment thereof in a certain amount.

[0206] The following examples are merely illustrative and should not be construed as limiting the scope of the present disclosure in any way. This is because many variations and equivalents will be apparent to those skilled in the art upon reading the present disclosure. The contents of all references, Genbank entries, patents and patent application publications cited throughout this application are hereby expressly incorporated by reference into this specification.

Example

[0207] Example 1: A Phase 3 randomized double-blind placebo-controlled multi-center trial to evaluate the safety and efficacy of ravulizumab in adult patients with naive generalized myasthenia gravis A Phase 3 randomized double-blind placebo-controlled multi-center trial was conducted to evaluate the safety and efficacy of ravulizumab administered to adult patients with gMG by intravenous (IV) infusion. The outline of this ALXN1210-MG-306 trial is shown in Figure 1.

[0208] 1. Rationale of the trial Ravulizumab specifically binds with high affinity to human terminal complement component (C5) and inhibits the enzymatic cleavage of C5, thereby preventing the generation of the inflammatory / thrombosis-promoting complement activation product C5a and the lytic and inflammatory / thrombosis-promoting membrane-damaging complex C5b-9 (involved in antibody-mediated NMJ disruption, loss of acetylcholine receptors, and neuromuscular conduction disorders associated with gMG). Eculizumab is approved under the trade name Soliris, for example, for the treatment of gMG.

[0209] Similar to eculizumab, ravulizumab also essentially inhibits C5 immediately and completely, but ravulizumab further inhibits complement continuously over a long dosing interval and is specifically designed to have a longer half-life than eculizumab (and has since been proven). Therefore, the required infusion frequency of ravulizumab (once every 8 weeks [q8w]) is lower than that of eculizumab (infused once every 2 weeks [q2w]). Considering that gMG is a chronic disease with a high treatment burden, the relative convenience of the dosing regimen of ravulizumab may improve patient satisfaction and treatment adherence and ultimately lead to an improvement in health outcomes.

[0210] The improved pharmacokinetic (PK) / pharmacodynamic profile of ravulizumab (less PK trough than eculizumab) offers the potential for improved therapeutic efficacy while maintaining a safety profile comparable to that of eculizumab. The q8w dosing regimen minimizes the risk of incomplete complement inhibition. The infusion frequency is relatively low (six infusions per year) (Figure 2), which may lead to an improvement in quality of life (QoL) by reducing the number of days off work or school, improving treatment adherence, and enhancing ease of use. With ravulizumab, conventional dosing and immediate onset of action are achieved, and terminal complement is effectively and completely inhibited by the end of the first infusion. The dosing regimen of ravulizumab is optimized to minimize exposure differences across the adult weight range by using a weight-based dosing paradigm that inhibits C5 immediately, completely, and continuously throughout the dosing interval. That is, in ravulizumab, the risk of inflammation, including damage to motor neuron endplates due to C5a mobilization, activation of inflammatory cells, and direct induction of the MAC complex, is minimized (Kusner, L. et al., Expert Rev. Clin. Immunol., 4:43-52, 2008).

[0211] 2. Risk-benefit assessment Ravulizumab offers patients and physicians the option of less frequent dosing, which can expand treatment access to patients who are unable to initiate treatment with eculizumab, who may discontinue eculizumab due to dosing frequency, or who are receiving eculizumab every two weeks at that time.

[0212] Neisseria meningitidis Increased susceptibility to infections caused by Neisseria meningitidis (N. meningitidis) is a known risk associated with complement inhibition. The main risk associated with ravulizumab is the risk of Neisseria meningitidis infection. As described herein, specific risk mitigation measures are in place to address this risk.

[0213] Immunogenicity Administration of any therapeutic protein containing ravulizumab may induce an immunogenic response, which may result in the production of anti-drug antibodies (ADA). The possible range of clinical outcomes may include severe hypersensitivity reactions and reduced efficacy (neutralization of PK and / or PD) due to the expression of neutralizing ADA (Casadevall, N. et al., N. Engl. J. Med., 346:469-75, 2002, Li, J. et al., Blood, 98:3241-8, 2001).

[0214] In the IV clinical trial of ravulizumab, among 261 patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with ravulizumab, ADA was detected in 1 patient during treatment. In the ALXN1210-HV-104 trial, ADA expressed during treatment was observed in 3 healthy subjects treated subcutaneously (SC) with ravulizumab and in 1 healthy subject treated IV with ravulizumab. All ADA positive values were low and negative for eculizumab cross-reactivity. No obvious effect of immunogenicity on the PK or PD of ravulizumab was observed.

[0215] Monitoring of immunogenicity in this trial is performed as described in Tables 10 and 11 and as otherwise described herein.

[0216] Local and systemic reactions Protein therapies administered intravenously (IV) carry the potential risk of causing local reactions (reactions at the injection site) and systemic reactions (reactions associated with the injection). Reactions at the injection site are reactions that are localized to the IV administration site of the drug and can include reactions such as erythema, pruritus, and bruising. Reactions associated with the injection are essentially systemic reactions and can be reactions mediated either immunologically or non-immunologically, and generally occur within a certain time period after drug administration. Immunologically mediated reactions may include allergic reactions (e.g., anaphylaxis), and non-immunologically mediated reactions are non-specific (e.g., headache, dizziness, nausea). Monitoring for these reactions is conducted as part of the routine safety assessment in this trial, as described herein.

[0217] 3. Objectives The primary objective of this trial is to evaluate the efficacy of ravulizumab compared to placebo in the treatment of gMG based on improvement in the MG-ADL profile. The secondary objective of this trial is to evaluate the efficacy of ravulizumab compared to placebo in the treatment of gMG based on improvement in the total QMG score.

[0218] The exploratory objectives of this trial are: (1) to evaluate the PK / PD and immunogenicity of ravulizumab in the treatment of gMG throughout this trial; (2) to evaluate the efficacy of ravulizumab compared to placebo in the treatment of gMG based on the incidence of all-cause hospitalizations or worsening of clinical symptoms; (3) to evaluate the efficacy of ravulizumab compared to placebo in the treatment of gMG based on improvement in the quality of life measurement results; and (4) to evaluate the efficacy of ravulizumab in the treatment of gMG based on other efficacy endpoints throughout this trial.

[0219] The safety objective of this trial is to characterize the overall safety of ravulizumab in the treatment of gMG.

[0220] 4. Endpoints The primary endpoint of the efficacy of this trial is the change from baseline in the total MG-ADL score at week 26 of the randomized control period.

[0221] The secondary endpoint of the efficacy of this trial is the change from baseline in the total QMG score at week 26.

[0222] The exploratory endpoints of the efficacy of this trial include the following. · Changes in the concentration of ravulizumab in serum over time · Changes in the concentration of free C5 in serum over time · Incidence of anti-drug antibodies developed under treatment over time · Incidence of all-cause hospitalization or worsening of clinical symptoms during the 26-week randomized control period · Change from baseline in the Revised 15-Component Myasthenia Gravis Quality of Life (MG-QOL15r) score at week 26 · Change from baseline in the Neuro-QOL Fatigue score at week 26 · Whether the total MG-ADL score improved by at least 3 points from baseline at week 26 · Whether the total QMG score improved by at least 5 points from baseline at week 26 · Change from baseline in the Myasthenia Gravis Composite (MGC) score at week 26 · Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Status (PIS) at week 26 · Change from baseline in Euro Quality of Life (EQ-5D-5L) at week 26

[0223] The safety endpoints of this trial are (1) the incidence of adverse events and serious adverse events over time, and (2) the changes from baseline in vital signs and laboratory evaluation results.

[0224] The objectives and endpoints of this trial are summarized in Table 9 herein. Table 9: Objectives and Endpoints of the ALXN1210-MG-306 Trial [Table 9-1] [Table 9-2]

[0225] 5. Overall Design ALXN1210-MG-306 is a Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multi-center trial to evaluate the safety and efficacy of ravulizumab in the treatment of gMG patients. The outline of the ALXN1210-MG-306 trial is shown in Figure 1. Approximately 160 eligible patients are stratified by region (North America, Europe, Asia-Pacific, and Japan) and randomized 1:1 to one of two treatment groups: (1) the ravulizumab infusion group or (2) the placebo infusion group. This trial has three periods: a screening period, a randomized control period, and an open-label extension (OLE) period.

[0226] After the 26-week randomized control period and the evaluation at Day 183 (Week 26), patients in the placebo group are administered a loading dose of ravulizumab under blinding, and patients in the ravulizumab group are administered ravulizumab at a dose of 900 mg under blinding. Starting from Week 28, all patients are initiated on a maintenance dose of ravulizumab q8w under open-label. In patients in the ravulizumab group, the ravulizumab dose of 900 mg under blinding is selected to maintain complete inhibition of C5 until the next scheduled maintenance dose at Week 28 (Day 197).

[0227] Eight weeks after administration of the last dose of the investigational drug, all enrolled patients will return for the 132nd week (±2 days) visit, which is the 30th visit, at the end of the trial (EOS), at which time the final trial assessment will be performed. If a patient drops out of the trial or completes the trial early (before the 29th visit, before week 124), for example, if lovelizumab is registered or approved (in accordance with country-specific regulations) before the 29th visit, the patient is recommended to return for a visit at the end of early termination (ET) / EOS, 8 weeks (±2 days) after the day of administration of the most recent dose of the investigational drug, at which time the final safety assessment as described herein will be performed as scheduled. Efforts will be made to follow up on the safety of all patients for 8 weeks from the day of administration of the most recent dose of the investigational drug.

[0228] At the screening visit, patients receiving IST treatment may continue their baseline IST treatment throughout the randomized control period and the OLE period. However, during the randomized control period of the trial, the dose of IST must not be changed, and no new IST may be added or discontinued, unless the investigator determines that it is medically necessary. Throughout the trial, if a patient shows worsening of clinical symptoms as defined in the protocol for this trial, rescue therapy (e.g., high-dose corticosteroids, plasma pheresis / plasma exchange, or intravenous immunoglobulin) may be approved. The rescue therapy to be used for a particular patient is at the discretion of the investigator.

[0229] Throughout the trial, if a patient shows worsening of clinical symptoms as defined herein, rescue therapy (e.g., high-dose corticosteroids, PP / PE, or IVIg) may be approved. The rescue therapy to be used for a particular patient is at the discretion of the investigator.

[0230] The primary endpoint of this trial is measured at Week 26 (Day 183). The endpoint is measured and analyzed regardless of the presence or absence of rescue therapy. As defined in the trial protocol, for patients who have completed the trial, EOS visit is defined as the last visit of the patient during the (maximum) 2-year OLE period. The total trial period for each individual patient is estimated to be 132 weeks (from enrollment to the end of safety follow-up), including an 8-week safety follow-up (starting from the administration of the last dose of the investigational drug to the patient). The active participation period of the patient is estimated to be 132 weeks (from enrollment to EOS visit).

[0231] The study implementation schedule (SOA) for the randomized control period is shown in Table 10, and the SOA for the OLE period is shown in Table 11.

[0232] Screening period (2 weeks to 4 weeks before Day 1) At the screening visit, after obtaining informed consent from the patient, the patient is screened for eligibility for the trial through a review of the medical history, demographic data, and laboratory evaluation. The review of the medical history includes confirmation of the MG diagnosis as defined by the inclusion criteria of this trial protocol, history of past treatment / therapy for MG (e.g., thymectomy, IST including corticosteroids, IVIg, and PE / PP), history of MG exacerbation or crisis (including the duration of each exacerbation / crisis), medications taken during each exacerbation / crisis, and treatment for each exacerbation / crisis.

[0233] When all inclusion criteria are met and none of the exclusion criteria apply, the patient is vaccinated against N. meningitidis, except when the patient has already received a vaccine within 3 years prior to enrollment in the trial. For patients who start treatment with the investigational drug less than 2 weeks after receiving the meningococcal vaccine, they are treated with appropriate prophylactic antibiotics until 2 weeks after vaccination.

[0234] During the screening period, if deterioration of clinical symptoms or MG crisis is observed in a patient, the sponsor of the clinical trial will be notified. After discussion with the sponsor of the clinical trial, it will be determined whether the patient can continue the trial.

[0235] Number of patients Patients will be screened until the estimated total number of patients reaches 160 and sufficient patients are enrolled to have approximately 80 patients per group.

[0236] Randomization At the time of randomization, eligibility will be evaluated in all patients based on the inclusion and exclusion criteria of the trial. All patients who have received vaccination and, at the time of randomization [Day 1], still meet all inclusion criteria and do not fall under any exclusion criteria and have been permitted by the investigator to be randomized will be randomized 1:1 into one of two treatment groups, namely, (1) the lovelizumab infusion group or (2) the placebo infusion group. Patients will be centrally randomized using Interactive Response Technology. The randomization will be stratified by region (North America, Europe, Asia-Pacific, and Japan).

[0237] Throughout the trial, rescue therapy will be permitted if the patient's health is at risk without it (e.g., in case of an emergency), or if the patient shows deterioration of clinical symptoms as defined in this clinical trial protocol. Rescue therapy (e.g., high-dose corticosteroids, PP / PE, or IVIg) will be permitted at the discretion of the investigator.

[0238] Patients should be informed about the worsening of clinical symptoms or potential signs and symptoms of MG crisis, contact the investigator, and instruct the investigator to evaluate the manifestation of such symptoms within 48 hours after notification. At the time of the visit for evaluation, the investigator or the person designated by the investigator shall conduct the evaluation as defined in this test implementation plan. The investigator or the designated person shall determine whether the patient meets the definition of worsening of clinical symptoms as defined in this specification and treat the patient accordingly.

[0239] The primary endpoint of this study will be measured at week 26 (day 183), regardless of the presence or absence of rescue therapy.

[0240] Patients randomized to the ravulizumab group will receive a loading dose of ravulizumab under blinded conditions on day 1, followed by a maintenance dose of ravulizumab under blinded conditions on day 15 (week 2), and thereafter, administered q8w for a total of 18 weeks of treatment. Patients randomized to placebo will receive a blinded dose of placebo on day 1, followed by a blinded dose of placebo on day 15 (week 2), and thereafter, administered q8w for a total of 18 weeks of administration. Both ravulizumab and placebo will be administered by intravenous infusion.

[0241] After the 26-week randomized control period and the evaluation on day 183 (week 26), patients in the placebo group will receive a loading dose of ravulizumab under blinded conditions, and patients in the ravulizumab group will receive ravulizumab at a dose of 900 mg under blinded conditions. This dose of 900 mg was selected to maintain complete inhibition of C5 until the next maintenance dose scheduled for week 28 (day 197). From week 28, all patients will start receiving the maintenance dose of ravulizumab q8w under open-label conditions.

[0242] The OLE period for each patient will start when the patient receives ravulizumab at week 26 (day 183) and continue until the earlier of the longest 2-year time point or the time point when the product is registered or approved (in accordance with country-specific regulations).

[0243] From screening to the end of the randomized control period, the implementation schedule is shown in Table 10, and the implementation schedule for the extension period is shown in Table 11. Table 10: Implementation Schedule from Screening to the End of the Randomized Control Period

Table 10-1

Table 10-2

Table 10-3

Table 11-1

Table 11-2

[0244] 6. Definition of the standard clinical trial protocol Table 12: Abbreviations and definitions during the trial and follow-up period

Table 12-1

Table 12-2

[0245] Worsening of clinical symptoms In this clinical trial protocol, the worsening of clinical symptoms is defined as follows. 1. Patients who develop myasthenic gravis crisis (defined as muscle weakness due to MG that is severe enough to require intubation or delay extubation after surgery). The respiratory failure is due to muscle weakness of the respiratory muscles. Severe bulbar (oropharyngeal) muscle weakness often accompanies muscle weakness of the respiratory muscles, or may be a prominent feature in some patients. Or 2. A significant worsening of symptoms where the score has deteriorated by 3 points or 2 points from the baseline in any one of the individual items of MG-Activities of Daily Living (MG-ADL) excluding diplopia or ptosis. Or 3. When rescue therapy is being administered to a patient whose health would be in a critical situation (e.g., an emergency) if rescue therapy were not carried out, at the discretion of the principal investigator or a physician designated by the principal investigator.

[0246] Unscheduled hospital visit Under exceptional circumstances, additional (unscheduled) hospital visits may be permitted at the discretion of the principal investigator outside of the scheduled hospital visits. The principal investigator shall, at their discretion, conduct treatments, examinations and evaluations, and endeavour to associate the corresponding data with the appropriate hospital visit.

[0247] Clinically trained evaluators A clinically trained evaluator is a study staff member who is qualified to perform the MG-ADL, QMG, and MGC assessments. Only clinically trained evaluators perform these assessments. Clinically trained evaluators are neurologists, physical therapists, or other study team members appointed by the principal investigator. Only the principal investigator or a neurologist performs the manual muscle test (MMT), components of the MGC, MGFA-PIS, and Myasthenia Gravis Foundation of America (MGFA) Classification. Training and certification of clinically trained evaluators in this study plan will be conducted either at investigator meetings or on an online training portal designated by the study sponsor.

[0248] Responsibility for the assessment of myasthenia gravis Responsibility for the assessment of MG is listed in Table 13. Throughout the study, the assessment of MG is performed by a clinically trained evaluator, preferably the same evaluator, at approximately the same time of day. Table 13: Assessment and responsibility for MG [Table 13] Abbreviations: MG-ADL = Myasthenia Gravis Activities of Daily Living Profile, MGC = Myasthenia Gravis Composite scale, MGFA = Myasthenia Gravis Foundation of America, MGFA-PIS = Myasthenia Gravis Foundation of America Post-Intervention Status, MMT = manual muscle test, QMG = Quantitative Myasthenia Gravis score for disease severity

[0249] Scientific rationale for the study design Based on public data, the MG-ADL profile has been validated as a well-established objective assessment of treatment efficacy over time in gMG patients (Howard, J. et al., Muscle Nerve, 56:328-30, 2016).

[0250] The safety parameters to be evaluated are those commonly used in clinical trials conducted in accordance with the guidelines of the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP).

[0251] Placebo was selected as the control, and patients were allowed to continue stable therapy with standard care (e.g., IST) throughout the duration of the study, thus enabling the safety and efficacy of ravulizumab when administered in addition to the patient's standard care to be comparable to the current standard of care in gMG patients.

[0252] Given the heterogeneity of the disease and the variability in symptom severity, there is no recognized single international standard of care, and targeted therapies with complement inhibitors (such as the recently introduced eculizumab) are not yet widely available to patients worldwide and are not yet considered the standard of care for all gMG patients. Placebo-controlled trials enable the evaluation of treatment effects and a double-blind design, which is an important trial condition to maintain when considering endpoints, including neurological scales, which are known to be particularly susceptible to the influence of the placebo effect. The placebo-controlled portion of the study of the present invention is limited to 26 weeks, after which all patients will transition to open-label treatment with ravulizumab for up to two years during the OLE period. Throughout the study, at all times, physicians are recommended to prioritize patient safety, and any rescue therapy is allowed for patients in whom a worsening of clinical symptoms is observed.

[0253] Basis for Dosage Lulizumab is currently undergoing a Phase 3 clinical trial in patients with PNH and aHUS, and PK / PD data are being extensively collected from all trials. The lulizumab dosing regimens for these indications are selected based on comprehensive modeling and simulation analysis of Phase 1 and Phase 2 PK / PD data in healthy subjects, as well as PK / PD / efficacy (lactate dehydrogenase) and safety data in PNH patients, and are considered to be optimal for immediately, completely, and continuously inhibiting terminal complement activity in all patients throughout each dosing interval and over the entire treatment course. In the current trial, a weight-based Phase 3 dosing regimen (Table 14) is being tested in patients with MG. Table 14: Lulizumab Dosing Based on Body Weight

Table 14

[0254] Consistent with the approved label of eculizumab for treating adult and pediatric patients with aHUS and adult patients with gMG, supplemental dosing of lulizumab is performed at 50% of the dose (rounded up if not a multiple of 300 mg due to vial composition) in combination with PP / PE rescue therapy. In adult patients with gMG, supplemental dosing of lulizumab is performed (at a dose of 600 mg) in combination with IVIg rescue therapy. Based on PK simulations considering public data describing the effect of co-administration with IVIg on the PK / PD of eculizumab, a supplemental lulizumab dose of 600 mg per week is selected (Table 1, Table 2, Fitzpatrick, A. et al., J. Peripher. Nerv. Syst., 16:84-91, 2011).

[0255] When rescue therapy with PE / PP or IVIg is given on non-dose days, administration of supplementary investigational product (or placebo) is required, whereas when infusion of PE / PP or IVIg is given on dose days (however, prior to administration of the investigational product), administration of supplementary investigational product (or placebo) is not required. When PE / PP or IVIg is administered at the scheduled time of the purpose of administration upon hospital visit, regular administration is carried out 60 minutes after completion of PE / PP or IVIg. In patients receiving PE / PP, when PE / PP or IVIg is administered at an unscheduled hospital visit for administration, a supplementary dose is administered 4 hours after completion of the PE / PP session, and in patients receiving IVIg, a supplementary dose is administered 4 hours after completion of the last continuous session(s) of IVIg, as described herein.

[0256] The favorable efficacy / risk profile of ravulizumab obtained from a recently completed Phase 3 trial in PNH patients confirms that terminal complement is inhibited immediately (after the first dose, i.e., after the loading dose), completely (free C5 < 0.5 μg / ml), and sustainably (over the entire active treatment cool-down) under the above-described investigational dosing regimen.

[0257] After a 26-week randomized control period and evaluation on Day 183 (Week 26), patients in the placebo group were administered a loading dose of ravulizumab under blinding, and patients in the ravulizumab group were administered ravulizumab at a dose of 900 mg under blinding. This dose of 900 mg was selected for the purpose of maintaining complete inhibition of C5 until the next maintenance dose scheduled for Week 28 (Day 197). From Week 28 (Day 197), all patients start maintenance dose of ravulizumab q8w under open label.

[0258] This q8w dosing regimen proposal facilitates a study of the PK drug exposure range useful for evaluating the exposure-response relationship of ravulizumab in gMG patients. The safety and tolerability of ravulizumab have been established over a wide range of PK exposures, including those expected in the gMG dosing regimen proposal in healthy subjects and patients.

[0259] Definition of End of Trial The patient is considered to have completed the trial in the following cases. · If the patient has completed the entire trial period, including the last visit during the OLE period, or · When the trial is terminated early, if the patient has completed the entire applicable trial period, including the EOS visit · If the patient terminates the trial early (and the EOS visit is completed) for the reason that the investigational drug has been registered or approved (in accordance with the regulations specific to each country)

[0260] The measurement of the primary endpoint is completed after the last visit of the last patient during the randomized control period. EOS is defined as the last visit date of the last patient in the trial, or, globally, the date on which the last scheduled treatment shown in the implementation schedule (see Tables 10 and 11) was performed in the last patient of the trial. The trial completion date corresponds to the last visit to examine the last patient in the trial or to perform an intervention regarding the primary endpoint or secondary endpoint and AE on the last patient.

[0261] 7. Trial Population Future approval of deviations from the trial protocol (also known as trial protocol waivers) in the criteria for subject recruitment and registration is not permitted.

[0262] Inclusion Criteria A patient is eligible for inclusion in the trial only if all of the following criteria are met.

[0263] 1. Age Male and female patients who are 18 years of age or older at the time of signing the informed consent 2. Patient Type and Disease Characteristics Diagnosed with MG at least 6 months (180 days) before the screening visit date (when confirmed according to the criteria defined in the trial protocol (see below)) 3. The diagnosis of MG is made by the following examinations. a. Positive in the serum test for anti-AChR Ab (confirmed at the time of screening), and b. Meets one of the following. · History of abnormal neuromuscular examination shown by single-fiber electromyography or repetitive nerve stimulation test · Positive history in the anti-cholinesterase test (e.g., edrophonium chloride test) · As evaluated by the treating physician, improvement of MG symptoms is observed with oral cholinesterase inhibitors 4. At the time of screening, the Myasthenia Gravis Foundation of America Clinical Classification is class II-IV. 5. At the time of screening and randomization (day 1), the MG-ADL profile is 6 or more. 6. Patients receiving treatment by any of the following have received treatment before the screening visit and have been taking it stably for the period specified below. · Azathioprine (AZA): Have been taking AZA for 6 months (180 days) or more and have been taking it continuously for 2 months (60 days) or more. · Immunosuppressive therapy agents (e.g., mycophenolate mofetil [MMF], methotrexate [MTX], cyclosporine [CYC], tacrolimus [TAC], or cyclophosphamide [CY]) Have been taking them for 3 months (90 days) or more and have been taking them stably for 1 month (30 days) or more. · Have been taking oral corticosteroids stably for 4 weeks (28 days) or more. · At the time of the screening visit, have been taking cholinesterase inhibitors stably for 2 weeks (14 days) or more. 7. To reduce the risk of Neisseria meningitidis infection, within 3 years before starting the test drug or at the time of starting the test drug, all patients are vaccinated against Neisseria meningitidis infection. For patients who start treatment with the test drug less than 2 weeks after receiving the Neisseria meningitidis vaccine, appropriate prophylactic antibiotics are administered until 2 weeks after vaccination. 8. Body weight At the time of screening, the body weight is 40 kg or more. 9. Pregnancy and contraception Patients who may become pregnant and patients with a partner who may become pregnant shall use a contraceptive method to avoid pregnancy during treatment and for 8 months after the last dose of the investigational drug. 10. Informed consent A signed informed consent can be provided. As part of the informed consent, · The principal investigator or his / her agent shall explain the nature of the trial to the patient or his / her legal representative and answer all questions regarding the trial. · Notify the patient that participation in the trial is voluntary. The patient or his / her legal representative shall sign a written informed consent that complies with the requirements of 21 CFR 50, local regulations, ICH guidelines, the requirements of the Health Insurance Portability and Accountability Act, and the IRB / IEC or the trial conducting facility, if applicable. · The medical record shall include a description of obtaining the informed consent document before registering the patient in the trial and the date of obtaining the informed consent document. The person authorized to obtain the informed consent shall also sign the ICF. · During the trial, the patient shall be re-consented to the latest version of the informed consent form (ICF(s)). Provide a copy of the ICF(s) to the patient. · The principal investigator shall retain the original signed ICF(s). Provide a copy of the signed ICF(s) to the patient. · Patients undergoing re-screening do not need to sign another ICF unless they have an updated ICF.

[0264] Exclusion criteria A patient will be excluded from the trial if any of the following criteria apply.

[0265] 1. Medical condition It is either an active or untreated thymoma. There is a history of thymic carcinoma or thymic malignancy (except when considered cured by adequate treatment and there is no evidence of recurrence for more than 5 years before screening). 2. There is a history of thymectomy within 12 months before screening. 3. There is a history of hypersensitivity reaction to any of the components included in the test drug, including hypersensitivity reaction to mouse protein. 4. There is a history of N. meningitidis infection. 5. It is human immunodeficiency virus (HIV) infection (proven by antibody titer of HIV-1 or HIV-2) 6. In the judgment of the investigator, there are known medical conditions or mental states (multiple possible) or risk factors that prevent the patient from fully participating in the trial, pose any additional risks to the patient, or confound the evaluation of the patient or the outcome of the trial. 7. For any reason, there is a history of hospitalization for more than 24 hours within 4 weeks (28 days) before screening. 8. In the judgment of the investigator, there are clinical features consistent with MG crisis / abhorrence or worsening of clinical symptoms at the time of screening visit or at any time before randomization. 9. Female patients who plan to become pregnant, are currently pregnant, or are breastfeeding 10. Female patients with a positive pregnancy test result at the time of screening or on Day 1 11. Pre-treatment / Combined treatment Using the following within the period specified below · IVIg within 4 weeks (28 days) before randomization (Day 1) · Use of PE within 4 weeks (28 days) before randomization (Day 1) · Use of rituximab within 6 months (180 days) before screening 12. Patients who have previously received treatment with a complement inhibitor (e.g., eculizumab) 13. Past / current experience in clinical trials Participation in another interventional clinical trial or use of any experimental therapy within 30 days prior to starting study drug on Day 1 of this study, or within 5 half-lives of study drug, whichever is longer

[0266] Screening ineligible Screen failures are defined as patients who consent to participate in a clinical trial but are not subsequently randomized to a treatment group. To meet the requirements published by Reporting Trials and to respond to regulatory inquiries, a minimum set of screen-failure information is required to ensure that screen-failure patients are reported with a high degree of transparency. The minimum information includes demographic characteristics, details of screen-failure, eligibility criteria, and any serious adverse events (SAEs).

[0267] Individuals who do not meet the criteria for inclusion in this study (screening failures) may be rescreened once, based on discussion and agreement between the investigator and medical monitor.

[0268] Patients who experience clinical deterioration or exacerbation / crisis of gMG during the screening period will be considered as screening failures. Such patients may be rescreened once medically stable with treatment at the investigator's discretion and with sponsor approval. At least 28 days of clinical stability must be observed prior to enrollment. To participate in the study, patients must meet all inclusion criteria and none of the exclusion criteria at the time of rescreening.

[0269] 8. Study Drugs Test drug to be administered Rabilizumab is formulated at pH 7.0 and supplied in 30 mL disposable vials. Each vial of Rabilizumab contains 300 mg (10 mg / mL) of Rabilizumab in 10 mM sodium phosphate, 150 mM sodium chloride, 0.02% polysorbate 80, and water for injection. The comparator is formulated as a corresponding colorless, clear, sterile solution that contains the same buffer components but no active ingredient. Further details are shown in Table 15 Table 15: Test articles to be administered

Table 15

[0270] The test articles are administered as shown in Table 16

[0271] During the randomized control period, patients in the Rabilizumab treatment group are administered a weight-based loading dose of Rabilizumab, and patients in the placebo treatment group are administered a weight-based loading dose of placebo on Day 1 (at the second visit). At the fourth visit (Week 2), patients in the Rabilizumab treatment group are administered a weight-based maintenance dose of Rabilizumab, and patients in the placebo treatment group are administered a weight-based maintenance dose of placebo q8w until the end of the randomized control period (see Table 16). After the end of the randomized control period, patients enter the OLE period

[0272] After the 26-week randomized control period and the evaluation on Day 183 (Week 26), patients in the placebo group are administered a loading dose of Rabilizumab under blinded conditions, and patients in the Rabilizumab group are administered Rabilizumab at a dose of 900 mg under blinded conditions. This dose of 900 mg was selected to maintain complete inhibition of C5 until the next scheduled maintenance dose at Week 28 (Day 197). Starting from Week 28, all patients are started on an open-label maintenance dose of Rabilizumab q8w Table 16: Reference chart for weight-based dosing

Table 16

[0273] Preparation / Handling / Storage / Investigational Medicinal Product Management The investigational medicinal product will be permitted at the investigational site upon receipt of all required essential documents, based on federal, state, and local regulations.

[0274] The investigational medicinal product will be administered only to patients enrolled in the trial, and only authorized investigational site staff will supply or administer the investigational medicinal product. All investigational medicinal products will be stored in an environmentally controlled (manual or automated) secure monitoring area and used only by the investigator and authorized investigational site staff, in accordance with the storage conditions indicated on the label.

[0275] Preparation of Investigational Medicinal Product The investigational medicinal product will be prepared and administered by trained members of the investigational site's trial team. The investigational medicinal product will be administered only to registered patients who have been confirmed as eligible to participate.

[0276] The preparation of the lovelizumab and placebo doses will be performed by a trained and qualified pharmacist in accordance with the in-site standards defined at the trial implementation site.

[0277] The handling and preparation of the materials used to prepare and administer the investigational medicinal product will be performed using aseptic techniques for sterile products.

[0278] None of the trial patients, the investigational site's trial personnel, the staff of the sponsor, the subcontractors from the sponsor, or any staff directly involved in the conduct of the trial will be informed of the patient's treatment assignment.

[0279] Further details regarding the preparation and administration of the investigational medicinal product, as well as the handling of the investigational medicinal product, can be found in the pharmacy manual.

[0280] Storage During the transportation of all test drugs received, the investigator or the commissioned party shall confirm that appropriate temperature conditions are maintained and that any discrepancies are reported and resolved before the test drugs are used.

[0281] Upon arrival at the clinical trial site, the test drugs shall be immediately removed from the delivery cooler and stored under refrigeration conditions of 2°C to 8°C (36°F to 46°F). The pharmacist shall immediately record the receipt of the test drugs and notify the vendor if the vials are damaged and / or if temperature deviations occurred during transportation. The test drugs shall be stored in a secure storage area with restricted access, and the temperature shall be monitored daily.

[0282] The diluent of the test drug shall be stored at 2°C to 8°C (36°F to 46°F) for up to 24 hours before administration. The solution shall be warmed to room temperature before administration.

[0283] The added admixture drugs shall be at room temperature before administration. The substance shall not be heated by means other than ambient temperature (e.g., using a microwave oven or other heat source).

[0284] Package and Label The primary package of ravulizumab consists of a 30 mL vial (Type I borosilicate glass) with a stopper and seal. The secondary package consists of one vial carton. Both the primary package (vial) and the secondary package (carton) contain a booklet label with relevant information. Further details are shown in Table 13 and the Pharmacy Manual. The placebo has an appearance similar to that of ravulizumab.

[0285] Clinical Trial Drug Management When receiving the drug shipment at the facility, the pharmacist shall check the contents, sign the packing invoice attached to the shipment, and retain the original for inspection by the clinical monitor in the pharmacy binder. In addition, record the receipt of the test drug (and the status of the test drug at the time of receipt) in the IRT system to enable drug randomization, resupply, accounting, and control of expired drugs.

[0286] Unless otherwise notified, empty vials and vials containing residual substances shall be stored until discarded or handled in accordance with the operating procedures for clinical trial drugs in local drug regulations for inspection and management of investigational drugs by the trial monitor. The disposal of used and unused vials shall be properly documented either locally or centrally. The management of investigational drugs shall be carried out by the IRT system, and a detailed description of the management of the investigational drug management module of IRT is included in the IRT User Guide. In the IRT module, the management of investigational drugs is carried out in two steps. After the person in charge of the trial site completes the first input for the management of investigational drugs in the system, the trial monitor shall confirm at that site that the appropriate status has been correctly entered for all investigational drugs. The pharmacist or the entrusted person shall maintain accurate records showing the date and quantity of the received investigational drugs, the distribution destination (management for each patient), and the description of all investigational drugs discarded accidentally or intentionally. These investigational drug management records are readily available upon request and are reviewed throughout the trial.

[0287] Each kit has a label and space for the pharmacist to record the patient's number and initials.

[0288] The trial monitor shall conduct an inventory check during the trial. In addition, the inventory records shall be readily available at any time for inspection by the regulatory authorities, local regulatory agencies, or independent individual audits.

[0289] For further information, please refer to the Pharmacy Manual.

[0290] Handling and Disposal All clinical trial substances supplied to the trial physician shall be stored in a safe place and allocated and distributed by appropriately trained personnel. Maintain detailed records of the quantity of investigational drugs received, distributed, and discarded.

[0291] To meet the regulatory requirements regarding the management of investigational drugs, at the end of the trial, all remaining inventory of Ravulizumab shall be reconciled and either discarded or returned to Alexion in accordance with the applicable regulations.

[0292] For further information, please refer to the Pharmacy Manual.

[0293] Randomization Patients will be randomized on Day 1 after being determined eligible by the investigator. Patients will be stratified by region (North America, Europe, Asia-Pacific, and Japan) and randomized 1:1 to either the Ravulizumab IV infusion group or the placebo IV infusion group. Central randomization will be performed using IRT.

[0294] Blinding None of the study site personnel, sponsor staff, sub-contractors from the sponsor, staff directly involved in the conduct of the trial, and all patients will be informed of the patient's treatment assignment. Double-blinding will be maintained by using the same investigational drug kits and labels for Ravulizumab and placebo. The placebo will have an appearance similar to that of Ravulizumab. The randomization code will be held by the IRT provider. After the 26-week randomized control period and the assessment on Day 183 (Week 26), patients in the placebo group will be administered a loading dose of Ravulizumab under blinding, and patients in the Ravulizumab group will be administered Ravulizumab at a dose of 900 mg under blinding. Starting from Week 28, all patients will initiate the maintenance dose of Ravulizumab q8w in open label. In patients in the Ravulizumab group, the Ravulizumab dose of 900 mg under blinding will be selected to maintain complete inhibition of C5 until the next scheduled maintenance dose on Week 28 (Day 197).

[0295] Unblinding should only be considered for the sake of patient safety. If the investigator determines that unblinding is necessary, the investigator shall contact the sponsor and make reasonable efforts to discuss the possibility of unblinding. After reasonable efforts have been made, the investigator shall use the IRT to unblind the patient's treatment assignment. The investigator shall record the date and reason for unblinding. In addition, the investigator shall notify the medical monitor that the patient has been unblinded. However, the medical monitor shall not disclose the patient's treatment assignment.

[0296] When an adverse event (AE) is unexpected or relevant and severe, the blinding shall be lifted only for the specific patient. Those responsible for the continuous conduct of the trial (administrators, monitors, investigators, etc.), as well as those responsible for data analysis and result interpretation at the conclusion of the trial (biostatisticians, etc.), shall maintain the blinding. Only those who need to be involved in safety related to the unblinded information, such as insurance institutions, independent ethics committees (IEC) and / or institutional review boards (IRB), shall have access to the unblinded information.

[0297] Any patient unblinded during the trial shall discontinue the trial.

[0298] Except when unblinded information is determined to be necessary for safety reasons, the investigator shall obtain only blinded information.

[0299] Combined therapy Record any medications and treatments that the patient has taken or received within 28 days before the start of screening and up to the first dose of the investigational drug, including past medications (including vitamins and herbal preparations) and treatments (any therapeutic interventions such as surgery / biopsy or physical therapy) discussed in the exclusion criteria. In addition, investigate the history of meningococcal vaccine inoculation going back 3 years from the first dose of the investigational drug.

[0300] Record all drug use and treatments administered during the trial. This includes all prescription medications, herbal products, vitamins, minerals, over-the-counter drugs, and any other current medications. Concomitant medications are recorded from the time of the first infusion of the investigational drug until 8 weeks after the last administration of the investigational drug to the patient. Record any changes in concomitant medications. Any other medications, other than those listed as prohibited drugs as defined herein, as well as any concomitant medications considered necessary for the standard care of the patient during the trial or for the treatment of any AE, are administered at the discretion of the investigator. However, it is the responsibility of the investigator to ensure that details of all medications are accurately recorded.

[0301] Compliance with the investigational drug The investigational drug is administered under the control of the investigator or designee as a controlled trial to ensure compliance with the administration of the investigational drug.

[0302] Palliative care and supportive care During the course of the trial, palliative care and supportive care are recognized for the underlying condition.

[0303] Recognized drugs Under specific circumstances and restrictions, the drugs described in the following section are recognized.

[0304] Cholinesterase inhibitors In patients participating in the trial who are receiving cholinesterase inhibitor treatment at the time of screening, the dosage and schedule of the cholinesterase inhibitor are maintained stably throughout the randomized control period and the OLE period. However, this does not apply if there is a medical necessity. An increase in cholinesterase therapy agents required due to a concurrent disease or other medical worsening cause is recognized, but once the dosage has been adjusted to a level where it can be returned to the starting dosage level of the trial, it is immediately returned to the starting dosage level of the trial, and the sponsor is notified of the change. 1. Treatment with cholinesterase inhibitors should be interrupted for at least 10 hours before the QMG test and the MGC test are performed. 2. When considering reducing cholinesterase inhibitors based on clinical evaluation, obtain approval from the sponsor before changing the dosage for patients continuing the trial.

[0305] Immunosuppressants During the trial, immunosuppressants such as corticosteroids, AZA, MMF, MTX, TAC, CYC or CY may be recognized. The immunosuppressant(s) to be used for each individual patient and the appropriate dosage level are left to the discretion of the treating physician / investigator. 1. Corticosteroids: For patients participating in the trial who are taking oral corticosteroids, such as prednisone, do not change the dosage / schedule throughout the double-blind trial period (i.e., the randomized control period). If, based on clinical evaluation, reducing or tapering the steroid dosage is considered during the randomized control period, obtain approval from the sponsor before changing the dosage for patients continuing the trial. Thereafter, if increasing the dosage level, the increase in the dosage level should be less than the dosage level recorded at baseline (the start of randomized treatment). 2. High-dose steroids are reserved for patients with worsening clinical symptoms as defined herein. If a rescue therapy for worsening clinical symptoms becomes necessary in a patient, make every effort to notify the sponsor within 24 hours of administration. 3. AZA, MMF, MTX, TAC, CYC or CY: For patients participating in the trial who are receiving the above immunosuppressants, do not change the administration regimen of the immunosuppressant throughout the randomized control period. If considering a change in the administration regimen due to known toxicity or side effects associated with the immunosuppressant to be administered, obtain approval from the sponsor before changing the dosage for patients continuing the trial. Do not add different immunosuppressants or replace them with different immunosuppressants during the 26-week randomized control period.

[0306] Plasma exchange / plasmapheresis / intravenous immunoglobulin In patients with worsening clinical symptoms as defined in this specification, the use of PE / PP or IVIg is permitted. The rescue therapy to be used for a specific patient is left to the discretion of the investigator in charge of the clinical trial. If a patient requires rescue therapy, every effort should be made to notify the sponsor within 24 hours.

[0307] On days when rescue therapy with PE / PP or IVIg is administered, administration of the supplementary investigational medicinal product (or placebo) is required. When infusion of PE / PP or IVIg is carried out on a dosing day, such administration must be carried out prior to administration of the investigational medicinal product. 1. When PE / PP or IVIg is administered during an unscheduled visit for the purpose of administration a. For patients receiving PE / PP: A supplementary dose is administered 4 hours after completion of the PE / PP session. b. For patients receiving IVIg: A supplementary dose is administered 4 hours after completion of the last continuous session(s) of IVIg. c. The supplementary dose may or may not vary depending on PE / PP or IVIg (Tables 1 and 2). 2. When PE / PP or IVIg is administered during a scheduled visit for the purpose of administration a. Regular administration is carried out 60 minutes after completion of PE / PP or IVIg. 3. There is no need to provide an interval between the supplementary dose and the regularly scheduled dose.

[0308] Prohibited Medicinal Products During the trial, the following concomitant medicinal products are not permitted. · Rituximab · Eculizumab (or other complement inhibitors)

[0309] If a patient uses rituximab or eculizumab (or other complement inhibitors) at any time during the trial, that patient will be withdrawn from the trial.

[0310] Rescue Therapy If rescue therapy is not implemented, when the patient's health condition reaches a critical situation (for example, in an emergency), or when the patient shows a worsening of clinical symptoms as defined in this specification, rescue therapy (for example, high-dose corticosteroids, PP / PE or IVIg) is approved. The rescue therapy used for a specific patient is left to the discretion of the treating physician in the trial. Record the date and time when the rescue drug was administered, as well as the name and administration regimen of the rescue drug.

[0311] If a patient requires rescue therapy, make every effort to notify the sponsor within 24 hours.

[0312] Interventions after the end of the trial After the patient completes participation in the trial, they return to the care of their treating physician.

[0313] 9. Cessation of interventions in the trial and discontinuation / withdrawal by the patient Cessation of interventions in the trial A patient may withdraw from the trial at any time at their own request, or may be withdrawn at any time at the discretion of the treating physician in the trial for reasons of safety, behavior, compliance or administration. If a patient discontinues the treatment in the trial, the treating physician should, if the patient consents, try to conduct the defined evaluation when the patient comes to the ET clinic, or, if not possible, make a follow-up call 8 weeks after administering the last dose of the investigational drug (Tables 10 and 11). With regard to safety, also make every effort to follow up all patients for a total of 8 weeks from the day the last dose of the investigational drug was administered. Notify the sponsor and the trial monitor as soon as possible. If a patient withdraws from the trial or cancels consent, no further data will be collected. Do not replace a patient who withdraws from the trial.

[0314] During the trial, if any of the following occurs, the patient should discontinue the investigational drug. 1. Severe allergic reactions that manifest 1 to 14 days after administration of the investigational drug (such as bronchospasm with wheezing or requiring ventilation assistance, symptomatic hypotension, or serum sickness-like reactions) 2. Severe control failure infections 3. Pregnancy or planned pregnancy, or 4. When the sponsor of the clinical trial deems it advisable for the patient to discontinue 5. Use of rituximab, eculizumab (or other complement inhibitors)

[0315] Before discontinuing the investigational drug for the patient, the investigator shall contact the medical monitor. If the patient discontinues treatment, the patient is recommended to return to the hospital for follow-up for ET (Tables 10 and 11) 8 weeks after the most recent administration of the investigational drug to the patient.

[0316] Record the reasons for discontinuation (e.g., the patient withdraws consent, the patient drops out of the treatment, physician's decision, AE, or other reasons defined in the eCRF).

[0317] If a female patient permanently discontinues the investigational drug due to pregnancy, the investigator shall make reasonable efforts to follow up in accordance with local laws and regulations until the outcome of the pregnancy is known.

[0318] If the patient withdraws consent regarding the disclosure of future information, the sponsor of the clinical trial shall retain all data collected prior to the withdrawal of consent and continue to use it.

[0319] If the patient drops out of the trial, the patient may request the destruction of any untested samples taken, and the investigator shall document this in the trial records of the trial facility and notify the trial monitor and the sponsor of the clinical trial.

[0320] Unable to follow up If the patient fails to return to the hospital for scheduled examinations multiple times and cannot be contacted by the trial facility, the patient shall be considered unable to follow up.

[0321] If the patient fails to return to the hospital for the necessary clinical trial medical treatment, the following measures shall be taken. 1. The trial facility attempts to contact the patient, as soon as possible, to make arrangements for missed visits, advise the patient on the importance of keeping to the assigned schedule of hospital visits, and confirm whether the patient wishes to continue with the trial and / or should continue with the trial. 2. Before considering a patient untraceable, the investigator or designee makes every effort to contact the patient (if possible, by making three telephone calls and, if necessary, sending a letter with proof of delivery to the patient's latest known address or carrying out an equivalent method in the region). These efforts to contact are documented in the patient's medical record. 3. If attempts to contact the patient remain unsuccessful, the patient is considered to have withdrawn consent, and subsequent missed visits are not considered deviations from the trial implementation plan.

[0322] 10. Evaluation and Procedures of the Trial Efficacy Evaluation Hospitalization For patients who have signed the ICF, information on all-cause hospitalizations is collected throughout the OLE period. Hospitalization is defined as all hospitalizations to a medical institution, regardless of the underlying relevance to MG. The date of admission / discharge, reason for hospitalization, relevance to MG, and other relevant information are collected. Hospitalization includes the following. 1. Visiting the emergency department in relation to MG, regardless of whether there is a hospitalization and regardless of the period. 2. Unscheduled hospitalization to a medical institution, regardless of the relevance to MG. 3. Performing MG-related infusions / treatments by hospitalization in a hospital facility (e.g., IVIg, PP, PE, ventilatory support). Hospitalization does not include the following. 1. Regular administration of investigational drugs. 2. Rehabilitation facilities. 3. Hospice facilities. 4. Nursing / living support / long-term care facilities. 5. Outpatient medical facilities. 6. Scheduled hospitalizations for the treatment of existing medical conditions (i.e., medical conditions initiated before obtaining informed consent). 7.Scheduled / Unscheduled Outpatient Surgery (e.g., used as a surgical facility) 8.Without hospitalization, visit the emergency department regardless of MG 9.In a hospital facility, perform infusions / treatments on an outpatient basis (e.g., IVIg, PP)

[0323] Worsening of clinical symptoms Collect information on worsening of clinical symptoms as defined in this document from patients who have signed the ICF throughout the entire OLE period. Visits to the hospital for the evaluation of worsening clinical symptoms should be made as soon as possible, within 48 hours after the onset of symptoms is notified to the investigator. The schedule of unscheduled additional hospital visits as defined in this document is at the discretion of the investigator. At this hospital visit, complete the following tests and procedures. 1.Measure vital signs and pulse oximetry, including the assessment of systolic blood pressure, blood pressure (BP), body temperature (°C or °F), oxygen saturation (SO2), and heart rate (HR). 2.Record all new medications or changes in combination medications, including all treatments for MG. 3.Evaluate and record all new AEs or changes in AEs since the previous hospital visit. 4.Conduct the MG-ADL by an evaluator who has received appropriate training, preferably the same evaluator throughout the trial. The recall period is the earlier of the past 7 days or the period since the most recent hospital visit. 5.Conduct the clinical evaluations QMG and MGC. These should be performed by an evaluator who has received appropriate training, preferably the same evaluator throughout the trial, at approximately the same time of day. 6.Collect a blood sample for AChR autoantibody testing. 7.Collect a blood sample for clinical specimen testing (Table 17). The tests detailed in Table 17 are to be performed by the central laboratory. The patient inclusion or exclusion criteria defined in the trial implementation plan are detailed in this document. Perform additional tests at any time during the trial. 8.Perform additional tests at the discretion of the investigator if medically indicated for the evaluation of worsening clinical symptoms. 9. At the time of admission or during the hospital stay due to deterioration of clinical symptoms, collect samples for PK / PD. a. If the test drug is not administered, collect a blood sample once for PK and free C5 assays. b. If the test drug is administered according to the schedule in the clinical trial protocol at the time of admission due to deterioration of clinical symptoms, collect two blood samples as trough and peak: [1] 5 to 90 minutes before injecting the test drug, and [2] within 30 minutes after the injection of the test drug is completed. c. If PP / PE or IVIg is performed on the patient during deterioration of clinical symptoms, administer a supplementary dose of the test drug. Collect blood samples for PK and free C5: [1] 5 to 90 minutes before PP / PE or IVIg, [2] after PP / PE or IVIg and before injecting the test drug, and [3] within 30 minutes after the injection of the test drug is completed. Table 17: Laboratory evaluations related to safety required in the clinical trial protocol

Table 17

[0324] Safety evaluation Physical examination Physical examination includes the evaluation of organs / body systems such as skin, head, ear, eye, nose, throat, neck, lymph nodes, pulse, chest, heart, abdomen, extremities, and musculoskeletal system, and general neurological examinations. The simplified physical examination consists of body system-related examinations based on the judgment of the clinical trial doctor and the patient's symptoms. Make the greatest effort to ensure that the physical examination is performed by the same qualified test staff for consistency.

[0325] Vital signs and pulse oxygen concentration Measure vital signs and pulse oxygen concentration every time at the time of admission, including the evaluation of systolic blood pressure and diastolic blood pressure (mmHg), body temperature (°C or °F), SO2, and HR (number of beats per minute). Vital signs are measured after the patient has been in the lying or sitting position for at least 5 minutes. Ideally, the BP of each patient is measured using the same arm.

[0326] Electrocardiogram As outlined in the implementation schedule (Tables 10 and 11), a unipolar 12 - lead electrocardiogram (ECG) is taken using an ECG device that automatically calculates the HR and measures the intervals of PR, QRS, QT, and QTc. After the patient is in the lying position for approximately 5 - 10 minutes, the ECG is taken. During the recording of the ECG, the patient is in the lying position but in a waking state.

[0327] The investigator or designee is responsible for examining the ECG, evaluating whether the ECG is within the normal range, and judging the clinical significance of the results.

[0328] Laboratory evaluation regarding safety in clinical practice The laboratory evaluation is conducted at the central laboratory facility. Any clinically significant abnormal results are followed up until they are resolved or stabilized.

[0329] Any laboratory evaluations required in the clinical trial protocol and as defined in this specification are all carried out in accordance with the laboratory manual and the implementation schedule (Tables 10 and 11).

[0330] The investigator examines the test report, documents the examination content, and records any clinically relevant changes among the changes that occurred during the trial. The test report is filed together with the original document.

[0331] Among the clinically significant abnormal test findings, those related to underlying diseases are not regarded as AEs. However, this is not the case if the investigator determines that they are more severe than the findings predicted by the patient's medical condition.

[0332] If the above - mentioned values do not return to the normal value / baseline within the period determined by the investigator to be appropriate, identify the cause and notify the trial sponsor.

[0333] Urinalysis and chemical analysis of urine In urine samples, analyze the parameters listed in (Table 17). If abnormalities are found in the macroscopic analysis results, perform a microscopic examination of the urine sample.

[0334] Also, analyze the urine sample to measure protein and creatinine, and calculate the urine protein:creatinine ratio.

[0335] Serological test for virus Before enrollment, all patients must undergo human immunodeficiency virus tests for HIV-1 and HIV-2. Patients who are HIV positive will not be enrolled.

[0336] Immunogenicity assessment Before administration of the test drug, collect a blood sample and test for the presence of ADA against labrilizumab in the serum. Further characterize the antibody response as appropriate, including binding antibodies, neutralizing antibodies, PK / PD, safety, and the activity of labrilizumab. Antibodies against labrilizumab are tested in serum samples collected from all patients according to the implementation schedule (Tables 10 and 11). Screen for antibodies bound to labrilizumab in the serum sample and report the titer of the sample with a confirmed positive. Detection and characterization of antibodies against labrilizumab are performed by the sponsor of the clinical trial or under the control of the sponsor of the clinical trial using a validated assay.

[0337] Monitoring of suicide risk Columbia-Suicidal Severity Rating Scale The Columbia-Suicide Severity Rating Scale (C-SSRS, Figures 4 and 5) is a validated questionnaire widely used across primary care, clinical practice, surveillance, research, and healthcare settings for the purpose of assessing suicidal thoughts and behaviors (Posner, K. et al., Am. J. Psychiatry, 168:1266 - 77, 2011). The C-SSRS is administered by the investigator or an appropriately trained delegate. The C-SSRS is evaluated as defined in the administration schedule (Tables 10 and 11). The C-SSRS is conducted for the purpose of ensuring the proper recognition and adequate management of patients with suicidal thoughts or behaviors.

[0338] Adverse Events and Serious Adverse Events Adverse events are reported by the patient (or, as appropriate, the caregiver, surrogate, or legal representative of the patient) to the investigator or a qualified delegate.

[0339] The investigator or a qualified delegate is responsible for the discovery, documentation, and recording of events that meet the definition of an AE or SAE, and also continues to be responsible for tracking events that are severe, considered related to the investigational product or the treatment in the study, or that caused the patient to discontinue taking the investigational product.

[0340] Period and Frequency for Collecting Information on Adverse Events and Serious Adverse Events All AEs are collected from the time of signing the ICF until 8 weeks after the last dose of the investigational product is administered.

[0341] Before starting the investigational product, medical events that started after obtaining informed consent are recorded.

[0342] All SAEs are recorded and reported to the study sponsor or delegate within 24 hours. The investigator submits any updated SAE data to the study sponsor within 24 hours of awareness.

[0343] After a clinical trial physician has decided to participate in the trial, there is no obligation to actively search for AEs or SAEs. However, after a patient drops out of the trial, at any time, if the clinical trial physician recognizes any SAE, including death, whether or not the event is related to the investigational drug, the clinical trial physician shall immediately notify the sponsor of the trial.

[0344] Methods for Detecting Adverse Events and Serious Adverse Events When detecting AEs and / or SAEs, care should be taken to avoid bias. To inquire about the occurrence of AEs, it is preferable to conduct open-ended, non-leading oral questions with patients.

[0345] Follow-up of Adverse Events and Serious Adverse Events After an AE / SAE is first reported, the clinical trial physician must actively follow up each patient at subsequent visits / communications. All SAEs shall be followed up until resolved, stabilized, otherwise explained, or the patient becomes non-followable (as defined in this document).

[0346] Regulatory Reporting Obligations for Serious Adverse Events · The clinical trial physician shall notify the sponsor of the SAE within 24 hours of first recognizing the event. · The sponsor has the legal responsibility to notify both the local regulatory authority and other regulatory authorities regarding the safety of the investigational drug under clinical trial. The sponsor shall comply with country-specific regulatory requirements related to safety reporting to regulatory authorities, IRB / IECs, and clinical trial physicians. · For suspected unexpected serious adverse reactions (SUSARs), prepare a report according to the regional regulatory requirements and the sponsor's policy by the Council for International Organizations of Medical Sciences (CIOMS) or MedWatch, and transfer it to the investigator if necessary. The SUSAR reporting procedures at Alexion comply with United States Title 21 Code of Federal Regulations (CFR) 312.32, as well as the European Union Clinical Trial Directive 2001 / 20 / EC and its annexes. · Guidance documents or national regulatory requirements in the participating countries, and where applicable, the IRB / IEC · The investigator who receives the safety report from the sponsor regarding SAEs or other specified safety information (e.g., summary or list of SAEs) shall review and confirm the report and notify the IRB / IEC according to the regional regulations where applicable.

[0347] Pregnancy For patients who may be pregnant, perform a serum pregnancy test (i.e., human chorionic gonadotropin-β) at screening and at EOS / ET. Perform a urine pregnancy test at all other required time points as shown in the implementation schedule (Tables 10 and 11). A pregnancy test must be negative before administering ravulizumab to a patient who may be pregnant.

[0348] If pregnancy is reported, the investigator shall notify the sponsor within 24 hours after becoming aware of the pregnancy.

[0349] Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, and ectopic pregnancy) are considered SAEs and reported.

[0350] Vaccines, and prophylactic administration of antibiotics As with any terminal complement antagonist, the use of ravulizumab increases the patient's susceptibility to Neisseria meningitidis (N. meningitidis) infection. To reduce the risk of N. meningitidis infection, all patients are vaccinated against N. meningitidis infection within 3 years prior to the start of the investigational drug, or at the time of the start of the investigational drug. Patients who start treatment with the investigational drug less than 2 weeks after receiving the N. meningitidis vaccine are treated with appropriate prophylactic antibiotics until 2 weeks after vaccination.

[0351] To prevent common pathogenic N. meningitidis serogroups, vaccines against N. meningitidis serogroups A, C, Y, W135, and B are recommended if available. Patients are vaccinated or revaccinated according to the latest national vaccination guidelines or regional practice regarding the combined use of complement inhibitors (e.g., eculizumab) and vaccination.

[0352] Vaccination may not be sufficient to prevent N. meningitidis infection. It is necessary to consider according to public guidance and regional practice regarding the appropriate use of antibacterial agents. In all patients, monitor for early signs of N. meningitidis infection, and if infection is suspected, evaluate immediately and treat with appropriate antibiotics if necessary.

[0353] During the course of the trial, to increase awareness of risks and prompt the disclosure of any potential signs or symptoms of infection seen in patients, give the patient a safety card and ask them to always carry it. As shown in the implementation schedule (Tables 10 and 11), as part of the consideration of the patient safety card, conduct further consideration and explanation of potential risks, signs, and symptoms each time the patient comes to the hospital. Record N. meningitidis vaccination(s).

[0354] Administration reaction of the investigational drug Local and systemic reactions Reactions at the injection site are reactions localized at the IV administration site of the test drug and include reactions such as erythema, pruritus, and contusion. Reactions related to injection are essentially systemic reactions and are reactions that can generally occur within several hours after administration of the test drug, mediated either immunologically or non-immunologically. Immunologically mediated reactions include allergic reactions (e.g., anaphylaxis), and non-immunologically mediated reactions are non-specific reactions (e.g., headache, dizziness, nausea). As part of the regular safety assessment of this trial, monitoring of these reactions is conducted.

[0355] Reactions related to injection Reactions related to injection are defined as AEs that the investigator assesses as possibly related, likely related, or definitely related to the test drug among the systemic AEs (e.g., fever, chills, flushing, changes in HR and BP, dyspnea, nausea, vomiting, diarrhea, and generalized rash) that occur during or within 24 hours from the start of IV injection.

[0356] Adverse events of particular note Meningococcal infection is collected as an adverse event of particular note (AESI) in this trial.

[0357] Pharmacokinetics Blood samples are collected at the time points and within the allowable ranges shown in the implementation schedule (see Tables 10 and 11) to evaluate the serum lovelizumab concentrations before and after treatment. Samples collected outside the assigned allowable range are considered deviations from the trial implementation plan. Unused samples are retained for up to 5 years and additional evaluations are performed as necessary.

[0358] Pharmacodynamics Blood samples are collected to evaluate free C5 in serum before and after treatment at the time points and within the allowable ranges shown in the implementation schedule (Tables 10 and 11). Samples collected outside the assigned allowable range are considered deviations from the trial implementation plan. Unused samples are retained for up to 5 years and additional evaluations are performed as necessary.

[0359] Biomarker At the time points shown in the implementation schedule (Tables 10 and 11), collect blood samples for the evaluation of AChR autoantibodies.

[0360] Use of medical resources and economic aspects of medical care Throughout the trial, the investigator or the contractor collects data on the use of medical resources and the economic aspects of medical care, which are related to medical treatment, for all patients. Record the data. Exclude the treatments, tests, and examinations required in the trial implementation plan.

[0361] Perform exploratory economic analysis using the collected data, and the analysis includes the following. · Number and duration of medical treatments including surgery and other prescribed treatments (inpatient and outpatient) · Length of hospital stay (total number of inpatient days or total length of hospital stay including the duration for each ward (e.g., intensive care unit)) · Number and types of tests and treatments for diagnosis and treatment · Outpatient diagnosis and treatment (including visits to physicians or emergency treatment rooms, tests and treatments, and medication)

[0362] 11. Statistical considerations The statistical methods described in this document are further detailed in a separate SAP. This SAP is created and completed before locking the database. The analysis is performed using SAS (registered trademark) statistical software system version 9.4 or later. Statistical analysis includes tabulation of summary data, estimation analysis, patient listing, and graphing. In the estimation derived from the efficacy analysis, the two-sided type I error (α error) is set at 5%. Include at least n, mean, standard deviation, minimum value, median, and maximum value in the summary statistics of continuous variables. For categorical variables, show the frequency and percentage.

[0363] The baseline value for analysis and reporting is the value based on the most recent non-missing measurement or the value before the first administration of the investigational drug. The treatment groups for analysis and reporting are based on the agreement outlined in Table 18. The "Overall" group is formed for the purpose of reporting demographics, baseline characteristics, and other pre-trial information (such as pre-trial SAE, medical history, or past medications). Details regarding the imputation of efficacy data are described in the SAP. Imputation of missing safety data is not performed.

[0364] Statistical hypothesis Primary hypothesis The primary hypothesis of this trial is that ravulizumab is superior to placebo in terms of improvement in the total MG-ADL score at week 26.

[0365] Regardless of the availability of rescue therapy, the treatment effect based on the primary endpoint is estimated by the mean difference in the change from baseline in the total MG-ADL score at week 26 between the ravulizumab group and the placebo group. The lower the corresponding estimated value, the more beneficial the treatment effect is indicated.

[0366] Secondary hypothesis (Conditioned on the rejection of the null hypothesis regarding the primary endpoint,) the multiplicity adjustment of the trial criteria includes the secondary hypothesis that ravulizumab is superior to placebo in terms of improvement in the total QMG score at week 26, as shown herein.

[0367] Hypotheses related to exploratory goals of efficacy 1. Ravulizumab is superior to placebo in terms of a decrease in the incidence of all-cause hospitalizations or worsening of clinical symptoms over 26 weeks. 2. Ravulizumab is superior to placebo in terms of improvement in the total MG-QOL15r score at week 26. 3. Ravulizumab is superior to placebo in terms of improvement in the total Neuro-QOL Fatigue score at week 26. 4. In terms of the improvement in the total MGC score at week 26, Lovelizumab is superior to placebo. 5. In terms of the 5-point response of QMG at week 26 (the total QMG score improves by 5 points or more from the baseline), Lovelizumab is superior to placebo. 6. In terms of the 3-point response of MG-ADL at week 26 (the total MG-ADL score improves by 3 points or more from the baseline), Lovelizumab is superior to placebo. 7. In terms of MGFA-PIS at week 26, Lovelizumab is superior to placebo. 8. In terms of the improvement in the EQ-5D-5L index score at week 26, Lovelizumab is superior to placebo. 9. In terms of the improvement in the EQ-5D-5L VAS score at week 26, Lovelizumab is superior to placebo.

[0368] The treatment effect corresponding to the change from the baseline continuous endpoint is estimated in the same way as the primary endpoint.

[0369] The treatment effect corresponding to the following binomial endpoints is estimated by the odds ratio (OR), which is the ratio of the corresponding endpoints when the Lovelizumab group is compared with the placebo group. a. Incidence of all-cause hospitalization or worsening of clinical symptoms over 26 weeks (regardless of the presence or absence of rescue therapy) b. 5-point response of QMG at week 26 (regardless of the presence or absence of rescue therapy) c. 3-point response of MG-ADL at week 26 (regardless of the presence or absence of rescue therapy)

[0370] If the estimated OR corresponding to the composite hospitalization endpoint is less than 1, it indicates that the treatment effect is beneficial. Similarly, if the estimated OR corresponding to the responder endpoint exceeds 1, it indicates that the treatment effect is beneficial.

[0371] The treatment effect corresponding to the MGFA-PIS endpoint is estimated by the proportional OR of the cumulative proportion across the ordinal categories of this endpoint (starting from "best outcome") when the ravulizumab group is compared to the placebo group at week 26, regardless of the presence of rescue therapy. If the estimated OR exceeds 1, it indicates that the treatment effect is beneficial.

[0372] Determination of sample size Approximately 160 patients are randomly assigned to ravulizumab and placebo in a 1:1 ratio (ravulizumab: placebo), stratified by region (North America, Europe, Asia-Pacific, and Japan), to achieve a nominal power of at least 90% to reject the null hypothesis of no treatment difference for the primary and secondary endpoints, with a two-sided type I error (α error) of 5%. The assumptions related to the calculation of statistical power are based on Study ECU-MG-301. Details are shown as defined in this specification. Table 18: Analysis population of the ALXN1210-MG-306 trial

Table 18

[0373] Statistical analysis Registration and breakdown Present the number of patients screened, patients who were ineligible at screening, and patients randomized. Present the registration information grouped by stratification factors and treatment groups. Summarize, with reasons, the number of patients who discontinued the trial during the randomized control period, OLE period, and the entire trial.

[0374] Demographics, baseline characteristics, inclusion criteria, exclusion criteria, and deviations from the trial protocol Report all demographic information and baseline characteristics for each treatment group and overall. No statistical tests will be performed for homogeneity between treatment groups.

[0375] Summarize the number and percentage of patients who do not meet the defined inclusion or exclusion criteria. Also, for major deviations from the clinical trial protocol, perform a similar summary based on pre-defined categories.

[0376] Medical history / surgical history, physical examination results, and history of myasthenia gravis Summarize the medical history and surgical history according to the Medical Dictionary for Regulatory (MedDRA) Activities, Version 20.1, or subsequently, by System Organ Class (SOC) and preferred terms. Also summarize MG and abnormal physical examination results.

[0377] Previous medications and concomitant medications For analysis and reporting purposes, consider any drug started before the first dose of the investigational drug as a previous drug, and any drug started at or after the first dose of the investigational drug as a concomitant drug. Summarize all previous medications and concomitant medications, including MG-specific drugs and rescue therapies (if applicable) during the trial.

[0378] Efficacy analysis Primary analysis of efficacy For the primary endpoint of efficacy (change from baseline in the total MG-ADL score at week 26), regardless of whether the patient received rescue therapy, use all available time series data (either complete data or partial data), and use a repeated measures mixed effects model (MMRM). Rescue therapy includes high-dose corticosteroids, PP / PE, or IVIg. Rescue therapy is permitted if the patient's health is in a critical situation (e.g., in an emergency) without implementing rescue therapy, or if the patient shows a worsening of clinical symptoms. In the primary analysis, no imputation of missing data is performed. This model includes the change from baseline in MG-ADL at each pre-specified time point (variable as the response variable), fixed effects by treatment category, the interaction of study visit and treatment×study visit, region, and the fixed covariate of the total baseline MG-ADL score. The treatment effect is evaluated by the contrast of the interaction term of treatment×visit at week 26. Use an unstructured covariance matrix to model the correlation between repeated measurements for each patient. If a convergence problem occurs, specify another covariance structure (details are shown in the SAP). Use the Kenward-Roger method to estimate the denominator degrees of freedom.

[0379] Sensitivity analysis for the primary endpoint For the primary endpoint of efficacy, two sensitivity analyses are performed to examine the robustness of the results of the MMRM in the primary analysis of efficacy.

[0380] 1. Placebo-based sensitivity analysis: In the placebo-based sensitivity analysis, regarding missing data, consider the mechanism of Missing Not At Random (MNAR), and in that case, it is estimated that patients who discontinue Lublizumab will follow a similar course of outcome as patients in the placebo group after discontinuing Lublizumab, based on the observed values before discontinuation.

[0381] 2. Switching point sensitivity analysis: In this approach, it is presumed that in patients in whom treatment with lovelizumab is discontinued, worsening as defined by a predefined adjustment of the primary efficacy endpoint will be seen.

[0382] Analysis of secondary and exploratory endpoints In the same way as for the primary endpoint, all continuous secondary and exploratory endpoints related to changes from baseline are analyzed.

[0383] Using a logistic regression model by treatment group and region, the composite endpoint of worsening of clinical symptoms or all-cause hospitalization is analyzed. In a similar format, each component is also analyzed (worsening of clinical symptoms and all-cause hospitalization separately).

[0384] Using a repeated measures mixed effects model, the 5-point responder endpoint of QMG and the 3-point responder endpoint of MG-ADL are analyzed. The model includes the response variable (variable as the dependent variable) at each predefined time point, the fixed effect by treatment category, the interaction of the trial visit and treatment × trial visit, region, and the fixed covariate of the total score of baseline QMG or MG-ADL (depending on the response variable). The treatment effect is evaluated by the contrast of the treatment × visit interaction term at week 26. Using an unstructured covariance matrix, the correlation between repeated measurements in each patient is modeled. If convergence problems occur, other covariance structures are specified (details are shown in the SAP).

[0385] The MGFA-PIS endpoint at week 26 is considered as an ordinal scale. Using treatment as the fixed effect by category and adjusting for region, logistic regression of the cumulative odds (accumulated over the categories starting from the best outcome) is performed.

[0386] Based on the OLE target population, the long-term efficacy data are descriptively summarized.

[0387] Multiple testing adjustment for primary and secondary endpoints Design the test to ensure that the first type of error on both sides in the whole is surely controlled at α = 0.05. First, test the main null hypothesis at α = 0.05. When it is statistically significant, test the secondary efficacy hypothesis at α = 0.05.

[0388] Analysis according to the clinical trial protocol for the primary endpoint and secondary endpoints The supplementary analysis according to the clinical trial protocol for the primary endpoint and secondary endpoints is performed in the same format as that for the full analysis set (FAS) based on the per-protocol set (PPS) that conforms to the clinical trial protocol.

[0389] Safety analysis Evaluate the safety and tolerability of Labrizumab based on adverse events, clinical laboratory findings, vital sign findings, and ECG abnormalities. The safety analysis is performed in the safety population and the OLE population based on the test period to be considered.

[0390] Analysis of adverse events The analysis and reporting of AEs are based on treatment-emergent adverse events (TEAEs), including treatment-emergent serious adverse events (TESAE) (defined as AEs that occurred at the time of the first dose of Labrizumab or after the first dose of Labrizumab during the randomized control period). The treatment-emergent AEs and TESAE are summarized by MedDRA SOC and preferred terms, severity, and the relationship with the test drug. Obtain the adverse event rate adjusted by the patient's age and characterize the long-term safety profile.

[0391] Analysis of clinical laboratory parameters, vital sign measurements, and electrocardiogram parameters Describe and summarize the test measurements at each visit and their changes from the baseline, and if applicable, the fluctuations from the baseline. Also summarize the significant ECG, vital sign, and pulse oximetry findings using descriptive analysis.

[0392] Other safety analyses Obtain the number and percentage of patients in each C-SSRS category, as well as the shift analysis results. Summarize the results of the pregnancy test.

[0393] Pharmacokinetic and pharmacodynamic analysis Report and summarize pharmacokinetic parameters such as peak and trough levels of ravulizumab in serum. Using sparse PK data, perform population PK analysis of ravulizumab to characterize the PK of ravulizumab in gMG patients. Using population PK analysis, estimate important ravulizumab PK parameters such as clearance, volume of distribution, and terminal half-life. Also evaluate the potential impact of internal and external factors on ravulizumab PK. Record and summarize pharmacodynamic data (free C5 before and after treatment). Examine the correlation between PK and PD. Consider additional analysis if applicable.

[0394] Immunogenicity analysis Evaluate the presence or absence of ADA in serum ravulizumab throughout the study period. The immunogenicity results are analyzed by summarizing the number and percentage of patients expressing detectable ADA. Evaluate the association between ADA and ravulizumab concentration, PD parameters, efficacy, and TEAE.

[0395] Exploratory biomarker analysis Descriptively summarize the level of acetylcholine receptor antibody titer at each visit and its change from baseline.

[0396] Interim analysis In the ALXN1210-MG-306 trial, no interim analysis is planned during the randomized control period. Once the last patient has completed the randomized control period, the database is locked, and the randomization schedule of the trial is unblinded, perform the primary analysis. During the OLE period, perform periodic analysis and reporting based on regulatory requirements. At the conclusion of the trial, perform the final analysis and reporting.

[0397] Further details regarding sample size determination The calculation of the test power is based on the change over time from the baseline of the total MG-ADL score observed in Study ECU-MG-301. A simulation-based approach is adopted to calculate the test power based on the model-based treatment effect in MG-ADL. To achieve a test power of at least 90% to reject the null hypothesis that there is no treatment effect based on the change from the baseline of the total MG-ADL score at week 26, a total of 160 patients are required. Further details are shown in the SAP.

[0398] Further details regarding the sensitivity analysis of the primary endpoint To evaluate the credibility of the primary analysis, the following sensitivity analyses are planned based on assumptions that are sufficiently unfavorable to the Lublizumab group (forming a persuasive stress test of the primary analysis).

[0399] Placebo-based sensitivity analysis In the placebo-based sensitivity analysis, regarding missing data, the mechanism of MNAR is considered. In that case, it is estimated that patients who drop out early from the Lublizumab group will follow a similar course of outcome as patients in the placebo group after discontinuing Lublizumab, based on the observed values before discontinuation (Little, R. & Yau, L., Biometrics, 52:1324 - 33, 1996, Ratitch, B. et al., Pharm. Stat., 12:337 - 47, 2013). It is estimated that patients who drop out early from the placebo will not show a similar outcome as placebo patients who continue the randomized treatment. After discontinuation of Lublizumab, the efficacy profile of the dropouts is estimated to be due to the efficacy of Lublizumab group patients if they had received treatment until the target time point, based on the assumption that the efficacy profile of the dropouts is similar to that of patients in the placebo group. On the other hand, the efficacy after early discontinuation is limited to the efficacy of the placebo group.

[0400] Switching point sensitivity analysis Based on the stress test method (inflection point analysis) after delta adjustment, further sensitivity analysis is performed. In this approach, it is assumed that in patients who dropped out of active treatment, deterioration defined by a pre-specified adjustment (Δ) is seen in the primary endpoint of efficacy compared to the efficacy scores observed in patients who continued the trial until the next visit (O’Kelley M RB, Statistics in Practice. 1 ed. Chichester, West Sussex, UK: John Wiley & Sons, Ltd; 2014. p. 257 - 368). Since a change in the QMG total score to negative indicates improvement, the pre-specified Δ value is a non-negative fixed quantity. For each Δ value, the treatment effect is determined. In patients who drop out, assuming this fixed deterioration is seen after the visit for dropout, a Δ value for which the nominal two-sided p-value exceeds 0.05 is regarded as an “inflection point” in the sense that it overturns the positive conclusion drawn from the primary analysis. After obtaining such an inflection point, clinical judgment is applied regarding the validity of the assumptions underlying this inflection point. This method is expected to reveal the factors required to overturn the conclusion of the trial based on various assumptions regarding missing data. When the Δ value is 0, it is considered equal to the primary analysis.

[0401] Overview of the array

Table 19 - 1

Table 19 - 2

Table 19 - 3

Table 19 - 4

Table 19 - 5

Claims

[Claim 1] The invention described in the specification.

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