Dosage and administration of anti-C5 antibodies for treating systemic myasthenia gravis

Abstract

Methods for the clinical treatment of systemic myasthenia gravis (gMG) using anti-C5 antibodies or antigen binding fragments thereof are provided.

Description

[0001] This application is a divisional application of an invention patent application that entered the Chinese national phase on September 18, 2021, with application number 202080021230.X, application date February 13, 2020, and invention name “Dosage and administration of anti-C5 antibodies for the treatment of generalized myasthenia gravis”.

[0002] Related Applications

[0003] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 805,350, filed on February 14, 2019, and U.S. Provisional Application No. 62 / 814,935, filed on March 7, 2019, the entire contents of which are incorporated herein by reference for all purposes.

[0004] Reference to electronically submitted sequence listings

[0005] The contents of the Sequence Listing in the electronically submitted ASCII text file (Name: 701828AX9_0041PC_ST25_Sequence_Listing.txt; Size: 55KB; and Creation Date: February 10, 2020) are incorporated herein by reference in its entirety. Background Art

[0006] The complement system works in concert with the rest of the body's immune system to defend against invasion by cellular and viral pathogens. There are at least 25 complement proteins, which are a complex collection of plasma proteins and membrane cofactors. Plasma proteins account for approximately 10% of the globulins in vertebrate serum. Complement components achieve their immune defense function by interacting in a complex but precise series of enzymatic cleavage and membrane binding events. The resulting complement cascade results in the production of products with opsonizing, immunomodulatory, and lytic functions.

[0007] Myasthenia gravis (MG) is a rare, debilitating acquired autoimmune neurological disease of the neuromuscular junction (NMJ) caused by a failure of neuromuscular transmission due to the binding of autoantibodies (auto-Ab) to proteins involved in signaling at the NMJ, including the nicotinic acetylcholine receptor (AChR) or, less commonly, the muscle-specific tyrosine kinase (MuSK) involved in AChR clustering.

[0008] MG may lead to life-threatening respiratory failure, called a myasthenic crisis. MG has a prevalence of 14-20 per 100,000 people in the United States, affecting approximately 60,000 Americans. It affects men and women equally, but the incidence in women is highest in their 20s and 30s, compared to the peak age of onset in men at 50s and 60s or 60s and 70s. Approximately 15% to 20% of subjects will experience a myasthenic crisis during the course of their disease, 75% of which occur within 2 years of diagnosis and require hospitalization and ventilatory support. The mortality rate from MG is approximately 4%, mostly due to respiratory failure.

[0009] The clinical features of myasthenia gravis are weakness and fatigability of voluntary skeletal muscles. MG may initially manifest as weakness of the eye muscles, affecting eyeball and eyelid movement, known as ocular MG (oMG). Ten percent of subjects have disease limited to the eye muscles. Ninety percent of subjects have generalized MG, with muscle weakness involving the neck, head, spine, medulla, respiratory, or limb muscles. Bulbar weakness involves muscles controlled by nerves originating from the bulbous part of the brainstem and manifests as difficulty speaking, chewing, swallowing, and head control.

[0010] Patients with generalized myasthenia gravis (gMG) differ from the ocular myasthenia gravis (oMG) population in that the neuromuscular inflammation and resulting clinical manifestations are not limited to the ocular muscles but involve all voluntary muscle groups: bulbar, respiratory, head, neck, trunk, or peripheral muscles, whether or not the eye is involved. Severe weakness and devastating consequences, including slurred speech, dysarthria, dysphagia, blurred vision, shortness of breath (on activity and at rest), upper and lower extremity weakness, limited mobility, markedly reduced ability to perform activities of daily living (ADL), extreme fatigue, and episodes of lung failure requiring mechanical ventilation are the hallmarks of gMG. Patients with gMG have a higher morbidity and a greater burden of disease than those with isolated oMG. gMG is a rare disease with an estimated prevalence of 145 to 278 per million. Patients with gMG suffer from a devastating inflammatory neuromuscular condition with limited treatment options.

[0011] Hospitalization for gMG exacerbations is common, requiring respiratory support, including mechanical ventilation secondary to respiratory failure (eg, myasthenic crisis) and placement of a gastrointestinal tube for nutritional support and prevention of dysphagia-related aspiration. Patients with more advanced gMG have been reported to have an increased mortality rate of up to 40% 10 years after diagnosis.

[0012] Although MG cannot be cured, there are therapies that reduce muscle weakness and improve neuromuscular function. Currently available myasthenia gravis treatments are aimed at modulating neuromuscular transmission, inhibiting the production or effects of pathogenic antibodies, or inhibiting inflammatory cytokines. There is currently no dedicated treatment that specifically targets the underlying pathophysiology of NMJ damage: anti-AChR antibody-AChR interactions cause complement activation through the classical pathway and inflammation, leading to destruction of the NMJ. There is no dedicated treatment to correct the autoimmune defect in MG. The disease is reasonably controlled in most subjects with MG through immunosuppressive therapy (IST)-the current standard of care, which usually combines cholinesterase inhibitors, corticosteroids and immunosuppressive drugs (most commonly azathioprine [AZA], cyclosporine and mycophenolate mofetil [MMF]). However, these therapies may not be optimal for all patients, and there is a class of subjects who have an insufficient response to or cannot tolerate IST, and some subjects require repeated treatment with plasma exchange (PE) and / or intravenous immunoglobulin (IVIg) to maintain clinical stability.

[0013] When uncontrolled, gMG patients experience ongoing inflammation, tissue destruction, and the attendant severe complications, including severe muscle weakness, impaired mobility, shortness of breath, lung failure, extreme fatigue, risk of aspiration, and significant impairment in ADLs. These patients are typically diagnosed in adulthood, with a median age of onset of 36 to 60 years. Due to complications associated with gMG, many patients are unable to work or have a reduced ability to work, have difficulty caring for themselves and others, and require assistance speaking, eating, walking, breathing, and performing ADLs.

[0014] Uncontrolled terminal complement activation is associated with animal models of experimental autoimmune gMG as well as other forms of autoimmune neuropathies in humans. Auto-Abs recognize target nerve or muscle tissue, including AChRs, which leads to uncontrolled terminal complement activation at the nerve or muscle surface.

[0015] Uncontrolled terminal complement activation driven by autoantibodies with membrane attack complex (MAC)-dependent cleavage and activation, and C5a-dependent inflammation at the NMJ leads to AChR loss and failure of neuromuscular transmission. Consistent with this model, complement component C3 fragments (C3a and C3b) and MAC C5b-9 have been found at the NMJs of MG patients.

[0016] Because MG has no cure and standard care is not effective for all patients, there is a need for improved approaches to treat these patients. Summary of the invention

[0017] 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, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered (or for administration) according to a specific clinical dosing regimen (i.e., at a specific dose and according to a specific dosing schedule).

[0018] Ravulizumab (also known as antibody BNJ441, ALXN1210, or Ultomiris) TM ) comprises a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 14 and 11, respectively, or antigen-binding fragments and variants thereof. Terms BNJ441, ALXN1210, Ravolizumab and Ultomiris TM are used interchangeably in this document but refer to the same antibody. Thus, an exemplary antibody for use in the methods described herein is Ravolizumab or an antibody comprising the heavy and light chain complementarity determining regions (CDRs) or variable regions (VRs) of Ravolizumab.

[0019] In some embodiments, the antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable (VH) region of Ravolizumab having the sequence shown in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the light chain variable (VL) region of Ravolizumab having the sequence shown in SEQ ID NO: 8. In some embodiments, the antibody comprises the CDR1, CDR2, and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5, and 6, respectively.

[0020] In some embodiments, the antibody comprises VH and VL regions having the amino acid sequences shown in SEQ ID NO: 12 and SEQ ID NO: 8, respectively. In some embodiments, the antibody comprises a heavy chain constant region as shown in SEQ ID NO: 13. In some embodiments, the antibody comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, all using EU numbering.

[0021] In some embodiments, the antibody comprises a CDR1, CDR2, and CDR3 heavy chain sequence as shown in SEQ ID NOs: 19, 18, and 3, respectively, and a CDR1, CDR2, and CDR3 light chain sequence as shown in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, all using EU numbering.

[0022] In some embodiments, the antibody competes for binding to the same epitope on C5 as the above antibodies and / or binds to the same epitope on C5 as the above antibodies. In some embodiments, the antibody has at least about 90% variable region amino acid sequence identity with the above antibodies (e.g., at least about 90%, 95%, or 99% variable region identity with SEQ ID NO: 12 and SEQ ID NO: 8).

[0023] In some embodiments, the antibody binds to human C5 with an affinity dissociation constant (KD) in the range of 0.1 nM ≤ KD ≤ 1 nM at pH 7.4 and 25°C. In some embodiments, the antibody binds to human C5 with a KD ≥ 10 nM at pH 6.0 and 25°C. In some embodiments, the antibody has [(KD of the antibody or its antigen-binding fragment against human C5 at pH 6.0 and 25°C) / (KD of the antibody or its antigen-binding fragment against human C5 at pH 7.4 and 25°C)] greater than 25.

[0024] In some embodiments, patients treated according to the methods described herein are vaccinated against meningococcal infection within 3 years prior to or at the start of treatment. In some embodiments, patients treated less than 2 weeks after receiving a meningococcal vaccine are also treated with appropriate prophylactic antibiotics until 2 weeks after vaccination. In some embodiments, patients treated according to the methods described herein are vaccinated against meningococcal serotypes A, C, Y, W135, and / or B.

[0025] In some embodiments, the dosage of the anti-C5 antibody or its antigen-binding fragment is based on the patient's weight. For example, in some embodiments, about 2400 mg, about 2700 mg, about 3000 mg, about 3300 mg and / or about 3600 mg of an anti-C5 antibody or its antigen-binding fragment is administered to the patient based on the patient's weight. In some embodiments, 2400 mg or 3000 mg of an anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing ≥40 to <60 kg. In some embodiments, 2700 mg or 3300 mg of an anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing ≥60 to <100 kg. In some embodiments, 3000 mg or 3600 mg of an anti-C5 antibody or its antigen-binding fragment is administered to a patient weighing ≥100 kg. In some embodiments, the dosage regimen is adjusted to provide the best desired response (e.g., an effective response).

[0026] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof is administered once on day 1 of the administration cycle, once on day 15 of the administration cycle, and once every eight weeks thereafter. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof is administered once every eight weeks after the administration cycle for an extended period of up to two years (e.g., at a dose of 3000 mg, 3300 mg, or 3600 mg).

[0027] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof is administered for 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 for the lifetime of the human patient.

[0028] In some embodiments, the patient is switched from receiving one C5 inhibitor to a different C5 inhibitor during the course of treatment. Different anti-C5 antibodies can be administered during different treatment periods. For example, in some embodiments, a method for treating a human patient with a complement-related disorder (e.g., generalized myasthenia gravis (gMG)) who is being treated with eculizumab is provided, the method comprising stopping 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 during a treatment period (e.g., 26 weeks) and then treated with another anti-C5 antibody (e.g., ravulizumab) during an extension period. In some embodiments, eculizumab is administered to the patient at a dose of 900 mg on days 1, 8, 15, and 22 of an administration cycle during the induction phase, followed by administration of 1200 mg of an eculizumab maintenance dose (e.g., 26 weeks total) on day 19 of the administration cycle and once every two weeks thereafter, followed by treatment with ravulizumab for an extension period of up to two years. In some embodiments, a method of treating a human patient with a complement-associated disorder who is being treated with ravulizumab is provided, the method comprising stopping treatment with ravulizumab and switching the patient to treatment with an alternative complement inhibitor. For example, the patient is treated with ravulizumab during a treatment period (e.g., 26 weeks) and then treated with another anti-C5 antibody (e.g., eculizumab) during an extension period.

[0029] Exemplary alternative complement inhibitors include, but are not limited to, antibodies or antigen-binding fragments thereof, small molecules, polypeptides, polypeptide analogs, peptide mimetics, siRNAs, 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 biologically active fragments thereof. In some embodiments, the alternative complement inhibitor inhibits one or both of the generation of anaphylactic toxic activity associated with C5a and / or the assembly of the membrane attack 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, complestatin, and K76 COOH.

[0030] In some embodiments, the treatment regimen described is sufficient to maintain a specific serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof. For example, in some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450 In some embodiments, the treatment maintains a serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof at 100 μg / ml or more. In some embodiments, the treatment maintains a serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof at 150 μg / ml or more. In some embodiments, the treatment maintains a serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof at 200 μg / ml or more. In some embodiments, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, at 250 μg / ml or greater. In some embodiments, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, at 300 μg / ml or greater. In some embodiments, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, at between 100 μg / ml and 200 μg / ml. In some embodiments, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, at about 175 μg / ml.

[0031] In some embodiments, to achieve an effective response, at least 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 10 ... In some embodiments, the anti-C5 antibody is administered to a patient in an amount and frequency that maintains 50 μg to 250 μg of antibody per milliliter of the patient's blood. In some embodiments, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain 100 μg to 200 μg of antibody per milliliter of patient blood. In some embodiments, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain 175 μg of antibody per milliliter of patient blood.

[0032] In some embodiments, in order to obtain an effective response, an anti-C5 antibody is administered to a patient in an amount and frequency that maintains a minimum free C5 concentration. For example, in some embodiments, an anti-C5 antibody is administered to a patient in an amount and frequency that maintains a free C5 concentration of 0.2 μg / mL, 0.3 μg / mL, 0.4 μg / mL, 0.5 μg / mL or less. In some embodiments, an anti-C5 antibody is administered to a patient in an amount and frequency that maintains a free C5 concentration of 0.309 to 0.5 μg / mL or less. In some embodiments, the treatment described herein reduces the free C5 concentration by more than 99% throughout the treatment period. In some embodiments, treatment reduces the free C5 concentration by more than 99.5% throughout the treatment period.

[0033] 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.

[0034] Any suitable means can be used to assess the efficacy of the treatment methods provided herein. In some embodiments, for gMG patients, treatment produces at least one therapeutic effect selected from the group consisting of, but not limited to, inflammation, tissue destruction, severe weakness, slurred speech, dysarthria, dysphagia, blurred vision, shortness of breath (active and resting), upper and lower extremity weakness, impaired mobility, a significant decrease in the ability to perform activities of daily living (ADL), extreme fatigue, and a reduction or cessation of episodes of pulmonary failure requiring mechanical ventilation. In another embodiment, the patient has a clinically meaningful improvement (reduction) in one or more measures of gMG severity selected from the group consisting of: MG-ADL, QMG, MG-QOL 15r, Neurological QOL Fatigue, EQ-5D-5L, MGFA-PIS, and / or MGC.

[0035] In some embodiments, treatment results in terminal complement inhibition.

[0036] In some embodiments, the present disclosure provides a method comprising administering a therapeutically effective amount of ravulizumab to a patient, wherein the patient is positive for autoantibodies that bind to nicotinic acetylcholine receptors (anti-AChR) and shows significant systemic weakness or bulbar signs and symptoms of myasthenia gravis, and wherein ravulizumab is administered to the patient for at least 26 weeks. In some embodiments, the patient has previously received therapy for myasthenia gravis, including anticholinesterase inhibitor therapy and immunosuppressant therapy (IST), and requires long-term plasma exchange or long-term IVIg to maintain clinical stability.

[0037] In some embodiments, the patient treated by the methods provided herein experiences a clinically significant improvement (reduction) in myasthenia gravis activities of daily living (MG-ADL) score after 26 weeks of treatment. In some embodiments, the therapeutic effect will be estimated by the mean value difference between the ravulizumab group and the placebo group on the change of the MG-ADL total score relative to baseline at the 26th week, without considering rescue therapy. The lower value of the corresponding estimated value will indicate a beneficial therapeutic effect. In some embodiments, as defined herein, when the patient's health is in danger, if rescue therapy (e.g., emergency) is not administered, or if the patient experiences clinical deterioration, rescue therapy will be allowed. In some embodiments, rescue therapy includes high-dose corticosteroids, PP / PE or IVIg. In some embodiments, the clinically significant improvement experienced by the patient is that the MG-ADL score of the patient is reduced by at least 3 points after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to the dichotomous endpoint of the 26th week MG-ADL 3-point response without considering the rescue therapy will be estimated by the odds ratio (OR) of the proportion of the corresponding endpoint of the ravulizumab group compared to the placebo group.

[0038] In some embodiments, the patient treated by the methods provided herein experiences a clinically significant improvement (reduction) in the quantitative myasthenia gravis (QMG) score after 26 weeks of treatment. In some embodiments, the therapeutic effect corresponding to the change relative to the baseline continuous endpoint will be estimated by the mean difference between the ravulizumab group and the placebo group in the change relative to the baseline in the QMG score at week 26, without considering rescue therapy. The lower value of the corresponding estimated value will indicate a beneficial therapeutic effect. In some embodiments, the clinically significant improvement experienced by the patient is that the QMG score of the patient is reduced by at least 5 points after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to the dichotomous endpoint of the 26th week QMG 5-point response without considering rescue therapy will be estimated by the odds ratio (OR) of the proportion of the corresponding endpoint of the ravulizumab group compared to the placebo group.

[0039] In some embodiments, patients treated by the methods provided herein experience a clinically significant improvement (reduction) in myasthenia gravis composite (MGC) score after 26 weeks of treatment. In some embodiments, the therapeutic effect corresponding to the change relative to the baseline continuous endpoint will be estimated by the mean difference between the ravulizumab group and the placebo group on the change relative to the baseline in the MGC score at week 26, without considering rescue therapy. A lower value of the corresponding estimate will indicate a beneficial therapeutic effect.

[0040] In some embodiments, the patient treated by the methods provided herein experiences a clinically significant improvement (reduction) in the quality of life as measured by the revised 15-component myasthenia gravis quality of life (MG-QOL 15r) score after 26 weeks of treatment. In some embodiments, the therapeutic effect corresponding to the change relative to the baseline continuous endpoint will be estimated by the mean difference between the ravulizumab group and the placebo group in the change relative to the baseline of the MG-QOL1 5r score at week 26, without considering rescue therapy. The lower value of the corresponding estimated value will indicate a beneficial therapeutic effect.

[0041] In some embodiments, patients treated by the methods provided herein experience a clinically meaningful improvement (reduction) in neurological fatigue as measured by a neurological QOL fatigue score after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to the change relative to the baseline continuous endpoint will be estimated by the mean difference between the ravulizumab group and the placebo group in the change relative to the baseline in the neurological QOL score at week 26, without considering rescue therapy. A lower value of the corresponding estimate will indicate a beneficial treatment effect.

[0042] In some embodiments, the patient treated by the methods provided herein experiences a clinically significant improvement (increase) in health status as measured by the EQ-5D-5L health status score after 26 weeks of treatment. In some embodiments, the patient treated by the methods provided herein experiences a clinically significant improvement (increase) in health status as measured by the EQ-5D-5L index score after 26 weeks of treatment. In some embodiments, the patient treated by the methods provided herein experiences a clinically significant improvement (increase) in health status as measured by the EQ-5D-5L VAS score after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to the change relative to the baseline continuous endpoint will be estimated by the mean difference between the ravolumab group and the placebo group on the change relative to the baseline in the EQ-5D-5L health status score (e.g., EQ-5D-5L index score or EQ-5D-5L VAS score at week 26), without considering rescue therapy. The lower value of the corresponding estimated value will indicate a beneficial treatment effect.

[0043] In some embodiments, the patient treated by the methods provided herein experiences a clinically significant improvement (increase) in health status as measured by the MGFA-PIS score after 26 weeks of treatment. The therapeutic effect corresponding to the MGFA-PIS endpoint will be estimated by the proportional odds ratio (OR) of the cumulative proportion of the sequential categories (starting from the best result) of this endpoint of the ravulizumab group compared to the placebo group at week 26, without considering rescue therapy. The estimated value of OR>1 will indicate a beneficial therapeutic effect.

[0044] In some embodiments, patients treated by the methods provided herein experience clinically meaningful improvements (increases) in health status as measured by a reduction in the incidence of all-cause hospitalization or clinical deterioration as defined herein after 26 weeks of treatment. In some embodiments, the treatment effect of the dichotomous endpoints of all-cause hospitalization or clinical deterioration as defined herein within 26 weeks without considering rescue therapy will be estimated by the odds ratio (OR) of the proportion of the corresponding endpoints of the ravulizumab group compared to the placebo group. An estimate of OR <1 corresponding to the comprehensive hospitalization endpoint will indicate a beneficial treatment effect, and similarly, an estimate of OR>1 corresponding to the responder endpoint will indicate a beneficial treatment effect.

[0045] In some embodiments, the present disclosure provides a method of treating generalized myasthenia gravis in a patient in need thereof, comprising administering ravulizumab to the patient, wherein the patient is positive for autoantibodies that bind to nicotinic acetylcholine receptors (anti-AChR) and exhibits significant generalized weakness or bulbar signs and symptoms of myasthenia gravis while receiving therapy for myasthenia gravis, including anticholinesterase inhibitor therapy and immunosuppressant therapy (IST), or requires long-term plasma exchange or long-term IVIg to maintain clinical stability; wherein ravulizumab is administered using a phased dosing schedule as defined herein, and wherein the patient has a clinically meaningful improvement (reduction) in at least one generalized myasthenia gravis severity measure selected from the group consisting of: MG-ADL, QMG, MG-QOL 15r, Neurological QOL Fatigue, EQ-5D-5L, MGFA-PIS and / or MGC.

[0046] In some embodiments, the present disclosure provides a method of treating generalized myasthenia gravis in a patient in need thereof, comprising administering ravulizumab to the patient, wherein the patient is positive for autoantibodies that bind to nicotinic acetylcholine receptors (anti-AChR) and exhibits significant generalized weakness or bulbar signs and symptoms of myasthenia gravis while receiving therapy for myasthenia gravis, including anticholinesterase inhibitor therapy and immunosuppressant therapy (IST), and requires long-term plasma exchange or long-term IVIg to maintain clinical stability; wherein ravulizumab is administered using a phased dosing schedule as disclosed herein, and wherein the patient has a clinically meaningful improvement (reduction) in two generalized myasthenia gravis severity measures selected from the group consisting of: MG-ADL, QMG, MG-QOL 15r, Neurological QOL Fatigue, EQ-5D-5L, MGFA-PIS and / or MGC.

[0047] In some embodiments, the present disclosure provides a method of treating generalized myasthenia gravis in a patient in need thereof, comprising administering ravulizumab to the patient, wherein the patient is positive for autoantibodies that bind to nicotinic acetylcholine receptors (anti-AChR) and exhibits significant generalized weakness or bulbar signs and symptoms of myasthenia gravis while receiving therapy for myasthenia gravis, including anticholinesterase inhibitor therapy and immunosuppressant therapy (IST), or requires long-term plasma exchange or long-term IVIg to maintain clinical stability; wherein ravulizumab is administered using a phased dosing schedule as disclosed herein, and wherein the patient has a clinically meaningful improvement (reduction) in three generalized myasthenia gravis severity measures selected from the group consisting of: MG-ADL, QMG, MG-QOL 15r, Neurological QOL Fatigue, EQ-5D-5L, MGFA-PIS, and / or MGC. In some embodiments, the patient has a clinically significant improvement (reduction) in four generalized myasthenia gravis severity measures selected from the group consisting of: MG-ADL, QMG, MG-QOL 15r, neurological QOL fatigue, EQ-5D-5L, MGFA-PIS and / or MGC. In some embodiments, the patient has a clinically significant improvement (reduction) in five generalized myasthenia gravis severity measures, wherein the five generalized myasthenia gravis severity measures are MG-ADL, QMG, MG-QOL 15r, neurological QOL fatigue, EQ-5D-5L, MGFA-PIS and / or MGC. In some embodiments, the patient has a clinically significant improvement (reduction) in six generalized myasthenia gravis severity measures, wherein the five generalized myasthenia gravis severity measures are MG-ADL, QMG, MG-QOL 15r, neurological QOL fatigue, EQ-5D-5L, MGFA-PIS and / or MGC. In some embodiments, the patient has clinically meaningful improvements (decreases) in seven generalized myasthenia gravis severity measures, five of which are MG-ADL, QMG, MG-QOL15r, Neurological QOL Fatigue, EQ-5D-5L, MGFA-PIS, and / or MGC.

[0048] In some embodiments, the present disclosure provides a method of treating generalized myasthenia gravis in a patient in need thereof, comprising administering ravulizumab by intravenous infusion. In some embodiments, ravulizumab is administered subcutaneously. In some embodiments, ravulizumab comprises a heavy chain amino acid sequence according to SEQ ID NO: 12 and a light chain amino acid sequence according to SEQ ID NO: 11. In some embodiments, ravulizumab is a ravulizumab variant comprising a heavy chain amino acid sequence according to SEQ ID NO: 14 and a light chain amino acid sequence according to SEQ ID NO: 11.

[0049] In some embodiments, the present disclosure provides a method of treating generalized myasthenia gravis in a patient in need thereof, comprising administering an anti-C5 antibody or antigen-binding fragment thereof, wherein the antibody is an anti-C5 antibody or antigen-binding fragment thereof comprising a heavy chain variable region amino acid sequence according to SEQ ID NO: 27 and a light chain variable region amino acid sequence according to SEQ ID NO: 28. In some embodiments, the antibody is an anti-C5 antibody or antigen-binding fragment thereof comprising a heavy chain variable region amino acid sequence according to SEQ ID NO: 35 and a light chain variable region amino acid sequence according to SEQ ID NO: 36. In some embodiments, the antibody is an anti-C5 antibody or antigen-binding fragment thereof comprising a heavy chain variable region amino acid sequence according to SEQ ID NO: 43 and a light chain variable region amino acid sequence according to SEQ ID NO: 44. In some embodiments, the antibody is an anti-C5 antibody or antigen-binding fragment thereof comprising a heavy chain variable region amino acid sequence according to SEQ ID NO: 45 and a light chain variable region amino acid sequence according to SEQ ID NO: 46.

[0050] In some embodiments, the present disclosure provides a method of treating generalized myasthenia gravis in a patient in need thereof, comprising administering a therapeutically effective amount of ravulizumab that maintains a concentration of between 50 and 100 μg / mL in the patient's serum.

[0051] In some embodiments, the present disclosure provides a method of treating generalized myasthenia gravis in a patient in need thereof, comprising administering a therapeutically effective amount of ravulizumab, wherein the patient discontinues administration of one or more ISTs after at least 26 weeks of treatment.

[0052] In some embodiments, the present disclosure provides a method of treating generalized myasthenia gravis in a patient in need thereof, comprising administering a therapeutically effective amount of ravulizumab, wherein the patient has a reduced need for long-term plasma exchange or long-term IVIg to maintain clinical stability after at least 26 weeks of treatment.

[0053] In some embodiments, the present disclosure provides a method of treating generalized myasthenia gravis in a patient in need thereof, 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.

[0054] In some embodiments, the present disclosure provides a method of treating generalized myasthenia gravis in a patient in need thereof, comprising administering a therapeutically effective amount of ravulizumab, wherein the patient has a reduced need for long-term plasma exchange or long-term IVIg to maintain clinical stability after at least 26 weeks of treatment.

[0055] 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, wherein the composition comprises an antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5, and 6, respectively.

[0056] In some embodiments, the antibody or antigen-binding fragment thereof comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, all using EU numbering.

[0057] In some embodiments, the composition comprising the antibody or antigen-binding fragment thereof is: (a) administered once on day 1 of the administration cycle at a dose of 2400 mg to patients weighing ≥40 to <60 kg, 2700 mg to patients weighing ≥60 to <100 kg, or 3000 mg to patients weighing ≥100 kg; and (b) administered on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg to patients weighing ≥40 to <60 kg, 3300 mg to patients weighing ≥60 to <100 kg, or 3600 mg to patients weighing ≥100 kg.

[0058] 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.

[0059] 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.

[0060] 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 ≤ KD ≤ 1 nM at pH 7.4 and 25° C. In some embodiments, the antibody or antigen-binding fragment thereof binds to human C5 with a KD ≥ 10 nM at pH 6.0 and 25° C.

[0061] In some embodiments, the antibody or antigen-binding fragment thereof is administered to patients weighing ≥40 to <60 kg: (a) once at a loading dose of 2400 mg on day 1 of the administration cycle; and (b) at a maintenance dose of 3000 mg on day 15 of the administration cycle and every eight weeks thereafter.

[0062] In some embodiments, the antibody or antigen-binding fragment thereof is administered to patients weighing ≥60 to <100 kg: (a) once at a loading dose of 2700 mg on day 1 of the administration cycle; and (b) at a maintenance dose of 3300 mg on day 15 of the administration cycle and every eight weeks thereafter.

[0063] In some embodiments, the antibody or antigen-binding fragment thereof is administered to a patient weighing ≥100 kg: (a) once at a loading dose of 3000 mg on day 1 of an administration cycle; and (b) at a maintenance dose of 3600 mg on day 15 of the administration cycle and every eight weeks thereafter.

[0064] In some embodiments, treatment with the antibody or antigen-binding fragment thereof maintains a serum trough concentration of the antibody or antigen-binding fragment thereof at 100 μg / mL or more during the administration period. In some embodiments, treatment with the antibody or antigen-binding fragment thereof maintains a serum trough concentration of the antibody or antigen-binding fragment thereof at 200 μg / mL or more during the administration period.

[0065] In some embodiments, treatment with the antibody or antigen-binding fragment thereof maintains a free antibody or antigen-binding fragment thereof concentration of 0.309 to 0.5 μg / mL or less.

[0066] In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 3000 mg, 3300 mg, or 3600 mg every eight weeks after the administration cycle for up to two years.

[0067] In some embodiments, the antibody or antigen-binding fragment thereof is formulated for intravenous administration.

[0068] In some embodiments, the patient treated with the antibody or antigen-binding fragment thereof has not been previously treated with a complement inhibitor.

[0069] In some embodiments, the administration period is for a total of 26 weeks of treatment.

[0070] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in terminal complement inhibition.

[0071] In some embodiments, treatment with the antibody or antigen-binding fragment thereof causes the patient to experience a clinically meaningful improvement (reduction) in the myasthenia gravis activities of daily living (MG-ADL) score after 26 weeks of treatment. In some embodiments, the clinically meaningful improvement experienced by the patient is a reduction of at least 3 points in the patient's MG-ADL score after 26 weeks of treatment.

[0072] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically meaningful improvement (reduction) in the quantitative myasthenia gravis (QMG) score after 26 weeks of treatment. In some embodiments, the clinically meaningful improvement experienced by the patient is a reduction in the patient's QMG by at least 5 points after 26 weeks of treatment.

[0073] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically meaningful improvement (reduction) in the Myasthenia Gravis Composite (MGC) score after 26 weeks of treatment.

[0074] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically meaningful improvement (reduction) in quality of life as measured by the Myasthenia Gravis Quality of Life (MG-QOL 15r) score after 26 weeks of treatment.

[0075] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically meaningful improvement (reduction) in neurological fatigue as measured by the Neurological QOL Fatigue score after 26 weeks of treatment.

[0076] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically meaningful improvement (reduction) in health status as measured by the European Quality of Life (EQ-5D-5L) health status score after 26 weeks of treatment.

[0077] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically meaningful improvement (reduction) in the Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) after 26 weeks of treatment.

[0078] In some embodiments, the myasthenia gravis is generalized myasthenia gravis (gMG). In some embodiments, the gMG patient is positive for anti-AChR antibodies.

[0079] In some embodiments, the antibody is Ravolizumab.

[0080] In some embodiments, a kit for treating myasthenia gravis (MG) in a human patient is provided, the kit comprising: (a) a dose of an antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence shown in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of a 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 in the method of any of the preceding claims.

[0081] In some embodiments, the antibodies or antigen-binding fragments thereof of the kit comprise a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, all using EU numbering.

[0082] In some embodiments, the antibody or antigen-binding fragment thereof of the kit is administered to a patient weighing ≥40 to <60 kg: (a) once at a loading dose of 2400 mg on day 1 of an administration cycle; and (b) at a maintenance dose of 3000 mg on day 15 of the administration cycle and every eight weeks thereafter.

[0083] In some embodiments, the antibody or antigen-binding fragment thereof of the kit is administered to a patient weighing ≥60 to <100 kg: (a) once at a dose of 2700 mg on day 1 of an administration cycle; and (b) at a maintenance dose of 3300 mg on day 15 of the administration cycle and every eight weeks thereafter.

[0084] In some embodiments, the antibody or antigen-binding fragment thereof of the kit is administered to a patient weighing ≥100 kg: (a) once at a dose of 3000 mg on day 1 of an administration cycle; and (b) at a maintenance dose of 3600 mg on day 15 of the administration cycle and every eight weeks thereafter.

[0085] In some embodiments, the antibody is Ravolizumab.

[0086] In some embodiments, the present disclosure provides an antibody comprising the CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence shown in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence shown in SEQ ID NO: 8, wherein the antibody is for administration in a treatment cycle.

[0087] In some embodiments, the antibody comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, all using EU numbering.

[0088] In some embodiments, the antibody is: (a) administered once on day 1 of an administration cycle at a dose of 2400 mg to patients weighing ≥40 to <60 kg, 2700 mg to patients weighing ≥60 to <100 kg, or 3000 mg to patients weighing ≥100 kg; and (b) administered on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg to patients weighing ≥40 to <60 kg, 3300 mg to patients weighing ≥60 to <100 kg, or 3600 mg to patients weighing ≥100 kg.

[0089] In some embodiments, the antibody is determined to be safe, tolerable, effective, and sufficiently non-immunogenic following multiple IV doses in MG patients.

[0090] In some embodiments, the antibody is Ravolizumab.

[0091] In some embodiments, a method of treating a human patient suffering from MG is provided, the method comprising administering to the patient an effective amount of an antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5, and 6, respectively.

[0092] In some embodiments, the antibody or antigen-binding fragment thereof comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, all using EU numbering.

[0093] In some embodiments, the antibody or antigen-binding fragment thereof is: (a) administered once on day 1 of an administration cycle at a dose of 2400 mg to patients weighing ≥40 to <60 kg, 2700 mg to patients weighing ≥60 to <100 kg, or 3000 mg to patients weighing ≥100 kg; and (b) administered on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg to patients weighing ≥40 to <60 kg, 3300 mg to patients weighing ≥60 to <100 kg, or 3600 mg to patients weighing ≥100 kg.

[0094] 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.

[0095] 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.

[0096] In some embodiments, the antibody or antigen-binding fragment thereof has a pH of 7.4 and 25°C with a K of 0.1 nM ≤ K D Affinity dissociation constants (K) in the range of ≤1 nM D ) binds to human C5. In some embodiments, the antibody or antigen-binding fragment thereof binds to human C5 at pH 6.0 and 25°C with a K D ≥10 nM binds to human C5.

[0097] In some embodiments, the antibody or antigen-binding fragment thereof is administered to a patient weighing ≥40 to <60 kg: (a) once at a dose of 2400 mg on day 1 of the administration cycle; and (b) at a dose of 3000 mg on day 15 of the administration cycle and every eight weeks thereafter.

[0098] In some embodiments, the antibody or antigen-binding fragment thereof is administered to patients weighing ≥60 to <100 kg: (a) once at a dose of 2700 mg on day 1 of the administration cycle; and (b) at a dose of 3300 mg on day 15 of the administration cycle and every eight weeks thereafter.

[0099] In some embodiments, the antibody or antigen-binding fragment thereof is administered to a patient weighing ≥100 kg: (a) once at a dose of 3000 mg on day 1 of an administration cycle; and (b) at a dose of 3600 mg on day 15 of the administration cycle and every eight weeks thereafter.

[0100] In some embodiments, treatment with the antibody or antigen-binding fragment thereof maintains a serum trough concentration of the antibody or antigen-binding fragment thereof at 100 μg / mL or more during the administration period. In some embodiments, treatment with the antibody or antigen-binding fragment thereof maintains a serum trough concentration of the antibody or antigen-binding fragment thereof at 200 μg / mL or more during the administration period.

[0101] In some embodiments, treatment with the antibody or antigen-binding fragment thereof maintains a free antibody or antigen-binding fragment concentration of 0.309 to 0.5 μg / mL or less.

[0102] In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 3000 mg, 3300 mg, or 3600 mg every eight weeks after the administration cycle for up to two years.

[0103] In some embodiments, the antibody or antigen-binding fragment thereof is formulated for intravenous administration.

[0104] In some embodiments, the patient has not been previously treated with a complement inhibitor.

[0105] In some embodiments, the administration period is a total of 26 weeks of treatment.In some embodiments, the treatment results in terminal complement inhibition.

[0106] In some embodiments, treatment with the antibody or antigen-binding fragment thereof causes the patient to experience a clinically meaningful improvement (reduction) in the myasthenia gravis activities of daily living (MG-ADL) score after 26 weeks of treatment. In some embodiments, the clinically meaningful improvement experienced by the patient is a reduction of at least 3 points in the patient's MG-ADL score after 26 weeks of treatment.

[0107] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically meaningful improvement (reduction) in the quantitative myasthenia gravis (QMG) score after 26 weeks of treatment. In some embodiments, the clinically meaningful improvement experienced by the patient is a reduction of at least 5 points in the patient's QMG after 26 weeks of treatment.

[0108] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically meaningful improvement (reduction) in the Myasthenia Gravis Composite (MGC) score after 26 weeks of treatment.

[0109] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically meaningful improvement (reduction) in quality of life as measured by the Myasthenia Gravis Quality of Life (MG-QOL 15r) score after 26 weeks of treatment.

[0110] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically meaningful improvement (reduction) in neurological fatigue as measured by the Neurological QOL Fatigue score after 26 weeks of treatment.

[0111] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically meaningful improvement (reduction) in health status as measured by the European Quality of Life (EQ-5D-5L) health status score after 26 weeks of treatment.

[0112] In some embodiments, treatment with the antibody or antigen-binding fragment thereof results in a clinically meaningful improvement (reduction) in the Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) after 26 weeks of treatment.

[0113] In some embodiments, myasthenia gravis is generalized myasthenia gravis (gMG). In some embodiments, gMG patients are positive for anti-AChR antibodies.

[0114] In some embodiments, the antibody is Ravolizumab.

[0115] Furthermore, the present disclosure encompasses any of the above-described embodiments used in any combination with any other of the above-described embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0116] Figure 1 is a schematic diagram depicting the design of the Phase III ALXN1210-MG-306 clinical trial in gMG patients.

[0117] Figure 2 Schematic diagram depicting the 8-week dosing schedule of ranivuzumab versus the 2-week dosing schedule of eculizumab (including actual infusion days) for patients participating in the Phase III ALXN1210-MG-306 study.

[0118] Figure 3A , Figure 3B and Figure 3C The European Quality of Life Survey (EQ-5D-5L) health status questionnaire used in the clinical trials disclosed herein.

[0119] Figure 4 is the Columbia-Suicidality Severity Rating Scale (C-SSRS) measured at patient baseline / screening.

[0120] Figure 5 is the Columbia-Suicidality Severity Rating Scale (CS SRS) measured since the patient's last visit. DETAILED DESCRIPTION

[0121] As used herein, the term "subject" or "patient" is a human patient (eg, a patient with generalized myasthenia gravis (gMG)). As used herein, the terms "subject" and "patient" are interchangeable.

[0122] As used herein, the phrase "requiring long-term plasma exchange" means that the patient has been regularly treated with plasma exchange therapy at least every 3 months within the past 12 months to control muscle weakness.

[0123] As used herein, the phrase "requiring long-term IVIg" means that the patient has been regularly treated with IVIg at least every 3 months in the past 12 months to control muscle weakness.

[0124] As used herein, the phrase "clinical deterioration" refers to patients who experience an MG crisis, which is defined as MG weakness severe enough to require intubation or delayed extubation after surgery, where respiratory failure is due to weakness of the respiratory muscles, severe bulbar (oropharyngeal) muscle weakness associated with respiratory muscle weakness, or is the predominant feature of the patient; or when there is a significant symptom deterioration to 3 points or a 2-point deterioration from baseline in any individual MG Activities of Daily Living (MG-ADL) item other than diplopia or ptosis; or the administration of rescue therapy to patients whose health would be at risk if rescue therapy was not given (e.g., emergency situations), in the opinion of the Investigator or Investigator-designated physician.

[0125] As used herein, "effective treatment" refers to treatment that produces a beneficial effect, such as an improvement in at least one symptom of a disease or condition. The beneficial effect may take the form of an improvement relative to a baseline, i.e., an improvement relative to a measurement or observation made before initiation of treatment according to the methods. Effective treatment may refer, for example, to a reduction in at least one symptom of MG.

[0126] The term "effective amount" refers to the amount of an agent that provides a desired biological, therapeutic, and / or preventive result. The result can be a reduction, improvement, alleviation, reduction, delay, and / or alleviation of one or more signs, symptoms, or causes of a disease, or any other desired change in a biological system. In one embodiment, an "effective amount" is, for example, an amount of an anti-C5 antibody or antigen-binding fragment thereof that has been clinically demonstrated to be useful for alleviating at least one symptom of MG. An effective amount can be administered in one or more administrations.

[0127] As used herein, the terms "induction" and "induction phase" are used interchangeably and refer to the first phase of a dosing regimen.

[0128] As used herein, the terms "maintenance" and "maintenance phase" are used interchangeably and refer to the second phase of the dosing regimen. In some embodiments, treatment is continued as long as clinical benefit is observed or until uncontrollable toxicity or disease progression occurs. The maintenance phase of ravulizumab administration can last for 6 weeks to the life of the subject. According to some embodiments, the maintenance phase lasts for 26-52, 26-78, 26-104, 26-130, 26-156, 26-182, 26-208 weeks or longer. In some embodiments, the maintenance phase lasts for more than 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 78, 104, 130, 156 or 182 weeks. According to some embodiments, the maintenance phase lasts for more than 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 years, or more. In some embodiments, the maintenance phase lasts for the rest of the subject's life.

[0129] In some embodiments, the multi-stage dosing regimen of levuluzumab includes a third stage. The third stage is used when MG patients must undergo a rescue procedure to maintain clinical stability, and includes the administration of plasma exchange / plasmapheresis (PE / PP) and / or the administration of IVIg. In this stage after plasmapheresis, a dose of levuluzumab is administered to replace the drug lost during plasma exchange / plasmapheresis. According to some embodiments, if PE / PP or IVIg rescue therapy is provided on a non-administration day, a supplementary study drug, such as levuluzumab, needs to be administered. In another embodiment, if PE / PP or IVIg infusion is provided on the administration day, it must be performed before the administration of the study drug. According to some embodiments, if PE / PP or IVIg is administered at an unscheduled dosing visit, a supplementary dose is administered to patients receiving PE / PP 4 hours after the completion of the PE / PP course. In another embodiment, patients receiving IVIg are administered a supplementary dose 4 hours after the completion of the last IVIg continuous course. In some embodiments, the supplementary dose may or may not vary according to PE / PP or IVIg (Tables 1 and 2). In some embodiments, if PE / PP or IVIg is administered during a scheduled dosing visit, the regular dose will be administered 60 minutes after completion of PE / PP or IVIg. In some embodiments, no interval is required between the supplemental dose and the regular scheduled dose.

[0130] Table 1: Supplemental doses when PE / PP is administered as rescue therapy at an unscheduled dosing visit

[0131]

[0132] 1 Dosing schedule will be based on the patient's most recently recorded body weight from the previous study / screening visit.

[0133] 2 A blinded dose was administered on Day 183 (Week 26) to patients randomized to the ravulizumab group who entered the open-label extension period.

[0134] 3 On Day 183 (Week 26), patients randomized to the placebo group and entering the open-label extension phase were given a blind loading dose.

[0135] Table 2: Supplemental doses when intravenous immune globulin is administered as rescue therapy at an unscheduled dosing visit

[0136]

[0137] 1 Dosing schedule will be based on the patient's most recently recorded body weight from the previous study / screening visit.

[0138] 2 A blinded dose was administered on Day 183 (Week 26) to patients randomized to the ravulizumab group who entered the open-label extension period.

[0139] 3 Patients randomized to placebo and entering the open-label extension phase were given a blinded loading dose on Day 183 (Week 26).

[0140] As used herein, the term "loading dose" refers to the initial dose administered to a patient. The loading amount can be, for example, 2400 mg, 2700 mg, or 3000 mg. The loading dose can be titrated based on body weight.

[0141] As used herein, the term "maintenance dose" or "maintenance phase" refers to the dose administered to a patient after a loading dose. For example, a maintenance dose may be 3000 mg, 3300 mg, or 3600 mg. The maintenance dose may be titrated based on body weight.

[0142] As used herein, the term "serum trough level" refers to the lowest concentration of an agent (e.g., an anti-C5 antibody or antigen-binding fragment thereof) or drug present in the serum. In contrast, a "peak serum level" refers to the highest concentration of an agent in the serum. An "average serum level" refers to the average concentration of an agent in the serum over time.

[0143] In one embodiment, the treatment regimen is sufficient to maintain a specific serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof. For example, in one embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450 05, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395 or 400 μg / mL or more. In one embodiment, the treatment maintains the serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 100 μg / mL or more. In another embodiment, the treatment maintains the serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 150 μg / mL or more. In another embodiment, the treatment maintains the serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 200 μg / mL or more. In another embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, at 250 μg / mL or greater. In another embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, at 300 μg / mL or greater. In another embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, at between 100 μg / mL and 200 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, at about 175 μg / mL.

[0144] In another embodiment, in order to obtain an effective response, an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient in an amount and frequency to maintain the minimum desired free C5 concentration. For example, in one embodiment, an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient in an amount and frequency to maintain a free C5 concentration of 0.2 μg / mL, 0.3 μg / mL, 0.4 μg / mL, 0.5 μg / mL or less. In another embodiment, an anti-C5 antibody or an antigen-binding fragment thereof is administered to a patient in an amount and frequency to maintain a free C5 concentration of 0.309 to 0.5 μg / mL or less. In another embodiment, the treatment described herein reduces the free C5 concentration by more than 99% throughout the treatment period. In another embodiment, the treatment reduces the free C5 concentration by more than 99.5% throughout the treatment period.

[0145] The term "antibody" describes a polypeptide comprising at least one antibody-derived antigen binding site (e.g., VH / VL region or Fv, or CDR). Antibodies include known forms of antibodies. Antibodies can be, for example, human antibodies, humanized antibodies, bispecific antibodies, chimeric antibodies, or camelid antibodies. Antibodies can also be Fab, Fab'2, scFv, SMIP, Affibody, or Nanobodies or single domain antibodies. The antibody may also be any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD and IgE, and hybrid isotypes, e.g., IgG2 / 4. The antibody may be a naturally occurring antibody, or may be an antibody altered by protein engineering techniques (e.g., by mutation, deletion, substitution, binding to a non-antibody portion). The antibody may include, for example, one or more variant amino acids (compared to a naturally occurring antibody) that alter the properties of the antibody (e.g., functional properties). Many such changes are known in the art, which affect, for example, the half-life of the antibody in a patient, effector function and / or immune response. The term antibody also includes artificial or engineered polypeptide constructs comprising at least one antibody-derived antigen binding site.

[0146] Anti-C5 antibody

[0147] The anti-C5 antibodies described herein bind to complement component C5 (e.g., human complement 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 therefrom) suitable for use herein can be produced using methods known in the art. Art-recognized anti-C5 antibodies can also be used. Antibodies that compete with any of these art-recognized antibodies for binding to C5 can also be used.

[0148] Eculizumab (also known as ) is an anti-C5 antibody comprising a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 10 and 11, respectively, or an antigen-binding fragment and variant thereof. Eculizumab is described in PCT / US2007 / 006606, the teachings of which are incorporated herein by reference. In one embodiment, the anti-C5 antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of eculizumab having the sequence shown in SEQ ID NO: 7, and the CDR1, CDR2, and CDR3 domains of the VL region of eculizumab having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 1, 2, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences shown in SEQ ID NO: 7 and SEQ ID NO: 8, respectively.

[0149] Ravolizumab (also known as BNJ441, ALXN 1210, or ) is an anti-C5 antibody comprising a heavy chain and a light chain having the sequences shown in SEQ ID NOs: 14 and 11, respectively, or an antigen-binding fragment or variant thereof. Ravolizumab is described in PCT / US2015 / 019225 and U.S. Patent No. 9,079,949, the teachings of which are incorporated herein by reference. Ravolizumab selectively binds to human complement protein C5, thereby inhibiting its cleavage into C5a and C5b during complement activation. This inhibition prevents the release of the proinflammatory mediator C5a and the formation of the cell lytic pore-forming membrane attack complex (MAC) C5b-9, while retaining the proximal or early components of complement activation (e.g., C3 and C3b) that are critical for microbial opsonization and immune complex clearance.

[0150] In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of Ravolizumab. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of Ravolizumab having the sequence shown in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the VL region of Ravolizumab having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NO: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NO: 4, 5, and 6, respectively. In another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences shown in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

[0151] Another exemplary anti-C5 antibody is antibody BNJ421 comprising heavy and light chains having the sequences shown in SEQ ID NOs: 20 and 11, respectively, or antigen-binding fragments and variants thereof. BNJ421 is described in PCT / US2015 / 019225 and U.S. Pat. No. 9,079,949, the entire teachings of which are hereby incorporated by reference.

[0152] In some embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of BNJ421 having the sequence shown in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the VL region of BNJ421 having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NO: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NO: 4, 5, and 6, respectively. In another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences shown in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

[0153] The exact boundaries of CDRs have been defined differently according to different methods. In some embodiments, the positions of CDRs or framework regions within the light chain or heavy chain variable domain may be as defined by Kabat et al. [(1991) "Sequences of Proteins of Immunological Interest." NIH Publication No. 91-3242, US Department of Health and Human Services, Bethesda, MD]. In this case, the CDR may be referred to as a "Kabat CDR" (e.g., "Kabat LCDR2" or "Kabat HCDR1"). In some embodiments, the positions of CDRs of the light chain or heavy chain variable region may be as defined by Chothia et al. (Nature, 342: 877-83, 1989). Therefore, these regions may be referred to as "Chothia CDRs" (e.g., "Chothia LCDR2" or "Chothia HCDR3"). In some embodiments, the positions of CDRs of the light chain or heavy chain variable region may be as defined by the Kabat-Chothia combined definition. In such embodiments, these regions may be referred to as "combined Kabat-Chothia CDRs" (Thomas, T. et al., Mol. Immunol., 33: 1389-401, 1996).

[0154] Another exemplary anti-C5 antibody is the 7086 antibody described in U.S. Pat. Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see U.S. Pat. Nos. 8,241,628 and 8,883,158). In another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain CDR1, CDR2, and CDR3 domain having the sequences shown in SEQ ID NOs: 21, 22, and 23, respectively, and a light chain CDR1, CDR2, and CDR3 domain having the sequences shown in SEQ ID NOs: 24, 25, and 26, respectively. In another embodiment, the antibody or antigen-binding fragment thereof comprises a VH region of the 7086 antibody having the sequence shown in SEQ ID NO: 27, and a VL region of the 7086 antibody having the sequence shown in SEQ ID NO: 28.

[0155] Another exemplary anti-C5 antibody is the 8110 antibody, also described in U.S. Pat. Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 29, 30, and 31, respectively, and the light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 32, 33, and 34, respectively. In another embodiment, the antibody comprises the VH region of the 8110 antibody having the sequence shown in SEQ ID NO: 35, and the VL region of the 8110 antibody having the sequence shown in SEQ ID NO: 36.

[0156] Another exemplary anti-C5 antibody is the 305LO5 antibody described in US2016 / 0176954A1. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain CDR1, CDR2, and CDR3 domain having the sequences shown in SEQ ID NOs: 37, 38, and 39, respectively, and a light chain CDR1, CDR2, and CDR3 domain having the sequences shown in SEQ ID NOs: 40, 41, and 42, respectively. In another embodiment, the antibody comprises a VH region of the 305LO5 antibody having the sequence shown in SEQ ID NO: 43, and a VL region of the 305LO5 antibody having the sequence shown in SEQ ID NO: 44.

[0157] 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 heavy chain and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises: a heavy chain comprising SEQ ID NO: 45 and a light chain comprising SEQ ID NO: 46.

[0158] Another exemplary anti-C5 antibody is the H4H12166PP antibody described in PCT / US2017 / 037226 and US2017 / 0355757A1. In one embodiment, the antibody comprises the heavy chain and light chain CDRs or variable regions of the H4H12166PP antibody. In another embodiment, the antibody or its antigen-binding fragment 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 its antigen-binding fragment comprises: a heavy chain comprising SEQ ID NO: 49 and a light chain comprising SEQ ID NO: 50.

[0159] In one embodiment, the 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 is switched from an anti-C5 antibody (e.g., eculizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody or H4H12166PP antibody) to another anti-C5 antibody (e.g., ravulizumab) during the course of treatment. In a specific embodiment, the patient is switched from eculizumab to ravulizumab during the course of treatment.

[0160] In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain CDR1 comprising or consisting of the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19). In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain CDR2 comprising or consisting of the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO: 18). In some embodiments, the anti-C5 antibodies described herein comprise: a heavy chain variable region comprising the following amino acid sequence:

[0161]

[0162] In some embodiments, an anti-C5 antibody described herein comprises: a light chain variable region comprising the following amino acid sequence:

[0163]

[0164] In some embodiments, the anti-C5 antibodies described herein may include a variant human Fc constant region that binds to a human neonatal Fc receptor (FcRn) with greater affinity than the native human Fc constant region from which the variant human Fc constant region is derived. The Fc constant region may include, for example, one or more (e.g., two, three, four, five, six, seven, or eight or more) amino acid substitutions relative to the native human Fc constant region from which the variant human Fc constant region is derived. The substitution may increase the binding affinity of an IgG antibody containing a 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 substitutions in the Fc constant region of an antibody increase the affinity of the Fc constant region to FcRn at pH 6.0 (while maintaining the pH dependence of the interaction) are known in the art and are illustrated in the working examples (see, e.g., PCT / US2015 / 019225 and U.S. Pat. No. 9,079,949, the disclosure of each of which is incorporated herein by reference in its entirety).

[0165] Substitutions that enhance the binding affinity of an antibody Fc constant region for FcRn are known in the art and include, for example, (1) M252Y / S254T / T256E triple substitution (Dall'Acqua, W. et al., J Biol. Chem., 281:23514-24, 2006); (2) M428L or T250Q / M428L substitutions (Hinton, P. et al., J Biol. Chem., 279:6213-6, 2004; Hinton, P. et al., J Immunol., 176:346-56, 2006); (3) N434A or T307 / E380A / N434A substitutions (Petkova, S. et al., Int. Immunol., 18:1759-69, 2006). Additional substitution pairs are also contemplated herein, such as P257I / Q311I, P257I / N434H, and D376V / N434H (Datta-Mannan, A. et al., J Biol. Chem., 282: 1709-17, 2007).

[0166] In some embodiments, the variant constant region has a substitution of valine at EU amino acid residue 255. In some embodiments, the variant constant region has a substitution of asparagine at EU amino acid residue 309. In some embodiments, the variant constant region has a substitution of isoleucine at EU amino acid residue 312. In some embodiments, the variant constant region has a substitution at EU amino acid residue 386.

[0167] In some embodiments, the variant Fc constant region comprises no more than 30 (e.g., no more than 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2) amino acid substitutions, insertions or deletions relative to the native constant region from which it is derived. In some embodiments, the 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 a methionine at position 428 and an asparagine at position 434, all with EU numbering. In some embodiments, the variant Fc constant region comprises a 428L / 434S double substitution as described in, eg, US Patent No. 8,088,376.

[0168] In some embodiments, the precise positions of these mutations may be offset from the natural human Fc constant region positions due to antibody engineering. For example, when used in an IgG2 / 4 chimeric Fc, the 428L / 434S double substitution may correspond to 429L and 435S, as found in BNJ441 (Ravolizumab) and in the M429L and N435S variants described in U.S. Pat. No. 9,079,949, the disclosure of which is incorporated herein by reference in its entirety.

[0169] In some embodiments, the variant constant region comprises a substitution at amino acid position 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, ​​384, 385, 386, 387, 389, 424, 428, 433, 434, or 436 (EU numbering) relative to the native human Fc constant region. In some embodiments, the substitution is selected from the group consisting of: methionine to glycine at position 237; alanine to proline at position 238; lysine to serine at position 239; isoleucine to lysine at position 248; alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine to threonine at position 250; phenylalanine, tryptophan, or tyrosine to methionine at position 252; threonine to serine at position 254; glutamic acid to arginine at position 255; Aspartic acid, glutamic acid or glutamine are substituted for threonine; alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine or valine are substituted for proline at position 257; histidine is substituted for glutamic acid at position 258; alanine is substituted for aspartic acid at position 265; phenylalanine is substituted for aspartic acid at position 270; alanine or glutamic acid is substituted for asparagine at position 286; threonine is substituted for histidine at position 289; alanine is substituted for asparagine at position 297; glycine is substituted for serine at position 298; alanine is substituted for valine at position 303 Acid; substitution of alanine for valine at position 305; substitution of alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan or tyrosine for threonine at position 307; substitution of alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine or threonine for valine at position 308; substitution of alanine, aspartic acid, glutamic acid, proline or arginine for leucine or valine at position 309; substitution of alanine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine or threonine for leucine or valine at position 311; substituted for glutamine at position 312 by alanine or histidine; substituted for aspartic acid at position 314 by lysine or arginine; substituted for asparagine at position 315 by alanine or histidine; substituted for lysine at position 317 by alanine; substituted for asparagine at position 325 by glycine; substituted for isoleucine at position 332 by valine; substituted for lysine at position 334 by leucine; substituted for lysine at position 360 by histidine; substituted for aspartic acid at position 376 by alanine; substituted for glutamic acid at position 380 by alanine; substituted for glutamic acid at position 382 by alanine;Substitution of alanine for asparagine or serine at position 384; substitution of aspartic acid or histidine for glycine at position 385; substitution of proline for glutamine at position 386; substitution of glutamic acid for proline at position 387; substitution of alanine or serine for asparagine at position 389; substitution of alanine for serine at position 424; substitution of alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan or tyrosine for methionine at position 428; substitution of lysine for histidine at position 433; substitution of alanine, phenylalanine, histidine, serine, tryptophan or tyrosine for asparagine at position 434; and substitution of histidine for tyrosine or phenylalanine at position 436, all using EU numbering. ;

[0170] Suitable anti-C5 antibodies for use in the methods described herein may 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 for use in the methods described herein may 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.

[0171] In one embodiment, the antibody has an affinity dissociation constant (K) of at least 0.1 (e.g., at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, or 0.975) nM at pH 7.4 and 25°C (and otherwise under physiological conditions). D ) binds to C5. In some embodiments, the K of the anti-C5 antibody or antigen-binding fragment thereof is D No greater than 1 (e.g., no greater than 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2) nM.

[0172] In some embodiments, [(K of the antibody against C5 at pH 6.0, 25°C) D ) / (K of antibody against C5 at pH 7.4, 25°C D)] greater than 21 (e.g., greater than 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500 40, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500 or 8000).

[0173] Methods for determining whether an antibody binds to a protein antigen and / or the affinity of an antibody for a protein antigen are known in the art. For example, the affinity of an antibody for a protein antigen can be detected and quantified using a variety of techniques, such as, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) methods (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ), or enzyme-linked immunosorbent assay (ELISA) (see, e.g., Benny KC Lo (2004) "Antibody Engineering: Methods and Protocols," Humana Press (ISBN: 1588290921); Johne, B. et al., J. Immunol. Meth., 160: 191-8, 1993; U. et al., Ann. Biol. Clin., 51: 19-26, 1993; U. et al., Biotechniques, 11:620-7, 1991). Additional methods for measuring, for example, affinity (eg, dissociation and association constants) are described in the working examples.

[0174] As used herein, the term “k a ” refers to the rate constant for the association of an antibody with an antigen. The term “k d ” refers to the rate constant for the dissociation of an antibody from an antibody / antigen complex. The term “KD” refers to the equilibrium dissociation constant for the antibody-antigen interaction. The equilibrium dissociation constant is derived from the ratio of the kinetic rate constants, K D =k a / k dSuch assays are preferably measured at 25° C. or 37° C. The kinetics of antibody binding to human C5 can be determined, for example, by surface plasmon resonance (SPR) on a BIAcore 3000 instrument at pH 8.0, 7.4, 7.0, 6.5 and 6.0 using an anti-Fc capture method to immobilize the antibody.

[0175] Methods for determining whether a particular antibody described herein inhibits C5 cleavage are known in the art. Inhibition of human complement component C5 can reduce the cytolytic capacity of complement in a subject's body fluid. Such a reduction in the cytolytic capacity of complement present in a body fluid can be measured by methods known in the art, such as by conventional hemolytic assays, such as those described in Kabat and Mayer (eds.), "Experimental Immunochemistry, 2nd ed.," 135-240, Springiield, IL, CC Thomas (1961), pp. 135-139, or conventional variants of such assays, such as chicken erythrocyte hemolysis (Hillmen, P. et al., N. Engl. J. Med., 350: 552-9, 2004). Methods for determining whether a candidate compound inhibits the cleavage of human C5 into forms C5a and C5b are known in the art (Evans, M. et al., Mol. Immunol., 32: 1183-95, 1995). The concentration and / or physiological activity of C5a and C5b in body fluids can be measured, for example, by methods known in the art. For C5b, the hemolytic assay or soluble C5b-9 assay discussed herein can be used. Other assays known in the art can also be used. Using these or other suitable assays, candidate agents capable of inhibiting human complement component C5 can be screened.

[0176] Immunological techniques (such as, but not limited to, ELISA) can be used to measure the protein concentration of C5 and / or its cleavage products to determine the ability of anti-C5 antibodies or antigen-binding fragments thereof to inhibit the conversion of C5 into biologically active products. In some embodiments, C5a generation is measured. In some embodiments, C5b-9 neo-epitope-specific antibodies are used to detect the formation of terminal complement.

[0177] Hemolysis assays can be used to determine the inhibitory activity of anti-C5 antibodies or antigen-binding fragments thereof on complement activation. To determine the effect of anti-C5 antibodies or antigen-binding fragments thereof on hemolysis mediated by the classical complement pathway in an in vitro serum test solution, for example, sheep erythrocytes coated with hemolysin or chicken erythrocytes sensitized with anti-chicken erythrocyte antibodies are used as target cells. The percentage of lysis is normalized by considering 100% lysis equal to the lysis that occurs in the absence of the inhibitor. In some embodiments, the classical complement pathway is activated by human IgM antibodies, for example, as in Classical Pathway Complement Kit ( COMPL CP310, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody or antigen-binding fragment thereof in the presence of human IgM antibodies. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorescent substrate and measuring the absorbance at an appropriate wavelength. As a control, the test serum is incubated in the absence of an anti-C5 antibody or antigen-binding fragment thereof. In some embodiments, the test serum is a C5-deficient serum reconstituted with a C5 polypeptide.

[0178] To determine the effect of anti-C5 antibodies or antigen-binding fragments thereof on alternative pathway-mediated hemolysis, unsensitized rabbit or 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 100% lysis equal to lysis that occurs in the absence of inhibitor. In some embodiments, the alternative complement pathway is activated by lipopolysaccharide molecules, e.g., as in Alternative Pathway Complement Kit ( COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with anti-C5 antibody or antigen-binding fragment thereof in the presence of lipopolysaccharide. The amount of C5b-9 produced is measured by contacting the mixture with enzyme-conjugated anti-C5b-9 antibody and fluorescent substrate and measuring fluorescence at the appropriate wavelength. As a control, the test serum is incubated in the absence of anti-C5 antibody or antigen-binding fragment thereof.

[0179] In some embodiments, C5 activity or its inhibition is quantified using CH50eq analysis. CH50eq analysis is a method for measuring total classical complement activity in serum. This test is a lysis analysis that uses antibody-sensitized erythrocytes as activators of the classical complement pathway and dilutes the test serum in various ways to determine the amount required to produce 50% lysis (CH50). For example, a spectrophotometer can be used to determine the percentage of hemolysis. CH50eq analysis provides an indirect measurement of the formation of the terminal complement complex (TCC) because the TCC itself is directly responsible for the measured hemolysis. In short, in order to activate the classical complement pathway, an undiluted serum sample (e.g., a recombinant human serum sample) is added to a microassay well containing antibody-sensitized erythrocytes to produce TCC. 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 wells are washed and a detection reagent is added to each well, which can detectably label and recognize the bound TCC. The detectable label can be, for example, a fluorescent label or an enzyme label. The results of the analysis are expressed in CH50 unit equivalents per milliliter (CH50 U Eq / mL).

[0180] Inhibition, e.g., inhibition associated with terminal complement activity, includes at least a 5% decrease in terminal complement activity (e.g., at least a 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%) compared to the effect of a control antibody (or antigen-binding fragment thereof) under similar conditions and at equimolar concentrations, e.g., in a hemolytic assay or a CH50eq assay. As used herein, substantial inhibition refers to an inhibition of a given activity (e.g., terminal complement activity) of at least 40% (e.g., at least 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or more). In some embodiments, the anti-C5 antibodies described herein contain one or more amino acid substitutions relative to the CDRs of eculizumab (i.e., SEQ ID NOs: 1-6), but still 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 inhibition activity of eculizumab in a hemolytic assay or a CH50eq assay.

[0181] The anti-C5 antibodies described herein have a serum half-life of at least 20 (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 humans. In another embodiment, the anti-C5 antibodies described herein have a serum half-life of at least 40 days in humans. In another embodiment, the anti-C5 antibodies described herein have a serum half-life of about 43 days in humans. In another embodiment, the anti-C5 antibodies described herein have a serum half-life of between 39 and 48 days in humans. Methods for measuring the serum half-life of antibodies are known in the art. In some embodiments, an anti-C5 antibody or antigen-binding fragment thereof described herein has a serum half-life that is at least 20% (e.g., at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 400%, 500%) longer than the serum half-life of eculizumab, e.g., as measured in one of the mouse model systems described in the working examples (e.g., a C5-deficient / NOD / scid mouse or a hFcRn transgenic mouse model system).

[0182] In one embodiment, the antibody competes with the antibodies described herein for binding to the same epitope on C5, and / or binds to the same epitope on C5 as the antibodies described herein. The term "binding to the same epitope" with respect to two or more antibodies refers to the binding of the antibodies to the same amino acid residue fragment, as determined by a given method. Techniques for determining whether an antibody binds to the "same epitope on C5" as the antibodies described herein include, for example, epitope mapping methods, such as x-ray analysis of antigen: antibody complex crystals, which provides epitope atomic resolution and hydrogen / deuterium exchange mass spectrometry (HDX-MS). Other methods monitor the binding of antibodies to peptide antigen fragments or mutant variants of antigens, in which loss of binding due to modification of amino acid residues within the antigen sequence is generally considered to be an indication of epitope components. Computational combinatorial methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity separate specific short peptides from a combinatorial phage display peptide library. Antibodies with identical VH and VL or identical CDR1, 2, and 3 sequences are expected to bind to the same epitope.

[0183] An antibody that "competes with another antibody for binding to a target" refers to an antibody that inhibits (partially or completely) the binding of another antibody to a target. Whether two antibodies compete with each other for binding to a target, that is, whether and to what extent an antibody inhibits the binding of another antibody to a target, can be determined using known competition experiments. In some embodiments, an antibody competes with another antibody and inhibits the binding of another antibody to a target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%. The level of inhibition or competition may vary, depending on which antibody is a "blocking antibody" (i.e., a cold antibody that is first cultivated with the target). Competing antibodies may bind to, for example, the same epitope, overlapping epitopes, or adjacent epitopes (e.g., demonstrated by steric hindrance).

[0184] The anti-C5 antibodies or antigen-binding fragments thereof described herein for use in the methods described herein can be produced using a variety of art-recognized techniques. Monoclonal antibodies can be obtained by various techniques familiar to those skilled in the art. Briefly, spleen cells from an animal immunized with the desired antigen are immortalized, typically by fusion with myeloma cells ( G. and Milstein, C., Eur. J. Immunol., 6:511-9, 1976). Alternative methods of immortalization include transformation with Epstein Barr Virus, oncogenes or retroviruses, or other methods well known in the art. Colonies generated by single immortalized cells are screened for the production of antibodies with the desired specificity and affinity for the antigen, and the production of monoclonal antibodies produced by such cells can be increased by various techniques, including injection into the peritoneal cavity of vertebrates. Alternatively, DNA sequences encoding monoclonal antibodies or binding fragments thereof can be isolated by screening DNA libraries from human B cells (Huse, W. et al., Science, 246:1275-81, 1989).

[0185] Composition

[0186] Pharmaceutical compositions comprising ravulizumab alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier are provided. Pharmaceutical compositions comprising ravulizumab provided herein are used, for example, to diagnose, detect, or monitor a condition, to prevent, treat, control, or ameliorate a condition or one or more symptoms thereof, and / or for use in research. Formulations of pharmaceutical compositions alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier are known in the art.

[0187] Additionally, provided herein are compositions comprising an anti-C5 antibody or antigen-binding fragment thereof for use in the treatment methods described herein, wherein a patient is switched from one anti-C5 antibody (e.g., eculizumab) to another anti-C5 antibody (e.g., ravulizumab) during the course of treatment.

[0188] The composition can be formulated as a pharmaceutical solution, for example, for administration to a subject to treat or prevent MG. The composition can include a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to and includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The composition can include a pharmaceutically acceptable salt, such as an acid addition salt or a base addition salt, a sugar, a carbohydrate, a polyol, and / or a tonicity adjusting agent.

[0189] The composition can be formulated according to known methods (Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) "Pharmaceutical Do sage Forms and Drug Delivery Systems," 7th edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) "Handbook of Pharmaceutical Excipients American Pharmaceutical Association," 3rd edition (ISBN: 091733096X)). In some embodiments, the composition can be formulated, for example, as a buffer solution of 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 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 year, 1 year, 2 years, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year ... month, 1 month, 10 months, 10 months, 11 months, 10 months, 10 months, 1 / 2 years or 2 years). Thus, in some embodiments, the compositions described herein are stable for at least 1 year at 2-8°C (eg, 4°C).

[0190] Pharmaceutical compositions can be in various forms. These forms include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersants or hot suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends in part on the expected mode of administration and therapeutic application. Compositions comprising compositions intended for systemic or local delivery can be, for example, in the form of injectable or infusible solutions. Compositions can be formulated to be administered by parenteral means (e.g., intravenous, subcutaneous, intraperitoneal or intramuscular injection). As used herein, "parenteral administration," "parenteral administration," and other grammatically equivalent phrases refer to modes of administration other than enteral and topical administration, usually by injection, including but not limited to intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intrajugular, and intrasternal injection and infusion. In one embodiment, the antibody is formulated for intravenous administration.

[0191] An exemplary non-limiting range of a therapeutically or prophylactically effective amount of ravulizumab or other anti-C5 antibodies (e.g., eculizumab, BNJ 421, 7086, 8110, SKY59, and H4H12166PP) provided herein is 600 to 5000 mg, for example 900 to 2000 mg. It should be noted that dosage values ​​may vary with the type and severity of the condition to be alleviated. It should be further understood that for any particular subject, a specific dosage regimen may be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed method.

[0192] Combination therapy

[0193] The anti-C5 antibodies provided herein can also be administered with one or more additional drugs or therapeutic agents for the treatment of MG. The additional agent can be, for example, a therapeutic agent recognized in the art for the treatment of MG. The combination can also include more than one additional agent, such as two or three additional agents. In various embodiments, the binding agent is administered 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]).

[0194] method

[0195] Provided herein are methods for treating a complement-associated disease (e.g., MG, e.g., gMG, e.g., gMG when the patient is anti-AChR antibody positive) in a human patient, comprising administering to the patient an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered (or for administration) according to a specific clinical dosing regimen (i.e., at a specific dose and according to a specific dosing schedule).

[0196] In some embodiments, MG comprises gMG. In some embodiments, gMG is characterized by comprising a subject or patient who is positive for autoantibodies that bind to AChR, who continues to exhibit significant systemic weakness or bulbar signs and symptoms of MG while receiving current standard of 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.

[0197] In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered once on day 1 of the administration cycle, once on day 15 of the administration cycle, and once every eight weeks thereafter. In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered every eight weeks after the administration cycle for an extended period of up to two years (e.g., at a dose of 3000 mg, 3300 mg, or 3600 mg).

[0198] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered for one or more administration cycles. In one embodiment, the administration cycle is a total of 26 weeks of treatment. In another embodiment, the treatment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 cycles. In another embodiment, the treatment continues for the lifetime of the human patient.

[0199] In another embodiment, the patient is switched from receiving one C5 inhibitor to a different C5 inhibitor during the course of treatment. Different anti-C5 antibodies can be administered during individual treatment periods. For example, in one embodiment, a method of treating a human patient with a complement-associated disorder (e.g., MG) being treated with eculizumab is provided, the method comprising stopping 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-associated disorder being treated with ravulizumab is provided, the method comprising stopping treatment with ravulizumab and switching the patient to treatment with an alternative complement inhibitor.

[0200] Exemplary alternative complement inhibitors include, but are not limited to, antibodies or antigen-binding fragments thereof, small molecules, polypeptides, polypeptide analogs, peptide mimetics, siRNAs, and aptamers. In one embodiment, the alternative complement inhibitor inhibits one or more of the following: complement components C1, C2, C3, C4, C5, C6, C7, C8, C9, factor D, factor B, properdin, MBL, MASP-1, MASP-2, or biologically active fragments thereof. In another embodiment, the alternative complement inhibitor inhibits anaphylactic activity associated with C5a and / or assembly of the membrane attack complex associated with C5b. In another embodiment, the alternative complement inhibitor is selected from CR1, LEX-CR1, MCP, DAF, CD59, factor H, cobra venom factor, FUT-175, compstatin, and K76 COOH.

[0201] Exemplary alternative anti-C5 antibodies include, but are not limited to, (i) eculizumab, (ii) an antibody or antigen-binding fragment thereof comprising: a heavy chain CDR1, CDR2, and CDR3 domain comprising SEQ ID NOs: 21, 22, and 23, respectively, and a light chain CDR1, CDR2, and CDR3 domain comprising SEQ ID NOs: 24, 25, and 26, respectively, (iii) an antibody or antigen-binding fragment thereof comprising: a heavy chain variable region comprising SEQ ID NO: 27 and a light chain variable region comprising SEQ ID NO: 28, (iv) an antibody or antigen-binding fragment thereof comprising: a heavy chain CDR1, CDR2, and CDR3 domain comprising SEQ ID NOs: 29, 30, and 31, respectively, and a light chain CDR1, CDR2, and CDR3 domain comprising SEQ ID NOs: 32, 33, and 34, respectively, (v) an antibody or antigen-binding fragment thereof comprising: a heavy chain variable region comprising SEQ ID NO: 35 and a light chain variable region comprising SEQ ID NO: NO: 36, (vi) an antibody or antigen-binding fragment thereof comprising: a heavy chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 37, 38 and 39, respectively, and a light chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 40, 41 and 42, respectively, (vii) an antibody or antigen-binding fragment thereof comprising: a heavy chain variable region comprising SEQ ID NO: 43 and a light chain variable region comprising SEQ ID NO: 44; and (viii) an antibody or antigen-binding fragment thereof comprising: a heavy chain comprising SEQ ID NO: 45 and a light chain comprising SEQ ID NO: 46.

[0202] In another embodiment, the patient is treated with Ravolizumab and then switched to treatment with 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, H4H12166PP antibody or eculizumab. In another embodiment, the patient is switched from an anti-C5 antibody (e.g., eculizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody or H4H12166PP antibody) to another anti-C5 antibody (e.g., Ravolizumab) during the course of treatment. In a specific embodiment, the patient is switched from eculizumab to Ravolizumab during the course of treatment.

[0203] In one embodiment, the anti-C5 antibody is administered (or for administration) according to a specific clinical dosing regimen (e.g., at a specific dose and or according to a specific dosing schedule). In one embodiment, the anti-C5 antibody is administered at a fixed dose that is independent of the patient's weight. As used herein, the terms "fixed dose," "flat dose," and "flat-fixed dose" are used interchangeably and refer to a dose that is administered to a patient without regard to the patient's weight or body surface area (BSA). Therefore, the fixed dose is not provided as a mg / kg dose, but rather as an absolute amount of the anti-C5 antibody or antigen-binding fragment thereof.

[0204] In one embodiment, the anti-C5 antibody is administered at 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg g, 975mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400mg, 2500mg, 2600 mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 44 00mg, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000mg, 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6100mg, 6200mg, 6300mg, 6400mg, 6500mg, 6600mg, 6700mg, 6800mg, 6900mg, 7000mg, 7100mg, 7200mg, 7300mg, 7400mg, 7500mg, 7600mg, 7700mg, 7800mg, 7900m The fixed dose of 1000 mg, 1000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg, 10900 mg or 11000 mg can be administered without regard to the patient's weight.

[0205] In another embodiment, the dosage of the anti-C5 antibody is based on the patient's weight.In another embodiment, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925mg, 950mg, 975mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400mg, 25 00mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg, 4200mg, 4 300mg, 4400mg, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000mg, 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6100mg, 6200mg, 6300mg, 6400mg, 6500mg, 6600mg, 6700mg, 6800mg, 6900mg, 7000mg, 7100mg, 7200mg, 7300mg, 7400mg, 7500mg, 7600mg, 7700mg, 7800mg , 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 of an anti-C5 antibody or an antigen-binding fragment thereof.

[0206] In another embodiment, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg are administered to patients weighing ≥60 to <100 kg. , 925mg, 950mg, 975mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400mg, 2 500mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 4400mg, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000mg, 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg , 6100mg, 6200mg, 6300mg, 6400mg, 6500mg, 6600mg, 6700mg, 6800mg, 6900mg, 7000mg, 7100mg, 7200mg, 7300mg, 7400mg, 7500mg, 7600mg, 7700mg, 7800m g, 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 of an anti-C5 antibody or an antigen-binding fragment thereof.

[0207] In one embodiment, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg are administered to patients weighing ≥ 100 kg. , 925mg, 950mg, 975mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100mg, 2200mg, 2300mg, 2400mg , 2500mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg, 420 0mg, 4300mg, 4400mg, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000mg, 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg , 6000mg, 6100mg, 6200mg, 6300mg, 6400mg, 6500mg, 6600mg, 6700mg, 6800mg, 6900mg, 7000mg, 7100mg, 7200mg, 7300mg, 7400mg, 7500mg, 7600mg, 770 10400mg, 10500mg, 10600mg, 10700mg, 10800mg, 10900mg or 11000mg.In some embodiments, dosage regimens are adjusted to provide the optimum desired response (eg, an effective response).

[0208] In another embodiment, the anti-C5 antibody is administered at a milligram / kilogram (mg / kg) dose. In one embodiment, the anti-C5 antibody is administered at a milligram / kilogram (mg / kg) dose. In one embodiment, the anti-C5 antibody is administered at a milligram / kilogram (mg / kg) dose. kg, 6.0mg / kg, 6.25mg / kg, 6.50mg / kg, 6.75mg / kg, 7.0mg / kg, 7.25mg / kg, 7.50mg / kg, 7.75mg / kg, 8.0mg / kg, 8.25mg / kg, 8.50mg / kg, 8.75mg / kg, 9.0mg / kg, 9.25mg / kg, 9.50mg / kg, 9.75mg / kg, 10.0mg / kg, 11.25mg / kg, 11.50mg / kg, 11.75mg / kg, 12.0mg / kg, 12.25mg / kg, 12.50mg / kg, 12.75m g / kg, 13.0mg / kg, 13.25mg / kg, 13.50mg / kg, 13.75mg / kg, 14.0mg / kg, 14.25mg / kg, 14.50mg / kg, 14.75mg / kg, 15.0mg / kg, 15.25mg / kg, 15.50mg / kg, 15.75mg / kg, 16.0mg / kg, 16.25mg / kg, 16.50mg / kg, 16.75mg / kg, 17.0mg / kg, 17.25mg / kg, 17.50mg / kg, 17.75mg / kg, 18.0mg / kg, 18.25mg / kg , 18.50mg / kg, 18.75mg / kg, 19.0mg / kg, 19.25mg / kg, 19.50mg / kg, 19.75mg / kg, 20.0mg / kg, 20.25mg / kg, 20.50mg / kg, 20.75mg / kg, 21.0mg / kg, 2 1.25mg / kg, 21.50mg / kg, 21.75mg / kg, 22.0mg / kg, 22.25mg / kg, 22.50mg / kg, 22.75mg / kg, 23.0mg / kg, 23.25mg / kg, 23.50mg / kg, 23.75mg / kg, 24.The anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of 0 mg / kg, 24.25 mg / kg, 24.50 mg / kg, 24.75 mg / kg or 25.0 mg / kg.

[0209] 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 every day. In another embodiment, the anti-C5 antibody is administered twice a day. In another embodiment, the anti-C5 antibody is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks. In another embodiment, the anti-C5 antibody is administered at a loading dose on day 1, followed by a different maintenance dose on day 15 and every eight weeks thereafter.

[0210] In another embodiment, in order to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains the minimum free C5 concentration. In one embodiment, 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 another embodiment, the anti-C5 antibody 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.

[0211] In some embodiments, patients treated according to the methods described herein have been vaccinated against meningococcal infection within three years prior to or at the time of starting the study drug. In one embodiment, patients who begin treatment less than two weeks after receiving a meningococcal vaccine receive appropriate prophylactic antibiotic therapy until two weeks after vaccination. In another embodiment, patients treated according to the methods described herein are vaccinated against meningococcal serotypes A, C, Y, W135, and / or B.

[0212] result

[0213] In some embodiments, treatment of MG includes improvement or amelioration of one or more symptoms associated with MG. Symptoms associated with MG include muscle weakness and fatigability. Muscles primarily affected by MG include those that control eye and eyelid movement, facial expression, chewing, speaking, swallowing, breathing, neck movement, and limb movement.

[0214] In some embodiments, treatment of MG includes improvement in clinical markers of MG progression. These markers include MG-ADL score, QMG score of disease severity, MGC, NIF, forced vital capacity, MGFA post-intervention status, and other quality of life measures. In some embodiments, MG-ADL is the primary score used to measure improvement in MG.

[0215] MG-ADL is an 8-point questionnaire that focuses on the relevant symptoms and functional performance of activities of daily living (ADL) in MG subjects (Table 3). The 8 items of MG-ADL are derived from the symptom-based components of the original 13-item QMG to assess disability related to the effects of MG secondary to eye (2 items), medulla oblongata (3 items), respiratory (1 item) and gross motor or limb (2 items) injuries. In this functional status instrument, each response is graded from 0 (normal) to 3 (most severe). The total MG-ADL score ranges from 0-24. In one embodiment, a clinically meaningful improvement in a patient's MG-ADL is, for example, a score reduction of 3 points or more after 26 weeks of treatment.

[0216] The current QMG scoring system includes 13 items: eye (2 items), face (1 item), medulla (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item); each is graded from 0 to 3, with 3 being the most severe (Table 4). The total QMG score ranges from 0 to 39. The QMG scoring system is an objective assessment of MG treatment and is based on quantitative testing of the sentinel muscle groups. The MGFA working group has recommended that the QMG score be used in prospective studies of MG treatment (Benatar, M. et al., Muscle Nerve, 45:909-17, 2012). In one embodiment, a clinically meaningful improvement in a patient's QMG is, for example, a decrease in the score of 5 points or more after 26 weeks of treatment.

[0217] Table 3: MG-ADL profile

[0218]

[0219]

[0220] Table 4: QMG scores for disease severity

[0221]

[0222] The MGC is a validated assessment tool for measuring the clinical status of subjects with MG (16). The MGC assesses 10 important areas of functioning most commonly affected by MG, and the scale is weighted for clinical significance for incorporation of subject-reported outcomes (Table 5; Burns, T. et al., Muscle Nerve, 54: 1015-22, 2016). The MGC will be performed at Screening, Day 1, Weeks 1-4, Week 8, Week 12, Week 16, Week 20, and Week 26 or ET (Visits 1-6, 8, 10, 12, 14, and 17 or ET). In one embodiment, a clinically meaningful improvement in a patient's MGC is, for example, a decrease in score of 3 points or more after 26 weeks of treatment.

[0223] Table 5: MG comprehensive scale

[0224]

[0225] The revised 15-item Myasthenia Gravis Quality of Life Inventory (MG-QOL 15r) is a health-related QoL assessment tool specifically designed for patients with MG (Table 6). The MG-QOL 15r is designed to provide information about patients' perceptions of impairment and disability, determine the degree of tolerance of disease manifestations, and is easy to administer and interpret. The MG-QOL 15r is completed by patients. Higher scores indicate greater levels of MG-related functional impairment and greater dissatisfaction with MG-related functional impairment. A clinically meaningful improvement in a patient's MG-QOL 15 is a decrease in the score after 26 weeks of treatment.

[0226] Table 6: Revised MG-QOL15r scale

[0227]

[0228] NeuroQOL fatigue is a reliable and validated brief 19-item fatigue survey completed by subjects or patients. Higher scores indicate more severe fatigue and greater impact of MG on activities (Table 7; Gershon, R. et al., Qual. Life Res., 21: 475-86, 2012). Clinically meaningful improvements in patients' NeuroQOL fatigue scores were reflected in the reduction in scores after 26 weeks of treatment.

[0229] Table 7: Neurological QOL fatigue

[0230]

[0231]

[0232] The European Quality of Life-5L (EQ-5D-5L) is a self-assessed health-related QoL questionnaire ( Figure 3A , Figure 3B and Figure 3C EQ-5D-5L basically consists of 2 pages: EQ-5D descriptive scale ( Figure 3B ) system and EQ Visual Analogue Scale (EQ VAS) ( Figure 3C ). The scale measures QoL on a 5-component scale, including mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. Each level is rated on a scale describing the severity of problems in the domain (e.g., I have no problems walking, slight problems, moderate problems, severe problems, or cannot walk). The patient is asked to indicate his / her health status by checking the box next to the most appropriate statement in each of the five scales. This decision produces a 1-digit number representing the level selected for the dimension. The numbers for the five dimensions can be combined into a 5-digit number describing the patient's health status. A clinically meaningful improvement in the patient's EQ 5D is reflected as a decrease in the score in each category after 26 weeks of treatment. This tool also has an overall health scale (EQ VAS), in which the rater selects a number between 1 and 100 to describe their health status, with 100 being the best health status imaginable. The EQ VAS records the patient's self-rated health status on a longitudinal visual analog scale, with endpoints labeled 'the best health status you can imagine' and 'the worst health status you can imagine'. The VAS can be used as a quantitative measure of health that reflects the patient's own judgment. Clinically meaningful improvement in the patient's EQ VAS was reflected in an increase in score after 26 weeks of treatment. The correlation between EQ-5D-5L and the dimensions of the World Health Organization 5 Health Questionnaire demonstrated convergent validity, (r=0.43, p<0.001) (see, Janssen, M. et al., Qual. Life Res., 22:1717-27, 2013). The EQ-5D-5L method is reliable, with an average test-retest reliability of 0.78 and 0.73 between-group coefficients (Brooks, R., Health Policy, 37:53-72, 1996; Chaudhury, C. et al., Biochemistry, 45:4983-90, 2006).

[0233] Subjects with increasing severity of MG may develop potentially fatal respiratory complications, including severe respiratory muscle weakness. Monitor respiratory function closely for evidence of respiratory failure in subjects with MG, and recommend ventilator support if serial measurements of forced vital capacity (FVC) or NIF continue to decrease, loss of upper airway integrity (difficulty handling oral secretions, swallowing, or speaking), or in the presence of respiratory failure. Perform FVC as one of the tests in the QMG. Perform NIF using a NIF meter.

[0234] The MGFA post-intervention status (MGFA-PIS) was used to assess MG clinical status. Changes in the status categories of improved, unchanged, worse, deteriorated, and death as well as minimal manifestation (MM) of MG can be assessed (Table 8).

[0235] Table 8: MGFA-PIS

[0236]

[0237] Patients administered ravulizumab exhibit reduced MG-ADL. In some embodiments, the subject has an initial MG-ADL score greater than 6. In some embodiments, the subject has an initial MG-ADL score greater than 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. In some embodiments, after one course of treatment with ravulizumab, the subject's MG-ADL score is reduced to less than 6. In some embodiments, after treatment with ravulizumab, the MG-ADL score is reduced 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. In some embodiments, after one course of treatment with ravulizumab, the patient's MG-ADL score is reduced by at least 1 point. In some embodiments, after one course of treatment with ravulizumab, the patient's MG-ADL is reduced by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 points.

[0238] According to some embodiments, the course of treatment with ravulizumab lasts 26 weeks. According to some embodiments, the course of treatment lasts 26-52, 26-78, 26-104, 26-130, 26-156, 26-182, 26-208 weeks or longer. In some embodiments, the course of treatment lasts more than 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 78, 104, 130, 156, or 182 weeks. According to some embodiments, the course of treatment lasts for more than 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 years, or more. In some embodiments, the course of treatment lasts for the rest of the subject's life.

[0239] According to some embodiments, during the course of treatment, one or more symptoms or scores associated with MG improve during the course of treatment and remain at the improved level throughout the course of treatment. For example, MG-ADL can improve after 26 weeks of treatment with a therapeutic antibody that specifically binds C5, and then remain at the improved level during the treatment period, i.e., 52 weeks of treatment with a therapeutic antibody that specifically binds C5. An example of a therapeutic antibody that binds C5 is Ravolizumab.

[0240] In some embodiments, the first sign of improvement occurs at week 26 of treatment with a therapeutic antibody that specifically binds C5. According to some embodiments, the first sign of improvement occurs 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 sign of improvement occurs 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.

[0241] In some embodiments, MG includes refractory gMG. In some embodiments, refractory gMG is characterized by including subjects or patients who are positive for autoantibodies that bind to AChRs, who continue to exhibit significant systemic weakness or bulbar signs and symptoms of MG while receiving current standard of care for myasthenia gravis, such as cholinesterase inhibitor therapy and IST, or who require long-term plasma exchange or long-term IVIg to maintain clinical stability. In some embodiments, refractory gMG is characterized by including subjects or patients who continue to exhibit significant systemic weakness or bulbar signs and symptoms of MG while receiving current standard of care for myasthenia gravis, such as cholinesterase inhibitor therapy and IST, or who require long-term plasma exchange or long-term IVIg to maintain clinical stability.

[0242] Kits and Unit Dosage Forms

[0243] Also provided herein are kits comprising a therapeutically effective amount of a pharmaceutical composition suitable for use in the aforementioned methods, the pharmaceutical composition comprising an anti-C5 antibody or antigen-binding fragment thereof, such as Ravolizumab, and a pharmaceutically acceptable carrier. The kit may also optionally include instructions, such as an administration schedule, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient suffering from MG. The kit may also include a syringe.

[0244] The kit may optionally include multiple packages of single-dose pharmaceutical compositions, each package containing an effective amount of an anti-C5 antibody or antigen-binding fragment thereof for a single administration according to the methods provided above. The kit may also include an instrument or device required for administering the pharmaceutical composition. The kit may provide one or more pre-filled syringes containing a certain amount of an anti-C5 antibody or antigen-binding fragment thereof.

[0245] The following examples are illustrative only and should not be construed as limiting the scope of the present disclosure in any way, because after reading the present disclosure, many variations and equivalents will become apparent to those skilled in the art. The contents of all references, Genbank entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.

[0246] Example

[0247] Example 1: A Phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety and efficacy of ravulizumab in complement inhibitor-naïve adult patients with generalized myasthenia gravis.

[0248] A Phase 3, randomized, double-blind, placebo-controlled, multicenter study was conducted to evaluate the safety and efficacy of ravulizumab administered by intravenous (IV) infusion to adult patients with gMG. A schematic diagram of the ALXN1210-MG-306 study is shown in Figure 1 middle.

[0249] 1. Research principles

[0250] Ravolizumab specifically binds to the human terminal complement component (C5) with high affinity, inhibits the enzymatic cleavage of C5, and thereby prevents the generation of the pro-inflammatory / pro-thrombotic complement activation product C5a and the cytolytic and pro-inflammatory / pro-thrombotic membrane attack complex C5b-9, which are responsible for the antibody-mediated NMJ disruption, loss of acetylcholine receptors, and failure of neuromuscular transmission associated with gMG. Approved for the treatment of, e.g., gMG.

[0251] Like eculizumab, ravulizumab also provides essentially immediate and complete C5 inhibition, but ravulizumab further provides sustained complement inhibition throughout the extended dosing interval; it was specifically designed (and subsequently demonstrated) to have an increased half-life relative to eculizumab. As a result, ravulizumab requires less frequent infusions (every 8 weeks [q8w]) than eculizumab (once every 2 weeks [q2w]). Given that gMG is a chronic disease with a significant treatment burden, the relative convenience of the ravulizumab dosing regimen is likely to increase patient satisfaction and treatment adherence, and ultimately lead to improved health outcomes.

[0252] Ravolizumab has an enhanced pharmacokinetic (PK) / pharmacodynamic profile with fewer PK troughs than eculizumab, potentially improving treatment efficacy while maintaining a safety profile similar to eculizumab. The q8w dosing schedule minimizes the risk of incomplete complement inhibition. The infusion frequency is relatively low (6 infusions per year) ( Figure 2 ), which offers the potential to improve quality of life (QoL) by reducing missed work or school days, better treatment compliance, and improved accessibility. Ravolizumab offers convenient dosing and immediate onset of action, with potent and complete terminal complement inhibition at the end of the first infusion. The dosing regimen of Ravolizumab has been optimized to reduce exposure differences across the adult weight range by utilizing a weight-based dosing pattern that provides immediate, complete, and sustained C5 inhibition throughout the dosing interval. Thus, Ravolizumab minimizes the risk of inflammation, including C5a recruitment and inflammatory cell activation, as well as direct MAC complex-induced motor nerve endplate damage (Kusner, L et al., Expert Rev. Clin. Immunol., 4: 43-52, 2008).

[0253] 2. Risk-return assessment

[0254] Ravolizumab offers patients and physicians the option of less frequent dosing, which increases access to care for patients who may not have started eculizumab treatment, who may have discontinued eculizumab due to dosing frequency, or who are currently receiving eculizumab every 2 weeks.

[0255] Neisseria meningitidis

[0256] Increased susceptibility to infection caused by Neisseria meningitidis (N. meningitidis) is a known risk associated with complement inhibition. The main risk associated with ravulizumab is the risk of meningococcal infection. As described herein, specific risk mitigation measures have been developed to address this risk.

[0257] Immunogenicity

[0258] Administration of any therapeutic protein, including ravulizumab, may induce an immunogenic response, possibly leading to anti-drug antibodies (ADA). The range of potential clinical consequences may include severe hypersensitivity reactions and reduced efficacy (PK and / or PD neutralization) due to the development of neutralizing ADA (Casadevall, N. et al., N. Engl. J. Med., 346:469-75, 2002; Li, J. et al., Blood, 98:3241-8, 2001).

[0259] Among 261 patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with ravulizumab in the ravulizumab IV clinical study, 1 patient developed treatment-emergent ADA. In study ALXN1210-HV-104, treatment-emergent ADA were observed in 3 healthy subjects treated with ravulizumab subcutaneously (SC) and 1 healthy subject treated with ravulizumab IV. All ADA positive titer values ​​were low and eculizumab cross-reactivity was negative. Immunogenicity had no apparent effect on the PK or PD of ravulizumab.

[0260] Immunogenicity monitoring for this study was performed as described in Tables 10 and 11 and as described elsewhere herein.

[0261] Local and systemic reactions

[0262] The protein treatment of IV administration has the potential risk of causing local (infusion site reaction) and systemic reaction (infusion-related reaction).Infusion site reaction is those reactions located at the IV administration site, and may include reactions such as erythema, itching and bruises.Infusion-related reactions are those reactions that are systemic in nature, and may be immune or non-immune mediated reactions, which usually occur within a few hours after administration.Immune-mediated reactions may include allergic reactions (e.g., allergic reactions (anaphylaxis)), while non-immune mediated reactions are non-specific (e.g., headache, dizziness, nausea).As described herein, monitoring of these reactions is carried out as part of the routine safety assessment of this study.

[0263] 3. Target

[0264] The primary objective of the study was to assess the efficacy of ravulizumab compared with placebo in the treatment of gMG based on improvement in the MG-ADL profile. The secondary objective of the study was to assess the efficacy of ravulizumab compared with placebo in the treatment of gMG based on improvement in the QMG total score.

[0265] The exploratory objectives of this study were to (1) evaluate the PK / PD and immunogenicity of ravulizumab in the treatment of gMG throughout the study, (2) assess the efficacy of ravulizumab compared with placebo in the treatment of gMG based on the incidence of all-cause hospitalization or clinical worsening, (3) assess the efficacy of ravulizumab compared with placebo in the treatment of gMG based on improvements in quality of life measures, and (4) assess the efficacy of ravulizumab in the treatment of gMG based on other efficacy endpoints throughout the study.

[0266] The safety objective of this study was to characterize the overall safety of ravulizumab in the treatment of gMG.

[0267] 4. end

[0268] The primary efficacy endpoint of the study was the change from baseline in the MG-ADL total score at week 26 of the randomized controlled period.

[0269] The secondary efficacy endpoint of the study was the change from baseline in the QMG total score at Week 26.

[0270] Exploratory efficacy endpoints of the study include the following:

[0271] Changes in serum ravulizumab concentrations over time;

[0272] Changes in serum C5 concentration over time;

[0273] The incidence of treatment-emergent anti-drug antibodies over time;

[0274] The incidence of all-cause hospitalization or clinical deterioration during the 26-week randomized controlled period;

[0275] Change from baseline in the revised 15-component Myasthenia Gravis Quality of Life (MG-QOL 15r) score at Week 26;

[0276] Change from baseline in neurological QOL fatigue scores at week 26;

[0277] Improvement of at least 3 points in the MG-ADL total score at week 26 compared with baseline;

[0278] An improvement of at least 5 points in the QMG total score at week 26 compared with baseline;

[0279] Change from baseline in the Myasthenia Gravis Composite (MGC) score at Week 26;

[0280] Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) at week 26;

[0281] Change from baseline in European quality of life (EQ-5D-5L) at Week 26.

[0282] Safety endpoints for this study were (1) the incidence of adverse events and serious adverse events over time and (2) changes from baseline in vital signs and laboratory assessments.

[0283] The objectives and endpoints of the study are summarized in Table 9 of this article.

[0284] Table 9: Objectives and endpoints of Study ALXN1210-MG-306

[0285]

[0286]

[0287] 5. Overall Design

[0288] ALXN1210-MG-306 is a Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter study designed to evaluate the safety and efficacy of ravulizumab in patients with gMG.

[0289] The ALXN1210-MG-306 study diagram is shown below. Figure 1 Approximately 1560 eligible patients were stratified by region (North America, Europe, Asia Pacific, and Japan) and randomized 1:1 to 1 of 2 treatment groups: (1) ravulizumab infusion or (2) placebo infusion. The study had 3 periods: screening, randomized controlled, and open-label extension (OLE).

[0290] After the 26-week randomized controlled period and the Day 183 (Week 26) assessment, patients in the placebo group received a blinded loading dose of ravulizumab and patients in the ravulizumab group received a blinded ravulizumab dose of 900 mg. Starting from Week 28, all patients started an open-label ravulizumab maintenance dose q8w. For patients in the ravulizumab group, a blinded ravulizumab dose of 900 mg was selected to ensure maintenance of complete C5 inhibition until the next planned maintenance dose at Week 28 (Day 197).

[0291] Eight weeks after the last dose of study drug was administered, all enrolled patients returned for an end-of-study (EOS) visit (Visit 30) at Week 132 (±2 days), during which the final study assessment was performed. If a patient withdraws from the study, or completes the study early (before Visit 29; Week 124), for example, if Ravolizumab was registered or approved (according to country-specific regulations) before Visit 29, the patient is encouraged to return for an early termination (ET) / EOS visit 8 weeks (±2 days) after the date of the last dose of study drug, during which the final planned safety assessment is performed as described herein. An attempt was made to track the safety of all patients 8 weeks from the date of the last dose of study drug.

[0292] Patients who were being treated with IST at the screening visit could continue to take their baseline IST throughout the randomized controlled and OLE periods. However, the dose of IST should not be changed, and no new IST should be added or stopped during the randomized controlled period of the study unless deemed medically necessary by the investigator. Throughout the study, rescue therapy (e.g., high-dose corticosteroids, plasmapheresis / plasma exchange, or intravenous immunoglobulin) was allowed if the patient experienced clinical deterioration as defined in the study protocol herein. Rescue therapy for a specific patient was at the discretion of the investigator.

[0293] Throughout the study, rescue therapy (e.g., high-dose corticosteroids, PP / PE, or IVIg) was allowed if patients experienced clinical deterioration as defined herein. Rescue therapy for a specific patient was at the discretion of the investigator.

[0294] The primary endpoint of this study was measured at Week 26 (Day 183). The endpoint was measured and analyzed without regard to rescue therapy. For those patients who completed the study, the EOS visit was defined as the patient's last visit during the (up to) 2-year OLE period as defined in the protocol. Including an 8-week safety follow-up starting after the last dose of study drug was administered to the patient, the overall study duration for an individual patient was estimated to be up to 132 weeks (from enrollment to the end of safety follow-up). The period of active patient participation was estimated to be up to 132 weeks (from enrollment to the EOS visit).

[0295] The schedule of activities (SOA) for the randomized control period and the OLE period are provided in Table 10 and Table 11, respectively.

[0296] Screening period (2 to 4 weeks before Day 1)

[0297] At the screening visit, after informed consent was obtained, patients were screened for study eligibility by medical history review, demographic data, and laboratory assessments. The medical history review included confirmation of the MG diagnosis as defined in the inclusion criteria of the protocol, history of previous treatment / treatment of MG (e.g., thymectomy, IST including corticosteroids, IVIg, and PE / PP), and history of MG exacerbations or crises, including the duration of each exacerbation / crisis, medications taken during each exacerbation / crisis, and treatment of each exacerbation / crisis.

[0298] If all inclusion and exclusion criteria were not met, patients received Neisseria meningitidis vaccination if they had not been vaccinated within 3 years before their study entry. Patients who started study medication less than 2 weeks after receiving meningococcal vaccination received appropriate prophylactic antibiotic therapy until 2 weeks after vaccination.

[0299] If a patient experiences clinical worsening or MG crisis during the screening period, the sponsor will be notified and, after discussion with the sponsor, a decision will be made as to whether the patient can continue in the study.

[0300] Number of patients

[0301] Patients were screened until enough patients were enrolled to reach an estimated total of 160 patients, approximately 80 patients in each group.

[0302] Randomization

[0303] At the time of randomization, all patients were reassessed for eligibility according to the study inclusion and exclusion criteria. All patients who were vaccinated, continued to meet all inclusion criteria and none of the exclusion criteria at the time of randomization [Day 1], and had investigator approval for randomization were randomized 1:1 to 1 of 2 treatment groups: (1) revoluumab infusion or (2) placebo infusion. Patients were centrally randomized using an interactive response technique. Randomization was stratified by region (North America, Europe, Asia Pacific, and Japan).

[0304] Throughout the study, rescue therapy (e.g., high-dose corticosteroids, PP / PE, or IVIg) was permitted when the patient's health was at risk if rescue therapy was administered (e.g., emergency situations) or if the patient experienced clinical deterioration as defined in this protocol. Rescue therapy used for a specific patient was at the discretion of the investigator.

[0305] Patients were informed of potential signs and symptoms of clinical worsening or MG crisis and were instructed to contact the Investigator for evaluation within 48 hours of notifying the Investigator of symptom onset. At the evaluation visit, the Investigator or the Investigator's designee performed the protocol-specified assessment. The Investigator or designee determined whether the patient met the definition of clinical worsening as defined herein and treated the patient accordingly.

[0306] The primary endpoint of this study was measured at week 26 (day 183) regardless of rescue therapy.

[0307] Patients randomized to the ravulizumab group received a blinded loading dose of ravulizumab on day 1, followed by a blinded maintenance dose of ravulizumab on day 15 (week 2) and q8w thereafter for a total of 18 weeks of treatment. Patients randomized to the placebo group received a blinded dose of placebo on day 1, followed by a blinded dose of placebo on day 15 (week 2) and q8w thereafter for a total of 18 weeks. Both ravulizumab and placebo were administered by intravenous infusion.

[0308] After the 26-week randomized controlled period and the Day 183 (Week 26) assessment, patients in the placebo group received a blinded loading dose of ravulizumab and patients in the ravulizumab group received a blinded ravulizumab dose of 900 mg; the 900 mg dose was selected to ensure maintenance of full C5 inhibition until the next planned maintenance dose at Week 28 (Day 197). Starting at Week 28, all patients began an open-label ravulizumab maintenance dose q 8w.

[0309] The OLE period for each patient began when the patient received a dose of ravulizumab at Week 26 (Day 183) and continued for up to 2 years or until product registration or approval (depending on country-specific regulations), whichever occurred first.

[0310] The schedule of screening activities at the end of the randomized controlled period is shown in Table 10, and the schedule of screening activities in the extension period is shown in Table 11.

[0311] Table 10: Timeline of activities: Screening at the end of the randomized controlled period

[0312]

[0313]

[0314] 1Evaluation for clinical deterioration will be performed as soon as possible and within 48 hours of symptom onset notified to the investigator. Additional evaluation visits will be scheduled at the investigator’s discretion.

[0315] 2 If a patient withdraws from the study prematurely during the randomized controlled period, an early termination visit will be conducted.

[0316] 3 See, for example, Table 3.

[0317] 4 Vital signs and pulse oximetry included systolic and diastolic blood pressure (millimeters of mercury [mmHg]), pulse oximetry (oxygen saturation [SO2]), heart rate (beats / minute), and temperature (degrees Celsius [℃] or degrees Fahrenheit [°F]). On dosing days, vital signs were collected before study drug administration and after the patient had rested for at least 5 minutes.

[0318] 5If necessary, based on the patient's health status and the researcher's clinical judgment.

[0319] 6MG-ADL assessments were performed by appropriately trained clinical assessors, preferably the same assessor, throughout the study. If the interval between visits was less than 7 days, the recall period for MG-ADL was the previous 7 days or since the last visit.

[0320] 7 If the patient is taking cholinesterase inhibitors, they should be discontinued for at least 10 hours prior to assessment.

[0321] 8 Clinical laboratory tests were performed in a central laboratory.

[0322] 9Pregnancy testing will be performed on all patients of childbearing potential at designated time points. Serum pregnancy testing will be performed at screening; urine pregnancy testing will be performed at all other required time points. A negative urine test result will be required prior to administration of ravulizumab to patients of reproductive potential at designated visits. Additional pregnancy testing (urine or serum) may also be performed at any visit at the discretion of the investigator.

[0323] 10Baseline (B) and trough (T) blood samples for serum PK, free C5 (PD) and ADA were collected before dosing (within 30 minutes before the start of infusion of study drug). Peak (P) blood samples for serum PK / PD samples were collected within 30 minutes after the completion of study drug infusion. Before the dose was administered, the T sample was drawn through the venous access created for the dose infusion. The P sample was taken from the non-infused arm on the other side of the patient. On Day 183 (Week 26), the T sample was considered a randomized controlled period assessment and the P sample was considered an extended period assessment. All collection times are recorded in the eCRF. In the event of clinical deterioration, if supplemental administration is described herein, blood samples for serum PK / PD and ADA analysis are collected.

[0324] 11 To reduce the risk of meningococcal infection (Neisseria meningitidis), all patients were vaccinated against meningococcal infection within 3 years before or when starting study drug. Patients who started study drug treatment less than 2 weeks after receiving meningococcal vaccine received appropriate prophylactic antibiotic therapy until 2 weeks after vaccination.

[0325] 12 Prior to the first dose of study medication, patients were given a patient safety information card. At each visit throughout the study, the investigators ensured that patients had the patient safety information card.

[0326] 13 All patients who continued to meet all inclusion criteria and had no exclusion criteria and who had been approved for randomization by the investigator were centrally randomized using the interactive response technique (IRT).

[0327] 14 Study drug was administered intravenously by infusion after completion of all other tests and procedures, excluding peak blood draws for PK / PD, free C5, and ADA.

[0328] Abbreviations: AChRAb = acetylcholine receptor antibody; ADA = antidrug antibody; B = baseline sample; C5 = complement component 5;

[0329] C-SSRS = Columbia-Suicide Severity Rating Scale; D = days; ECG = electrocardiogram; EQ-5D-5L = European quality of life; ET = early termination;

[0330] HIV = human immunodeficiency virus; MG = myasthenia gravis; MG-ADL = myasthenia gravis profile of activities of daily living; MGC = myasthenia gravis composite score; MGFA = Myasthenia Gravis Foundation of America; MGFA-PIS = MGFA post-intervention status; N. meningitidis = Neisseria meningitidis;

[0331] P = peak sample; PK / PD = pharmacokinetics / pharmacodynamics; QMG = quantitative myasthenia gravis disease severity score; QoL = quality of life;

[0332] T = valley sample; W = week.

[0333]

[0334]

[0335]

[0336]

[0337] 6. Standard Scheme Definition

[0338] Table 12: Abbreviations and definitions of study and follow-up phases

[0339]

[0340]

[0341]

[0342] Clinical deterioration

[0343] For this protocol, clinical deterioration was defined as follows:

[0344] 1. Patients who experience an MG crisis, defined as weakness due to MG severe enough to require intubation or delayed extubation after surgery. Respiratory failure is due to respiratory muscle weakness. Severe bulbar (oropharyngeal) muscle weakness often accompanies respiratory muscle weakness or may be the predominant feature in some patients; or,

[0345] 2. Significant symptomatic deterioration to a score of 3 points, or a 2-point deterioration in any of the individual MG-ADL items except diplopia or ptosis; or

[0346] 3. Administering rescue therapy to a patient whose health would be in jeopardy if not administered (eg, emergency situation) in the opinion of the Investigator or the Investigator's designated physician.

[0347] Unplanned visits

[0348] In special circumstances, additional (unplanned) visits beyond the scheduled visits are permitted at the investigator's discretion. Procedures, tests, and assessments are performed at the investigator's discretion, and efforts are made to map the corresponding data to the appropriate visit.

[0349] Appropriately trained clinical assessors

[0350] Appropriately trained clinical assessors are investigators certified in the MG-ADL, QMG, and MGC assessments. Only appropriately trained clinical assessors may administer these assessments. Appropriately trained clinical assessors are neurologists, physical therapists, or other members of the research team delegated by the investigator. Only the investigator or neurologist will perform the Manual Muscle Test (MMT), MGC components, MGFA-PIS, and Myasthenia Gravis Foundation of America (MGFA) grading. Clinical assessor training and certification for this protocol will occur at an investigator meeting or through an online training portal designated by the sponsor.

[0351] Myasthenia Gravis Assessment Responsibilities

[0352] The responsibilities for MG assessment are listed in Table 13. MG assessments were performed by appropriately trained clinical assessors at approximately the same time of day throughout the study, and preferably by the same assessor.

[0353] Table 13: MG Assessment and Responsibilities

[0354]

[0355]

[0356] Abbreviations: MG-ADL = myasthenia gravis profile of activities of daily living; MGC = myasthenia gravis composite scale; MGFA = myasthenia gravis foundation of America; MGFA-PIS = myasthenia gravis foundation of America postintervention status; MMT = manual muscle test; QMG = quantitative myasthenia gravis score of disease severity.

[0357] Scientific rationale for study design

[0358] Published data support that the MG-ADL profile is an established, sensitive, and objective assessment of treatment response over time in patients with gMG (Howard, J. et al., Muscle Nerve, 56:328-30, 2016).

[0359] The safety parameters evaluated are commonly used in clinical studies according to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) guidelines.

[0360] Placebo was selected as a control, and patients were allowed to continue stable treatment with standard of care therapy (e.g., IST) throughout the study, allowing comparison of the safety and efficacy of ravulizumab when administered to patients with gMG in addition to the patient's current standard of care therapy.

[0361] Given the heterogeneity of the disease and fluctuations in symptom severity, no single international standard of care is accepted, and targeted therapy with complement inhibitor drugs, such as the recently introduced eculizumab, is not yet widely available to patients worldwide and is not yet considered the standard of care for all patients with gMG. Placebo-controlled studies allow for the evaluation of treatment effects and allow for double-blind designs; important study conditions to maintain when considering endpoints including neurological scales, which are known to be particularly susceptible to placebo effects. The placebo-controlled portion of this study was limited to 26 weeks, after which all patients transitioned to open-label treatment with revolucumab for up to 2 years during the OLE. At all time points throughout the study, physicians were encouraged to prioritize patient safety, and full rescue therapy was permitted if patients experienced clinical deterioration.

[0362] Rationality of dosage

[0363] Ravolizumab is currently being studied in Phase 3 clinical studies in patients with PNH and aHUS, with PK / PD data extensively collected from all studies. The Ravolizumab dose regimen for these indications was selected based on comprehensive modeling and simulation analysis of Phase 1 and Phase 2 PK / PD data in healthy volunteers and PK / PD / efficacy (lactate dehydrogenase) and safety data in patients with PNH and is considered the best option to achieve immediate, complete, and sustained inhibition of terminal complement activity within each dosing interval and throughout treatment for all patients. In the current study, a weight-based Phase 3 dose regimen was tested in patients with gMG (Table 14).

[0364] Table 14: Dosing of Ravolizumab Based on Weight

[0365]

[0366] Abbreviation: q8w = every 8 weeks.

[0367] Consistent with the approved labeling for eculizumab for the treatment of adult and pediatric patients with aHUS and adult patients with gMG, supplemental doses of revolutumab were given at 50% (rounded up if not an integer of 300 mg due to vial configuration) with concomitant PP / PE rescue therapy and. For adult patients with gMG, supplemental doses of revolutumab were given with concomitant IVIg rescue therapy (at 600 mg). The weekly 600 mg supplemental dose of revolutumab was selected based on PK simulations, taking into account published data describing the effect of IVIg co-administration on the PK / PD of eculizumab (Table 1; Table 2; Fitzpatrick, A. et al., J Peripher. Nerv. Syst., 16:84-91, 2011).

[0368] If PE / PP or IVIg rescue therapy is provided on a non-dosing day, supplemental study drug (or placebo) administration is required; if PE / PP or IVIg infusion is provided on a dosing day, supplemental study drug (or placebo) administration is not required, but it occurs before study drug administration. If PE / PP or IVIg is administered at a scheduled dosing visit, the regular dose is administered 60 minutes after the completion of PE / PP or IVIg. If PE / PP or IVIg is administered at an unscheduled dosing visit, for patients receiving PE / PP: administer the supplemental dose 4 hours after the completion of the PE / PP course; for patients receiving IVIg: administer the supplemental dose 4 hours after the completion of the last continuous course of IVIg as described herein.

[0369] The favorable benefit / risk profile of ravulizumab in a recently completed Phase 3 study in patients with PNH demonstrated immediate (after the first or loading dose), complete (free C5 < 0.5 μg / mL), and sustained (throughout the active treatment course) terminal complement inhibition at the dose regimen studied above.

[0370] After the 26-week randomized controlled period and the Day 183 (Week 26) assessment, patients in the placebo group received a blinded loading dose of ravulizumab and patients in the ravulizumab group received a blinded ravulizumab dose of 900 mg; the 900 mg dose was selected to ensure maintenance of complete C5 inhibition until the next planned maintenance dose at Week 28 (Day 197). Beginning at Week 28 (Day 197), all patients began an open-label ravulizumab maintenance dose q8w.

[0371] The proposed q8w dosing schedule facilitates the study of a range of PK drug exposures that will aid in assessing the exposure-response relationship of ravulizumab in patients with gMG. The safety and tolerability of ravulizumab have been established over a wide range of PK exposures in healthy volunteers and patients, including those expected at the proposed gMG dosing schedule.

[0372] Study End Definition

[0373] Patients were considered to have completed the study if:

[0374] The patient has completed all phases of the study, including the last visit of the OLE phase, or

[0375] If the study is completed early, the patient has completed all applicable periods of the study, including EOS visits

[0376] Patient completes study early (and completes EOS visit) because study drug is registered or approved (according to country-specific regulations)

[0377] The measurement of the primary endpoint was completed after the last visit of the last patient in the randomized controlled period. EOS was defined as the date of the last visit of the last patient in the study or the date of the last scheduled procedure as shown in the activity schedule of the last patient in the global study (see Table 10 and Table 11). The study completion date corresponded to the last visit at which the last patient in the study was examined or received intervention for the primary or secondary endpoints and AEs.

[0378] 7. Study population

[0379] Prospective approval of protocol deviations from recruitment and enrollment guidelines, also known as protocol waivers, is not permitted.

[0380] Inclusion criteria

[0381] Patients are eligible to participate in the study only if all of the following guidelines apply:

[0382] age

[0383] 1. Male and female patients must be ≥ 18 years old when signing the informed consent form

[0384] Patient types and disease characteristics

[0385] 2. Diagnosed with MG at least 6 months (180 days) prior to the screening visit date, as confirmed by protocol-specific guidelines (see below).

[0386] 3. MG diagnosis is made through the following tests:

[0387] a. A positive anti-AChR Ab serology test confirmed at screening, and

[0388] b. One of the following

[0389] History of abnormal neuromuscular transmission testing confirmed by single-fiber electromyography or repetitive nerve stimulation;

[0390] A history of a positive anticholinesterase test (e.g., edrophonium chloride test);

[0391] Improvement of MG signs with oral cholinesterase inhibitors as assessed by the treating physician.

[0392] 4. Myasthenia Gravis Foundation of America clinical classification is II to IV at screening.

[0393] 5. MG-ADL profile ≥6 at screening and randomization (Day 1).

[0394] 6. Patients receiving any of the following treatments are currently receiving treatment and taking a stable dose within the time period specified below before the screening visit date:

[0395] Azathioprine (AZA): Patients who have taken AZA for ≥ 6 months (180 days) and have been taking a stable dose for ≥ 2 months (60 days);

[0396] Immunosuppressive therapy (e.g., mycophenolate mofetil [MMF], methotrexate [MTX], cyclosporine [CYC], tacrolimus [TAC], or cyclophosphamide [CY]) for ≥ 3 months (90 days) and stable dose for ≥ 1 month (30 days);

[0397] Oral corticosteroids, taken at a stable dose for ≥ 4 weeks (28 days);

[0398] Cholinesterase inhibitors, taking a stable dose for ≥ 2 weeks (14 days) at the screening visit.

[0399] 7. To reduce the risk of meningococcal infection (Neisseria meningitidis), all patients were vaccinated against meningococcal infection within 3 years before or at the time of starting the study drug. Patients who started the study drug less than 2 weeks after receiving the meningococcal vaccine received appropriate prophylactic antibiotic treatment until 2 weeks after vaccination.

[0400] weight

[0401] 8. Body weight ≥40kg during screening.

[0402] Pregnancy and contraception

[0403] 9. Patients of childbearing age and patients with childbearing partners should use contraception to avoid pregnancy during treatment and within 8 months after the last dose of study drug.

[0404] Informed consent

[0405] 10. Able to sign the informed consent form. As part of the informed consent form:

[0406] The researcher or his / her representative will explain the nature of the study to the patient or his / her legally authorized representative and answer all questions regarding the study.

[0407] Patients are informed that their participation is voluntary. Patients or their legally authorized representatives must sign an informed consent that complies with 21CFR50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act requirements (if applicable), and IRB / IEC or site requirements.

[0408] The medical record includes a statement that written informed consent was obtained before the patient participated in the study and the date the written consent was obtained. The person who authorized the informed consent also signed the ICF.

[0409] Patients re-agreed to the most recent version of the Informed Consent Form (ICF) during their participation in the study. A copy of the ICF was provided to the patient.

[0410] The researcher retains the original version of the signed ICF. The patient is provided with a copy of the signed ICF.

[0411] Rescreened patients do not need to sign another ICF unless an updated ICF is available.

[0412] Exclusion criteria

[0413] Patients were excluded from the study if any of the following criteria applied:

[0414] Medical conditions

[0415] 1. Any active or untreated thymoma. History of thymic carcinoma or thymic malignancy, unless considered cured by adequate treatment without evidence of recurrence within ≥5 years before screening;

[0416] 2. History of thymectomy within 12 months before screening;

[0417] 3. History of allergy to any ingredient in the study drug, including allergy to mouse protein;

[0418] 4. History of Neisseria meningitidis infection;

[0419] 5. Human immunodeficiency virus (HIV) infection (proven by HIV-1 or HIV-2 antibody titer);

[0420] 6. Known medical or psychological conditions or risk factors that the researcher believes interfere with the patient's full participation in the study, pose any additional risks to the patient, or confound the patient's assessment or study results;

[0421] 7. History of hospitalization for ≥24 hours for any reason within 4 weeks (28 days) before screening;

[0422] 8. Clinical features consistent with MG crisis / exacerbation or clinical deterioration at the screening visit or at any time before randomization according to the investigator;

[0423] 9. Female patients who are planning to become pregnant, are pregnant or breastfeeding;

[0424] 10. Female patients with positive pregnancy test results at screening or on day 1.

[0425] Prior / concomitant treatment

[0426] 11. Use the following during the time periods specified below:

[0427] IVIg within 4 weeks (28 days) before randomization (Day 1);

[0428] · Use of PE within 4 weeks (28 days) before randomization (day 1);

[0429] Use of rituximab within 6 months (180 days) before screening.

[0430] 12. Patients who have previously received complement inhibitors (e.g., eculizumab).

[0431] Previous / contemporaneous clinical research experience

[0432] 13. Participation in another interventional study or use of any experimental treatment within 30 days prior to starting study drug on Day 1 of this study or within 5 half-lives of study drug, whichever is greater.

[0433] Screening failure

[0434] Screen failures are defined as patients who consented to participate in a clinical study but were not subsequently randomized to a treatment group. A minimum set of screen failure information is required to ensure transparent reporting of patients with screen failures, to meet publication requirements of the Integrated Reporting Trial Standards, and to respond to regulatory agency inquiries. Minimum information includes demographics, screen failure details, eligibility criteria, and any serious adverse events (SAEs).

[0435] Subjects who did not meet the criteria for participation in this study (screening failure) could be rescreened one more time based on discussion and agreement between the investigator and the medical monitor.

[0436] Patients who experience clinical worsening or acute attack / crisis of gMG during the screening period will be considered screening failures. Such patients may be rescreened with Sponsor approval once they are treated and medically stable, in the opinion of the Investigator. A minimum of 28 days of clinical stability must exist prior to enrollment. Patients must meet all inclusion criteria and not meet any exclusion criteria at the time of rescreening to enter the study.

[0437] 8. Study Drugs

[0438] Study Drug Administered

[0439] Ravolizumab was formulated at pH 7.0 and provided in 30 mL disposable vials. Each vial of Ravolizumab contained 300 mg of Ravolizumab (10 mg / mL) in 10 mM sodium phosphate, 150 mM sodium chloride, 0.02% polysorbate 80, and water for injection. The comparative product was formulated into a matching sterile, clear, colorless solution with the same buffer components but without the active ingredient. Additional details are presented in Table 15.

[0440] Table 15: Study Drugs Administered

[0441]

[0442] Source: Product Specifications

[0443] Study medication was administered as indicated in Table 16.

[0444] During the randomized controlled period, patients in the ravulizumab or placebo treatment group received a weight-based loading dose of ravulizumab or placebo, respectively, on Day 1 (Visit 2). At Visit 4 (Week 2), at the end of the randomized controlled period, patients in the ravulizumab or placebo treatment group received a weight-based maintenance dose of either ravulizumab or placebo, respectively, q 8 w (see Table 16). After completing the randomized controlled period, patients entered the OLE period.

[0445] After the 26-week randomized controlled period and the Day 183 (Week 26) assessment, patients in the placebo group received a blinded loading dose of ravulizumab and patients in the ravulizumab group received a blinded ravulizumab dose of 900 mg; the 900 mg dose was selected to ensure maintenance of full C5 inhibition until the next planned maintenance dose at Week 28 (Day 197). Starting at Week 28, all patients began an open-label ravulizumab maintenance dose q8w.

[0446] Table 16: Reference chart for weight-based dosing

[0447]

[0448] 1 Dosing schedule is based on the patient's most recently recorded body weight from the previous study / screening visit.

[0449] 2 A blinded dose was administered on Day 183 (Week 26) to patients randomized to the ravulizumab group who entered the open-label extension period.

[0450] Preparation / Handling / Storage / Responsibility

[0451] Based on federal, state, and local regulations, study medication is released to the site upon receipt of all required essential documentation.

[0452] Only patients enrolled in the study may receive study medications, and only authorized site personnel may supply or administer study medications. All study medications are stored in secure, environmentally controlled, and monitored (manual or automated) areas according to labeled storage conditions, with access limited to investigators and authorized site personnel.

[0453] Study drug preparation

[0454] Study medication was prepared and administered by trained members of the on-site research team. Study medication was administered only to enrolled patients who were confirmed eligible to participate.

[0455] Preparation of ravulizumab and placebo doses was performed by qualified, research-trained pharmacy staff according to site-specific local standards.

[0456] Handling and preparation of materials used to prepare and administer study drug was performed using aseptic techniques for sterile products.

[0457] All study patients, study site personnel, sponsor staff, sponsor designees, and all personnel directly involved in the conduct of the study were blinded to the patients' treatment assignments.

[0458] Further details regarding preparation and dosing of study medication and disposal of study medication are provided in the Pharmacy Manual.

[0459] storage

[0460] The investigator or designee verifies that all study medications received maintain appropriate temperature conditions during transportation and that any discrepancies are reported and resolved prior to use of the study medication.

[0461] Upon arrival at the study site, study medications were immediately removed from the shipping cooler and stored under refrigeration at 2°C to 8°C (36°F to 46°F). Pharmacists immediately documented receipt of study medications and notified distributors in the event of vial damage and / or temperature excursions during shipping. Study medications were stored in a secure, restricted-access storage area, and temperature was monitored daily.

[0462] Diluted solutions of study drug were stored at 2°C to 8°C (36°F to 46°F) for up to 24 hours prior to administration. Solutions were allowed to warm to room temperature prior to administration.

[0463] The mixed drug product was at room temperature prior to administration. The material was not heated by means other than ambient air temperature (e.g., by using microwaves or other heat sources).

[0464] Packaging and labeling

[0465] The primary packaging of revulizumab consisted of a 30 mL vial (type I borosilicate glass) with a stopper and seal. The secondary packaging consisted of a single vial carton. Both the primary (vial) and secondary (carton) packaging included a booklet label with relevant information. Additional details are presented in Table 13 and the pharmacy brochure. Placebo had the same appearance as revulizumab.

[0466] Accountability

[0467] When a drug shipment is received at the site, the pharmacist verifies the contents, signs the package invoice provided with the shipment, and keeps an original copy in the pharmacy binder for review by the site supervisor. In addition, study drug receipt (and the condition of the study drug upon receipt) is reported to the IRT system to allow for drug randomization, resupply, estimation, and drug expiration control.

[0468] Unless otherwise notified, empty bottles and vials with residual material are retained for inspection and accountability by the study monitor until destroyed or disposed of in accordance with the local pharmacy's standard operating procedures for clinical study medications. The destruction of used and unused vials, whether local or centralized, is properly recorded. Medication accountability is managed through the IRT system, and detailed instructions for administering the IRT Medication Accountability module are included in the IRT User Guide. The IRT module performs accountability in two stages, with site personnel completing an initial accountability entry in the system, followed by confirmation by the study monitor that the site correctly entered the appropriate status for all study medications. The pharmacist or designee maintains accurate records that document the date and amount of study medication received, to whom it was dispensed (on a patient-by-patient basis), and an accounting of any study medication that was accidentally or intentionally destroyed. These medication accountability records are readily available upon request and are reviewed throughout the study.

[0469] Each kit has a label and a place for the pharmacist to record the patient's number and initials.

[0470] Study monitors review inventory during the study. In addition, inventory records are readily available for inspection by regulatory agencies, local regulators, or independent auditors.

[0471] See pharmacy brochure for additional information.

[0472] Handling and Disposal

[0473] All clinical study materials provided to investigators are stored in a secure location and are distributed and dispensed by appropriately trained personnel. Detailed records are maintained of the quantities of study drug received, dispensed, and destroyed.

[0474] To meet regulatory requirements for drug accountability, all remaining ravulizumab inventory was reconciled at the end of the study and destroyed or returned to Alexion in accordance with applicable regulations.

[0475] Please refer to the pharmacy brochure for additional information.

[0476] Randomization

[0477] After investigator confirmation of patient eligibility, patients underwent randomization on day 1. Patients were stratified by region (North America, Europe, Asia Pacific, and Japan) and randomized 1:1 to either IV infusion of ravulizumab or IV infusion of placebo. Patients were centrally randomized using IRT.

[0478] Blind

[0479] All investigation site personnel, sponsor staff, sponsor designated personnel, staff directly related to the study and all patients are unaware of the patient treatment allocation. Double blinding is maintained by using the same research drug kit and label as levofloxacin and placebo. Placebo has the same appearance as levofloxacin. The random code is maintained by the IRT supplier. After the 26-week randomized controlled period and the 183rd day (the 26th week), the patients in the placebo group received the blinded loading dose of levofloxacin and the patients in the levofloxacin group received the blinded levofloxacin dose of 900mg. Starting from the 28th week, all patients started the open label levofloxacin maintenance dose q8w. For the patients in the levofloxacin group, the blinded levofloxacin dose of 900mg was selected to ensure that complete C5 inhibition is maintained until the next planned maintenance dose of the 28th week (the 197th day).

[0480] Unblinding should be done only for the safety of the patient. If the Investigator believes that unblinding is necessary, the Investigator shall make reasonable attempts to contact the Sponsor to discuss possible unblinding. After making reasonable attempts, the Investigator uses the IRT to unblind the patient's treatment assignment. The Investigator records the date, time, and reason for unblinding. The Investigator also informs the Medical Monitor that the patient is unblinded; however, the Investigator does not disclose the patient's treatment assignment to the Medical Monitor.

[0481] Unblinding is only done for specific patients when the adverse event (AE) is unexpected or relevant and serious. Blinding is maintained by those responsible for the ongoing study (e.g. managers, supervisors, investigators, etc.) and those responsible for data analysis and interpretation of results at the end of the study (e.g. bioassay personnel). Unblinded information is only available to health authorities, independent ethics committees (IECs), and / or institutional review boards (IRBs) if participation is required.

[0482] Any patient who was not blinded during the study was discontinued from the study.

[0483] Investigators received only blinded information unless unblinded information was judged necessary for safety reasons.

[0484] Concomitant therapy

[0485] Previous medications (including vitamins and herbal preparations) taken or received by the patient within 28 days prior to the start of screening, including those discussed in the exclusion criteria and procedures (any therapeutic interventions such as surgery / biopsy or physical therapy) until the first dose of study medication, were recorded. In addition, meningococcal vaccination history within 3 years prior to the first dose of study medication was collected.

[0486] All medication use and procedures performed during the study were recorded. This included all prescription medications, herbal products, vitamins, minerals, over-the-counter medications, and any other current medications. Concomitant medications were recorded from the first infusion of study medication until 8 weeks after the patient's last dose of study medication. Any changes in concomitant medications were also recorded. It was at the discretion of the Investigator whether to take any concomitant medications that were considered necessary for the patient's standard of care or treatment of any AE during the study, as well as any other medications other than those defined herein as contraindicated medications. However, it was the Investigator's responsibility to ensure that detailed information regarding all medications was recorded.

[0487] Study drug adherence

[0488] Study medications were administered in a controlled environment under the supervision of the investigator or designee to ensure compliance with study medication administration.

[0489] Palliative and supportive care

[0490] Palliative and supportive care for underlying conditions was permitted during the study.

[0491] Permitted drugs

[0492] The use of the medications described in the following sections is permitted under certain circumstances and restrictions.

[0493] Cholinesterase inhibitors

[0494] For patients who were receiving a cholinesterase inhibitor at screening, the dose and schedule of their cholinesterase inhibitor remained stable throughout the randomized control and OLE periods unless there was a compelling medical need. Increases in cholinesterase therapy due to intercurrent illness or other medical deterioration were permitted, but the dose was restored to the starting dose level as soon as practicable and the Sponsor was notified of the change.

[0495] 1. Stop cholinesterase inhibitor therapy at least 10 hours before QMG and MGC testing.

[0496] 2. If a reduction in the cholinesterase inhibitor is being considered based on clinical evaluation, obtain sponsor approval before changing the dose so that the patient can continue on study.

[0497] Immunosuppressants

[0498] The following immunosuppressants were allowed during the study: corticosteroids, AZA, MMF, MTX, TAC, CYC, or CY. The immunosuppressant used for an individual patient and its appropriate dose level were at the discretion of the treating physician / investigator.

[0499] 1. Corticosteroids: For patients entering the study receiving oral corticosteroids, such as prednisone, no dose / schedule changes were made during the entire double-blind study period (i.e., randomized controlled period). If a reduction or gradual reduction in steroid dose was considered during the randomized controlled period based on clinical evaluation, sponsor approval was obtained prior to the change so that the patient could continue in the study. If the dose level was subsequently increased, the dose level increase did not exceed the dose level reported at baseline (start of randomized treatment).

[0500] 2. High-dose steroids are reserved for patients who experience clinical deterioration as defined herein. If a patient requires rescue therapy due to clinical deterioration, every effort should be made to notify the Sponsor within 24 hours of administration.

[0501] 3. AZA, MMF, MTX, TAC, CYC or CY: For patients entering the study receiving the above immunosuppressants, the dosing regimen of the immunosuppressant will not be changed throughout the randomized controlled period. If a change in the dosing regimen is considered due to known toxicity or side effects associated with a given immunosuppressant, the sponsor's approval will be obtained before the dose is changed so that the patient can continue to participate in the study. No different immunosuppressants will be added or substituted during the 26-week randomized controlled period.

[0502] Plasma exchange / plasmapheresis / intravenous immunoglobulin

[0503] Patients who experience clinical deterioration as defined herein are permitted to use PE / PP or IVIg. Rescue therapy for a specific patient is at the discretion of the investigator. If a patient requires rescue therapy, every effort should be made to notify the Sponsor within 24 hours.

[0504] If rescue PE / PP or IVIg therapy is provided on non-dosing days, supplemental study drug (or placebo) administration is required; if PE / PP or IVIg infusions are provided on dosing days, they must occur prior to study drug administration.

[0505] 1. If PE / PP or IVIg is administered during an unscheduled dosing visit

[0506] a. Patients receiving PE / PP: Administer supplemental dose 4 hours after completion of PE / PP course.

[0507] b. Patients receiving IVIg: Administer the supplemental dose 4 hours after completion of the last continuous course of IVIg.

[0508] c. Supplemental dosage may or may not vary based on PE / PP or IVIg (Tables 1 and 2).

[0509] 2. If PE / PP or IVIg is administered at an unscheduled dosing visit,

[0510] a. Administer regularly 60 minutes after completion of PE / PP or IVIg.

[0511] 3. No gap is required between supplemental doses and regularly scheduled doses.

[0512] Not allowed drugs

[0513] The following concomitant medications were prohibited during the study:

[0514] ·Rituximab

[0515] Eculizumab (or other complement inhibitors)

[0516] The use of rituximab or eculizumab (or other complement inhibitors) by a patient at any time during the study resulted in discontinuation of the patient from the study.

[0517] Rescue therapy

[0518] If rescue therapy is not administered (e.g., emergency), or if the patient experiences clinical deterioration as defined herein, rescue therapy (e.g., high-dose corticosteroids, PP / PE, or IVIg) is allowed when the patient's health is at risk. The rescue therapy used for a specific patient is at the discretion of the investigator. The date and time of rescue medication administration and the name and dosing regimen of the rescue medication were recorded.

[0519] If a patient requires rescue therapy, every effort should be made to notify the Sponsor within 24 hours.

[0520] Post-study intervention

[0521] At completion of study participation, patients returned to the care of their treating physician.

[0522] 9. Discontinuation of Study Intervention and Patient Discontinuation / Withdrawal

[0523] Discontinuation of study intervention

[0524] Patients may withdraw from the study at any time at their own request or at the discretion of the investigator for safety, behavioral, compliance or administrative reasons. If a patient stops study treatment, the investigator attempts to perform (if the patient agrees) the assessment specified for the ET visit, or if not possible, a follow-up call 8 weeks after the last dose of study drug is administered (Tables 10 and 11). An attempt is also made to conduct a total of 8 weeks of safety follow-up for all patients from the date of the last dose of study drug. The sponsor and site supervisor will be notified as soon as possible. If a patient withdraws from the study or withdraws consent, no additional data will be collected. Patients who withdraw from the study will not be replaced.

[0525] Patients will stop study medication if any of the following occur during the study:

[0526] 1. Severe hypersensitivity reactions occurring 1 to 14 days after administration of the study drug (e.g., bronchospasm with wheezing or requiring ventilator support, or symptomatic hypotension or serum sickness-like reactions);

[0527] 2. Severe uncontrolled infection;

[0528] 3. Pregnant or planning to become pregnant; or

[0529] 4. The sponsor believes that this is in the best interest of the patient.

[0530] 5. Use of rituximab, eculizumab (or other complement inhibitors)

[0531] The investigator contacted the medical monitor before the patient discontinued study drug. If the patient discontinued treatment, the patient was encouraged to return for an ET visit 8 weeks after the patient's last dose of study drug (Tables 10 and 11).

[0532] The reason for treatment discontinuation was recorded (eg, patient withdrawal of consent, patient withdrawal from the procedure, physician decision, AE, or other reason specified in the eCRF).

[0533] If a female patient permanently discontinues study medication due to pregnancy, the investigator will make reasonable follow-up attempts in accordance with local laws and regulations until the pregnancy outcome is known.

[0534] If a patient withdraws consent for disclosure of future information, Sponsor will retain and continue to use all data collected prior to the withdrawal of consent.

[0535] If a patient withdraws from the study, the patient may request that any samples collected but not tested be destroyed and the investigator record this in the site study record and notify the site supervisor and sponsor.

[0536] Lost to follow-up

[0537] Patients were considered lost to follow-up if they repeatedly failed to return for scheduled follow-up visits and could not be contacted with the study center.

[0538] If a patient fails to return to the clinic for a required study visit, the following actions must be taken:

[0539] 1. The site will attempt to contact the patient as soon as possible and reschedule missed visits, counsel the patient on the importance of maintaining the assigned visit schedule and determine whether the patient wishes and / or should continue on the study.

[0540] 2. The researcher or designee will make every effort to re-contact the patient (three phone calls if possible and, if necessary, a certified letter to the patient's last known mailing address or local equivalent) before the patient is considered lost to follow-up. These contact attempts are documented in the patient's medical record.

[0541] 3. If the patient still could not be contacted, the patient was considered to have withdrawn consent, and future missed visits were not considered protocol deviations.

[0542] 10. Research Assessment and Procedures

[0543] Efficacy evaluation

[0544] Hospitalization

[0545] Information related to all-cause hospitalizations was collected from the time the patient signed the ICF until the OLE. Hospitalization was defined as admission to any healthcare facility, regardless of its potential relationship to MG. Date of admission / discharge, reason for hospitalization, relationship to MG, and other relevant information were collected.

[0546] Hospitalization includes the following:

[0547] 1. Emergency room visits related to MG, regardless of hospital admission or duration;

[0548] 2. Unplanned admission to a medical institution, regardless of the relationship to MG;

[0549] 3. Hospitalization for MG-related infusions / treatments received in a hospital facility (e.g., IVIg, PP, PE, ventilator support).

[0550] Hospitalization does not include the following:

[0551] 1. Routine study drug administration;

[0552] 2. Rehabilitation facilities;

[0553] 3. Hospice facilities;

[0554] 4. Nursing / Assisted Living / Extended Care Facilities;

[0555] 5. Outpatient care facilities;

[0556] 6. Planned admission to hospital for treatment of a pre-existing condition (i.e., a condition that began before informed consent was obtained);

[0557] 7. Planned / unplanned outpatient surgery (e.g., used as a surgical facility);

[0558] 8. Emergency room visit not related to MG, no need for hospital admission;

[0559] 9. Outpatient infusion / therapy management in hospital settings (e.g., IVIg, PP).

[0560] Clinical deterioration

[0561] Information related to clinical deterioration as defined herein was collected from the time the patient signed the ICF until the OLE. The visit to assess clinical deterioration was conducted as soon as possible within 48 hours of symptom onset notified to the investigator. Additional unscheduled visits as defined herein were scheduled at the investigator's discretion. The following tests and procedures were completed at this visit:

[0562] 1. Measure vital signs and pulse oximetry, including assessment of systolic and blood pressure (BP), temperature (°C or °F), oxygen saturation (SO2), and heart rate (HR).

[0563] 2. Record any new medications or changes in concomitant medications, including all treatments for MG.

[0564] 3. Evaluate and record any new AEs or changes in AEs since the last visit.

[0565] 4. MG-ADL is administered by an appropriately trained assessor (preferably the same assessor) throughout the study. The recall period is the previous 7 days or since the last visit, whichever is earlier.

[0566] 5. Clinical assessments of QMG and MGC administration; these assessments are performed by appropriately trained assessors (preferably the same assessor) at approximately the same time of day throughout the study.

[0567] 6. Collect blood sample for AChR automated Ab test.

[0568] 7. Blood samples were collected for clinical laboratory tests (Table 17). The tests detailed in Table 17 were performed by the central laboratory. The protocol-specific requirements for inclusion or exclusion of patients were detailed herein. Additional tests were performed at any time during the study.

[0569] 8. Additional testing may be performed at the investigator's discretion if evaluation of clinical deterioration is medically indicated.

[0570] 9. PK / PD sampling at or during clinical deterioration visits:

[0571] a. If study drug was not administered, collect 1 blood sample for PK and free C5 analysis.

[0572] b. If study drug is administered at the Clinical Worsening Visit, collect 2 blood samples, trough and peak, according to the protocol schedule, [1] 5 to 90 minutes before study drug infusion and [2] within 30 minutes after completion of study drug infusion.

[0573] c. If the patient received PP / PE or IVIg at the time of clinical deterioration, a supplemental dose of study drug was administered. Blood samples for PK and free C5 were collected [1] 5 to 90 minutes before PP / PE or IVIg, [2] after PP / PE or IVIg and before study drug infusion, and [3] within 30 minutes after completion of study drug infusion.

[0574] Table 17: Safety laboratory assessment required by the program

[0575]

[0576] Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; C5 = complement component 5; eCRF = electronic case report form; hCG = human chorionic gonadotropin; HIV-1 = human immunodeficiency virus type 1; HIV-2 = human immunodeficiency virus type 2; RBC = red blood cell; SGOT = serum aspartate aminotransferase; SGPT = serum alanine aminotransferase; WBC = white blood cell.

[0577] Safety Assessment

[0578] Physical examination

[0579] The physical examination included assessment of the following organs / body systems: skin, head, ears, eyes, nose, throat, neck, lymph nodes, pulse, chest, heart, abdomen, extremities; musculoskeletal and general neurological examination. The abbreviated physical examination included relevant examinations of body systems based on the investigator's judgment and the patient's symptoms. Every effort was made to have the same qualified research staff perform the physical examinations for uniformity.

[0580] Vital signs and pulse oximetry

[0581] Vital signs and pulse oximetry were measured at each visit and included assessment of systolic and diastolic BP (mmHg), temperature (°C or °F), SO2, and HR (beats per minute). Vital signs were obtained after the patient had been supine or sitting for at least 5 minutes. Ideally, BP was measured in the same arm for each patient.

[0582] Electrocardiogram

[0583] As outlined in the activity schedule (Tables 10 and 11), a single 12-lead electrocardiogram (ECG) was obtained using an ECG machine that automatically calculated HR and measured PR, QRS, QT, and QTc intervals. The patient lay supine for approximately 5 to 10 minutes before the ECG was obtained and remained supine but awake during the ECG.

[0584] The investigator or designee is responsible for reviewing the ECG to assess whether the ECG is within normal range and to determine the clinical significance of the results.

[0585] Clinical safety laboratory assessment

[0586] Laboratory Assessment Testing is performed at a central laboratory facility. Any clinically significant abnormal results are followed until resolved or stabilized.

[0587] All protocol-required laboratory assessments defined in this article were performed according to the laboratory manual and schedule of activities (Tables 10 and 11).

[0588] The investigator reviews the laboratory reports, documents the review, and records any clinically relevant changes that occur during the study. The laboratory reports are archived with the source documents.

[0589] Clinically significant abnormal laboratory findings related to the underlying disease were not considered AEs unless judged by the investigator to be more serious than expected for the patient's condition.

[0590] If such values ​​do not return to normal / baseline within a time that is reasonable in the investigator's judgment, the cause is determined and the Sponsor is notified.

[0591] Urinalysis and urine chemistry

[0592] The urine samples were analyzed for the parameters listed in (Table 17). If the macroscopic analysis results were abnormal, the urine samples were examined microscopically.

[0593] Urine samples are also analyzed to measure protein and creatinine, allowing the urine protein:creatinine ratio to be calculated.

[0594] Viral serology

[0595] All patients were required to undergo human immunodeficiency virus testing for HIV-1 and HIV-2 prior to enrollment. HIV-positive patients were not included.

[0596] Immunogenicity assessment

[0597] Before study drug administration, blood samples were collected to test for the presence of ADA to Ravulizumab in the serum. Further characterization of antibody responses, including binding and neutralizing antibodies, PK / PD, safety, and activity of Ravulizumab, was performed as appropriate. Antibodies to Ravulizumab were assessed in serum samples collected from all patients according to the activity schedule (Tables 10 and 11). Antibodies binding to Ravulizumab were screened in serum samples, and the titers of confirmed positive samples were reported. Antibody detection and characterization of Ravulizumab were performed by the sponsor or under the supervision of the sponsor using validated analysis.

[0598] Suicide risk monitoring

[0599] Columbia Suicide Severity Rating Scale

[0600] Columbia-Suicide Severity Rating Scale (C-SSRS; Figure 4 and Figure 5 ) is a validated questionnaire widely used in primary care, clinical practice, surveillance, research, and institutional settings to assess suicidal ideation and behavior (Posner. K. et al., Am. J Psychiatry, 168: 1266-77, 2011). The C-SSRS is administered by the researcher or a designated person who has undergone appropriate training. The C-SSRS is assessed as specified in the activity schedule (Tables 10 and 11). The C-SSRS is being implemented to ensure that patients who are experiencing suicidal ideation or behavior are appropriately identified and adequately managed.

[0601] Adverse events and serious adverse events

[0602] Adverse events are reported by the patient (or, when appropriate, by the caregiver, surrogate, or legally authorized representative of the patient) to the investigator or a qualified designee.

[0603] The investigator or qualified designee is responsible for detecting, recording, and documenting events that meet the definition of an AE or SAE and for follow-up of serious events that are considered to be related to study drug or study procedures; or events that lead to patient discontinuation of study drug.

[0604] Time period and frequency of collecting adverse event and serious adverse event information

[0605] All AEs were collected from the signing of the ICF until 8 weeks after the last dose of study drug.

[0606] Recording of medical events that began before study drug initiation but after informed consent was obtained was performed.

[0607] All SAEs are recorded and reported to the Sponsor or designee within 24 hours. The Investigator submits any updated SAE data to the Sponsor within 24 hours of becoming aware of it.

[0608] The Investigator has no obligation to actively search for AEs or SAEs after study participation has ended. However, if the Investigator learns of any SAE, including death, at any time after a patient has withdrawn from the study, the Investigator will promptly notify the Sponsor, regardless of whether the event was related to study drug.

[0609] Methods for detecting adverse events and serious adverse events

[0610] When detecting AEs and / or SAEs, care should be taken not to introduce bias. Open-ended, non-leading verbal questioning of patients is the preferred method for inquiring about the occurrence of AEs.

[0611] Follow-up of adverse events and serious adverse events

[0612] Following the initial AE / SAE report, the investigator is asked to actively follow up each patient at subsequent visits / contacts. All SAEs will be followed until resolved, stabilized, the event is otherwise explained, or the patient is lost to follow-up (as defined herein).

[0613] Regulatory reporting requirements for serious adverse events

[0614] ·The researcher notifies the sponsor SAE within 24 hours of first becoming aware of the incident.

[0615] The sponsor has a legal responsibility to inform local and other regulatory authorities about the safety of the investigational drug in clinical studies. The sponsor complies with country-specific regulatory requirements related to safety reporting to the regulatory agency IRB / IEC and investigators.

[0616] Reports to the Council for International Organizations of Medical Sciences (CIOMS) or MedWatch are prepared for suspected unexpected serious adverse reactions (SUSARs) in accordance with local regulatory requirements and sponsor policies and forwarded to investigators when necessary. Alexion's procedures for reporting SUSARs comply with the U.S. Code of Federal Regulations (CFR) Title 21 312.32 and the European Clinical Trials Directive 2001 / 20 / EC and related detailed regulations.

[0617] Guidance documents or national regulatory requirements of participating countries and, where applicable, the IRB / IEC.

[0618] • Investigators who receive an Investigator Safety Report or other specific safety information (e.g., SAE Summary or Listing) from the Sponsor describing the SAE review and acknowledge the report and notify the IRB / IEC as appropriate according to local requirements.

[0619] Pregnant

[0620] For patients of childbearing potential, a serum pregnancy test (i.e., β-human chorionic gonadotropin) is performed at Screening and at EOS / ET. A urine pregnancy test is performed at all other required time points as indicated in the activity schedule (Tables 10 and 11). A negative pregnancy test is required prior to administering ravulizumab to patients of childbearing potential.

[0621] If a pregnancy was reported, the investigator was to notify the Sponsor within 24 hours of learning of the pregnancy.

[0622] Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomaly, and ectopic pregnancy) were considered SAEs and reported.

[0623] Vaccine and antibiotic prevention

[0624] As with any terminal complement antagonist, use of ravulizumab increases the susceptibility of patients to meningococcal infection (Neisseria meningitidis). To reduce the risk of meningococcal infection, all patients were vaccinated against meningococcal infection within 3 years before or at the time of starting study drug. Patients who started study drug therapy less than 2 weeks after receiving a meningococcal vaccine received appropriate prophylactic antibiotic therapy until 2 weeks after vaccination.

[0625] Vaccines against serotypes A, C, Y, W135, and B, when available, are recommended to protect against common pathogenic meningococcal serotypes. Patients should be vaccinated or revaccinated according to current national vaccination guidelines or local practice for vaccination with complement inhibitors (e.g., eculizumab).

[0626] Vaccination may not be sufficient to prevent meningococcal infection. Appropriate use of antimicrobials should be considered in accordance with official guidelines and local practice. Monitor all patients for early signs of meningococcal infection and if infection is suspected, evaluate promptly and treat with appropriate antibiotics if necessary.

[0627] To increase risk awareness and facilitate rapid disclosure of any potential signs or symptoms of infection experienced by patients during the study, patients were provided with safety cards to carry with them at all times. Additional discussion and explanation of potential risks, signs, and symptoms were conducted at each visit as part of review of the patient safety card, as described in the activity schedule (Tables 10 and 11). Vaccination status for Neisseria meningitidis was recorded.

[0628] Study drug administration response

[0629] Local and systemic reactions

[0630] Infusion site reactions are those reactions located at the IV study drug administration site and include reactions such as erythema, itching, and bruising. Infusion-related reactions are systemic in nature and may be immune or non-immune mediated, typically occurring within a few hours after study drug administration. Immune-mediated reactions include allergic reactions (e.g., anaphylaxis), while non-immune mediated reactions are non-specific (e.g., headache, dizziness, nausea). Monitoring of these reactions is part of the routine safety assessment of this study.

[0631] Infusion-related reactions

[0632] Infusion-related reactions were defined as systemic AEs occurring during or within 24 hours of the start of the intravenous infusion (e.g., fever, chills, flushing, changes in HR and BP, dyspnea, nausea, vomiting, diarrhea, and generalized rash) that were assessed by the investigator as possibly, probably, or definitely related to the study drug.

[0633] Adverse Events of Special Interest

[0634] This study collected meningococcal infection as an adverse event of special interest (AESI).

[0635] Pharmacokinetics

[0636] Blood samples were obtained to assess serum ravulizumab concentrations before and after treatment at the time points and windows specified in the active schedule (see, Tables 10 and 11). Samples obtained outside of the allocated windows were considered protocol deviations. Unused samples were retained for up to 5 years for additional assessment if necessary.

[0637] Pharmacodynamics

[0638] Blood samples were obtained at the time points and windows specified in the activity schedule (Tables 10 and 11) to assess serum free C5 before and after treatment. Samples obtained outside the allocated windows were considered protocol deviations. Unused samples were retained for up to 5 years for additional assessments when necessary.

[0639] Biomarkers

[0640] Blood samples were obtained at the time points specified in the activity schedule (Tables 10 and 11) for AChR autologous Ab assessment.

[0641] Medical resource utilization and health economics

[0642] Healthcare resource utilization and health economic data related to medical encounters were collected for all patients by the investigator or designee throughout the study period. Data were recorded. Protocol-required procedures, tests, and contacts were excluded.

[0643] The data collected were used to conduct an exploratory economic analysis and included:

[0644] The number and duration of medical care received, including surgeries and other selected procedures (inpatient and outpatient);

[0645] Duration of hospital stay (total number of days or length of stay, including duration in a ward (e.g., intensive care unit));

[0646] ·The number and type of diagnostic and therapeutic tests and procedures;

[0647] Outpatient medical care and treatment (including doctor or emergency room visits, tests and procedures, and medications).

[0648] 11. Statistical considerations

[0649] The statistical methods described in this article are further elaborated in a separate SAP. The SAP was developed and completed before the database was locked. Statistical software system version 9.4 or higher was used for analysis. Statistical analysis included summary data tables, inferential analysis, patient lists and numbers. Inference of power analysis was based on 2-sided type I error (α) = 5%. Summary statistics for continuous variables included at least n, mean, standard deviation, minimum, median and maximum. For categorical variables, frequencies and percentages were presented.

[0650] Baseline values ​​for analysis and reporting were based on the last non-missing measurement on or before the day of the first dose of study drug. Treatment groups for analysis and reporting were based on the conventions outlined in Table 18. 'Total' groups were formed to report demographic data, baseline characteristics, and other pre-study information, such as pre-study SAEs, medical history, or prior medications. Details on the imputation of efficacy data are described in SAP. Missing safety data were not imputed.

[0651] Statistical assumptions

[0652] Main assumptions

[0653] The primary hypothesis of this study was that ravulizumab would be superior to placebo in improving the MG-ADL total score at week 26.

[0654] The treatment effect based on the primary endpoint was estimated by the mean difference in the change from baseline in the MG-ADL total score at week 26 between the ravulizumab group and the placebo group, regardless of rescue therapy 1. Lower values ​​of the corresponding estimate indicate a beneficial treatment effect.

[0655] Secondary assumptions

[0656] The following secondary hypotheses were included in the per-study multiplicity adjustment (assuming the null hypothesis for the primary endpoint was rejected) and are provided herein.

[0657] Ravolizumab was superior to placebo in improving the QMG total score at week 26.

[0658] Hypotheses Related to Exploratory Efficacy Goals

[0659] 1. Ravolizumab was superior to placebo in reducing the incidence of all-cause hospitalization or clinical worsening over 26 weeks.

[0660] 2. Ravolizumab was superior to placebo in improving the MG-QOL1 5r total score at week 26.

[0661] 3. Ravolizumab was superior to placebo in improving the total neurological QOL fatigue score at week 26.

[0662] 4. Ravolizumab was superior to placebo in improving the MGC total score at week 26.

[0663] 5. Ravolizumab was superior to placebo in terms of QMG 5-point response (QMG total score improved by ≥5 points relative to baseline) at Week 26.

[0664] 6. Ravolizumab was superior to placebo in terms of MG-ADL 3-point response (MG-ADL total score improved by ≥3 points relative to baseline) at week 26.

[0665] 7. Ravolizumab was superior to placebo in terms of MGFA-PIS at week 26.

[0666] 8. Ravolizumab was superior to placebo in improving the EQ-5D-5L index score at week 26.

[0667] 9. Ravolizumab was superior to placebo in terms of improvement in EQ-5D-5L VAS scores at week 26.

[0668] Estimates of the treatment effect corresponding to changes from baseline for continuous end points were similar to those for the primary end point.

[0669] The treatment effects corresponding to the following dichotomous end points were estimated by the odds ratio (OR) of the proportion of the corresponding end point in the ravulizumab group versus the placebo group:

[0670] a. Incidence of all-cause hospitalization or clinical deterioration within 26 weeks, without considering rescue therapy.

[0671] b. QMG 5-point response at week 26, without consideration of rescue therapy.

[0672] c. MG-ADL 3-point response at week 26, without consideration of rescue therapy.

[0673] An estimate of OR < 1 for the composite hospitalization endpoint indicates a beneficial treatment effect, and similarly, an estimate of OR > 1 for the responder endpoint indicates a beneficial treatment effect.

[0674] The treatment effect corresponding to the MGFA-PIS endpoint will be estimated by the OR of the cumulative proportion of this endpoint in the ravulizumab group compared to the common category (starting from the best outcome) at Week 26, regardless of rescue therapy, compared to the placebo group. An estimate of OR>1 indicates a beneficial treatment effect.

[0675] Sample size determination

[0676] Approximately 160 patients were randomized to the ravulizumab and placebo groups stratified by region (North America, Europe, Asia Pacific, and Japan) in a 1:1 ratio (ravulizumab:placebo group) to ensure at least 90% nominal power to reject the null hypothesis of no treatment differences for the primary and secondary endpoints based on a 2-sided type I error (α) = 5%. Assumptions related to the statistical power calculations were based on study ECU-MG-301. Details are provided as defined herein.

[0677] Table 18: Study ALXN1210-MG-306 Analysis Set

[0678]

[0679] 1For this purpose, applicable major protocol deviations will be identified prior to database lock and study unblinding.

[0680] Statistical analysis

[0681] Registration and disposal

[0682] The numbers of patients screened, those who failed screening, and those who were randomized are presented. Enrollment information is presented by stratification factor and treatment group. The numbers and reasons for discontinuation of treatment in the randomized controlled phase, OLE phase, and the entire study are summarized.

[0683] Demographics, baseline characteristics, inclusion and exclusion criteria, and protocol deviations

[0684] All demographic information and baseline characteristics are reported by treatment group and overall. No statistical tests were performed to determine homogeneity between treatment groups.

[0685] The number and percentage of patients who did not meet specific inclusion or exclusion criteria were summarized. A similar summary of major protocol deviations was provided based on prespecified categories.

[0686] Medical / surgical history, physical examination, and history of myasthenia gravis

[0687] Medical and surgical history were summarized by system organ class (SOC) and priority terms according to the Medical Dictionary for Regulatory Activities (MedDRA), version 20.1 or later. MG and abnormal physical examinations were also summarized.

[0688] Prior and concomitant medications

[0689] For analysis and reporting purposes, any medication started before the first dose of study drug was considered prior medication; medications started at or after the first dose of study drug were considered concomitant medications. All prior and concomitant medications, including MG-specific medications and rescue therapies (if any) during the study period were summarized.

[0690] Efficacy analysis

[0691] Primary efficacy analysis

[0692] Using all available longitudinal data (complete or partial), a mixed effects model (MMRM) for repeated measures was used for the primary efficacy endpoint (change from baseline in the total MG-ADL score at week 26), regardless of whether the patient received rescue therapy. Rescue therapy included high-dose corticosteroids, PP / PE, or IVIg. If rescue therapy was not administered (e.g., emergency), or if the patient experienced clinical deterioration, it was allowed when the patient's health was at risk. For the primary analysis, missing data were not imputed. The model included changes in baseline scores of MG-ADL as response variables at each pre-specified time point, fixed categorical effects of treatment, study visits and interactions between treatment and study visits, and region; and fixed covariates for baseline MG-ADL total scores. The treatment effect was assessed by comparison of the visit treatment period at week 26. An unstructured covariance matrix was used to model the correlation between repeated measures within each patient. If convergence problems occurred, other covariance structures were implemented (details will be provided in SAP). The Kenward-Rogers method was used to estimate the denominator degrees of freedom.

[0693] Sensitivity Analysis of the Primary End Point

[0694] Two sensitivity analyses of the primary efficacy endpoint were performed to explore the robustness of the MMRM results to the primary efficacy analysis:

[0695] 1. Sensitivity analysis based on placebo:

[0696] The placebo-based sensitivity analysis accounted for the missing not at random (MNAR) mechanism for missing data, in which patients who discontinued ravulizumab early were assumed to follow a similar outcome trajectory to the placebo group after discontinuation of ravulizumab, taking into account the observed values ​​before discontinuation.

[0697] 2. Critical point sensitivity analysis:

[0698] This approach assumed that patients who discontinued ravulizumab treatment experienced a progression, defined as a prespecified adjustment for the primary efficacy endpoint.

[0699] Secondary and Exploratory Endpoint Analyses

[0700] Analyses of all continuous secondary and exploratory end points related to change from baseline were similar to those for the primary end point.

[0701] The composite endpoint of clinical worsening or all-cause hospitalization was analyzed using a logistic regression model with treatment group, region, and individual components (clinical worsening and all-cause hospitalization, respectively) were also analyzed in a similar manner.

[0702] The QMG 5-point and MG-ADL 3-point response endpoints were analyzed using mixed-effects repeated measures models. The models included response variables as dependent variables, fixed categorical effects of treatment, study visit and interaction of treatment and study visit, and region at each pre-specified time point; and fixed covariates of baseline QMG or MG-ADL total score (depending on the response variable). Treatment effects were assessed by comparison of visit treatment periods at week 26. Unstructured covariance matrices were used to model the correlations between repeated measures within each patient. If convergence issues occurred, other covariance structures were implemented (details will be provided in SAP).

[0703] The MGFA-PIS endpoint was considered as an ordinal scale at week 26. Logistic regression of the cumulative odds (cumulative across categories starting from the best outcome) was performed using treatment as a fixed categorical effect and adjusting for region.

[0704] A descriptive summary of the long-term efficacy data was performed based on the OLE set.

[0705] Adjustment for Multiplicity of Primary and Secondary End Points

[0706] This study was designed to be robustly controlled for an overall 2-sided type I error of α = 0.05. The primary null hypothesis was first tested at α = 0.05. If statistically significant, the secondary efficacy hypothesis was then tested at α = 0.05.

[0707] Per-Protocol Analyses of Primary and Secondary End Points

[0708] Supplementary per-protocol analyses of the primary and secondary endpoints were performed based on the per-protocol set (PPS) in the same manner as the FAS.

[0709] Security Analysis

[0710] The safety and tolerability of ravulizumab were evaluated based on adverse events, clinical laboratory test results, vital sign results, and ECG abnormalities. Safety analyses were performed in the safety population and the OLE set based on the study period considered.

[0711] Adverse event analysis

[0712] AEs were analyzed and reported based on treatment-emergent adverse events (TEAEs), including treatment-emergent serious adverse events (TESAEs), defined as AEs occurring at or after the first dose of ravulizumab during the randomized controlled period. Treatment-emergent AEs and TESAEs were summarized by MedDRA SOC and preferred terms, severity, and relationship to study drug. Patient-year adjusted event rates were generated to characterize the long-term safety profile.

[0713] Analysis of clinical laboratory parameters, vital signs measurements, and electrocardiogram parameters

[0714] Laboratory measurements at each visit were summarized descriptively, along with their change from baseline and shift from baseline, if applicable. Important ECG, vital sign, and pulse oximetry results were also summarized using descriptive analysis.

[0715] Other safety analyses

[0716] The number and percentage of patients in each C-SSRS category and offset analyses were generated. The results of pregnancy tests were summarized.

[0717] Pharmacokinetic and pharmacodynamic analysis

[0718] Pharmacokinetic parameters, such as peak and trough serum ravulizumab concentrations, were reported and summarized. Population PK analysis of ravulizumab was performed using sparse PK data to characterize the PK of ravulizumab in patients with gMG. Population PK analysis was used to estimate key ravulizumab PK parameters, such as clearance, volume of distribution, and terminal half-life. The potential impact of intrinsic and extrinsic factors on the PK of ravulizumab was also evaluated. Pharmacodynamic data (free C5 before and after treatment) were reported and summarized. The correlation between PK and PD was explored. Additional analyses were considered if applicable.

[0719] Immunogenicity analysis

[0720] The presence of ADA in serum ravulizumab was assessed during the study. Immunogenicity results were analyzed by summarizing the number and percentage of patients with detectable ADA. The correlation of ADA with ravulizumab concentrations, PD parameters, efficacy, and TEAEs was evaluated.

[0721] Exploratory biomarker analysis

[0722] AChR antibody levels at each visit and their changes from baseline were summarized descriptively.

[0723] Interim Analysis

[0724] No interim analyses were planned for Study ALXN1210-MG-306 during the randomized controlled period. The primary analysis was performed when the last patient completed the randomized controlled period, the database was locked, and the study randomization schedule was unblinded. Periodic analyses and reports were performed during the OLE as required by regulations. The final analysis and reports were performed at the end of the study.

[0725] Additional details on sample size determination

[0726] Power calculations were based on the longitudinal change from baseline in MG-ADL total score observed in Study ECU-MG-301. Power was calculated based on a model-based treatment effect in MG-ADL using a simulation-based approach. A total of 160 patients were required to ensure at least 90% power to reject the null hypothesis of no treatment effect based on the change from baseline in MG-ADL total score at Week 26. Further details are provided in the SAP.

[0727] Additional details of the sensitivity analysis of the primary endpoint

[0728] To assess the confidence of the primary analysis, the following sensitivity analyses were planned based on sufficiently unfavorable assumptions for the ravulizumab group to constitute a convincing stress test of the primary analysis.

[0729] Sensitivity analysis based on placebo

[0730] The placebo-based sensitivity analysis took into account the MNAR mechanism for missing data, where it was assumed that patients in the early discontinuation group of ravulizumab followed a similar outcome trajectory to the placebo group after discontinuation of ravulizumab, taking into account 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 was assumed that patients who discontinued placebo early had similar unobserved outcomes to placebo patients who continued to receive randomized treatment. The assumption that the efficacy profile of patients who withdrew after discontinuation of ravulizumab was similar to that of patients in the placebo group if received at the time point of interest provides an efficacy estimate that can be attributed to patients in the ravulizumab group while restricting the efficacy after early discontinuation to that of the placebo group.

[0731] Critical point sensitivity analysis

[0732] Additional sensitivity analyses were performed based on a δ-adjusted stress testing approach (critical point analysis). This approach assumes that patients who discontinue active treatment experience a deterioration in the primary efficacy endpoint defined by a pre-specified adjustment (δ) compared to the observed efficacy score of patients who continue in the study to the next visit (O'Kelley M RB, Statistics in Practice. 1st ed. Chichester, West Sussex, UK: John Wiley & Sons, Ltd; 2014. pp. 257-368). Since a negative change in the QMG total score indicates improvement, the preset value of δ is a non-negative fixed quantity. For each δ value, a treatment effect is determined, and δ values ​​with a nominal 2-sided p value exceeding 0.05 are considered "critical points", i.e., when patients who are assumed to withdraw experience this fixed deterioration after the discontinuation visit, the positive conclusions drawn from the primary analysis will be reversed. After determining such a critical point, clinical judgment will be applied to the reasonableness of the assumptions underlying this critical point. It is expected that this approach will inform what is needed to overturn the conclusions of the study under different assumptions about missing data. Setting the δ value to zero is considered equivalent to the primary analysis.

[0733] Sequence Summary

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

Claims

1. 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, wherein the composition comprises an antibody or antigen-binding fragment thereof comprising the CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and the CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively.

2. A composition for use according to claim 1, wherein the antibody or the antigen-binding fragment thereof comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, all using EU numbering.

3. A composition for use according to any one of the preceding claims, wherein the antibody or the antigen-binding fragment thereof: (a) Administer once on day 1 of the administration cycle at a loading dose of: i. 2400 mg for patients weighing ≥40 to <60 kg, ii. 2700 mg for patients weighing ≥60 to <100 kg, or iii. 3000 mg for patients weighing ≥100 kg; and (b) on Day 15 of the administration cycle and every eight weeks thereafter at a maintenance dose of: i. Administer 3000 mg to patients weighing ≥40 to <60 kg, ii. 3300 mg for patients weighing ≥60 to <100 kg, or iii Administer 3600 mg to patients weighing ≥100 kg.

4. A composition for use according to any one of the preceding claims, wherein the antibody or the antigen-binding fragment thereof comprises the heavy chain variable region of SEQ ID NO: 12 and the light chain variable region of SEQ ID NO:

8.

5. A composition for use according to any one of the preceding claims, wherein the antibody or the antigen-binding fragment thereof further comprises a heavy chain constant region of SEQ ID NO:

13.

6. A composition for use according to any one of the preceding claims, 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.

7. A composition for use according to any one of the preceding claims, wherein the antibody or the antigen-binding fragment thereof has a pH of 7.4 and 25°C at 0.1 nM ≤ K D Affinity dissociation constants (K) in the range of ≤1 nM D ) binds to human C5.

8. A composition for use according to any one of the preceding claims, wherein the antibody or the antigen-binding fragment thereof has a K of 1. D ≥10nM binding to human C5.

9. The composition for use according to any one of the preceding claims, wherein the antibody or the antigen-binding fragment thereof is administered to a patient weighing ≥40 to <60 kg: (a) administered once on day 1 of the administration cycle as a loading dose of 2400 mg; and (b) a maintenance dose of 3000 mg on day 15 of the administration cycle and every eight weeks thereafter.

10. The composition for use according to any one of claims 1 to 8, wherein the antibody or the antigen-binding fragment thereof is administered to a patient weighing ≥60 to <100 kg: (a) administered once on day 1 of the administration cycle as a loading dose of 2700 mg; and (b) a maintenance dose of 3300 mg on day 15 of the administration cycle and every eight weeks thereafter.

11. A composition for use according to any one of claims 1 to 8, wherein the antibody or the antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg: (a) administered once on day 1 of the administration cycle as a loading dose of 3000 mg; and (b) a maintenance dose of 3600 mg on day 15 of the administration cycle and every eight weeks thereafter.

12. The composition for use according to any one of the preceding claims, wherein the treatment maintains a serum trough concentration of the antibody or the antigen-binding fragment thereof at 100 μg / mL or greater during the administration period.

13. A composition for use according to any preceding claim, wherein said treatment maintains a serum trough concentration of said antibody or said antigen-binding fragment thereof at 200 μg / mL or greater during said administration period.

14. A composition for use according to any preceding claim, wherein the treatment maintains the free antibody or antigen-binding fragment thereof concentration at 0.309 to 0.5 g / mL or less.

15. The composition for use according to any one of the preceding claims, wherein the antibody or the antigen-binding fragment thereof is administered at a dose of 3000 mg, 3300 mg or 3600 mg every eight weeks after the administration cycle for up to two years.

16. A composition for use according to any preceding claim, wherein the antibody or the antigen-binding fragment thereof is formulated for intravenous administration.

17. A composition for use according to any preceding claim, wherein the patient has not been previously treated with a complement inhibitor.

18. A composition for use according to any preceding claim, wherein the administration period is a total of 26 weeks of treatment.

19. A composition for use according to any preceding claim, wherein the treatment results in terminal complement inhibition.

20. A composition for use according to any preceding claim, wherein the treatment causes the patient to experience a clinically meaningful improvement (reduction) in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score after 26 weeks of treatment.

21. The composition for use according to claim 20, wherein the clinically meaningful improvement experienced by the patient is a decrease in the patient's MG-ADL score of at least 3 points after 26 weeks of treatment.

22. A composition for use according to any preceding claim, wherein the treatment results in a clinically meaningful improvement (reduction) in the Quantitative Myasthenia Gravis (QMG) score after 26 weeks of treatment.

23. The composition for use according to claim 22, wherein the clinically meaningful improvement experienced by the patient is a decrease in the patient's QMG by at least 5 points after 26 weeks of treatment.

24. A composition for use according to any preceding claim, wherein the treatment results in a clinically meaningful improvement (reduction) in the Myasthenia Gravis Composite (MGC) score after 26 weeks of treatment.

25. A composition for use according to any preceding claim, wherein the treatment results in a clinically meaningful improvement (reduction) in quality of life as measured by the Myasthenia Gravis Quality of Life (MG-QOL 15r) score after 26 weeks of treatment.

26. A composition for use according to any preceding claim, wherein the treatment results in a clinically meaningful improvement (reduction) in neurological fatigue as measured by the Neurological QOL Fatigue score after 26 weeks of treatment.

27. A composition for use according to any preceding claim, wherein the treatment results in a clinically meaningful improvement (reduction) in health status as measured by the European Quality of Life (EQ-5D-5L) health status score after 26 weeks of treatment.

28. A composition for use according to any preceding claim, wherein the treatment results in a clinically meaningful improvement (reduction) in the Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Status (PIS) after 26 weeks of treatment.

29. A composition for use according to any one of claims 1 to 28, wherein the myasthenia gravis is generalized myasthenia gravis (gMG).

30. The composition for use according to claim 29, wherein the gMG patient is positive for anti-AChR antibodies.

31. A composition for use according to any preceding claim, wherein the antibody is Ravolizumab.

32. 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 CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence shown in SEQ ID NO: 12, and CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence shown in SEQ ID NO: 8; and (b) instructions for use of the antibody or antigen-binding fragment thereof according to any one of the preceding claims.

33. A kit according to claim 32, wherein the antibody or the antigen-binding fragment thereof comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, all using EU numbering.

34. The kit of claim 32, wherein the antibody or the antigen-binding fragment thereof is administered to a patient weighing ≥40 to <60 kg: (a) administered once on day 1 of the administration cycle as a loading dose of 2400 mg; and (b) a maintenance dose of 3000 mg on day 15 of the administration cycle and every eight weeks thereafter.

35. The kit of claim 32, wherein the antibody or antigen-binding fragment thereof is administered to a patient weighing ≥60 to <100 kg: (a) administered once on day 1 of the administration cycle at a dose of 2700 mg; and (b) a maintenance dose of 3300 mg on day 15 of the administration cycle and every eight weeks thereafter.

36. The kit of claim 32, wherein the antibody or the antigen-binding fragment thereof is administered to a patient weighing ≥100 kg: (a) administered once at a dose of 3000 mg on day 1 of the administration cycle; and (b) a maintenance dose of 3600 mg on day 15 of the administration cycle and every eight weeks thereafter.

37. The kit of any one of claims 32 to 36, wherein the antibody is Ravolizumab.

38. An antibody for use in an administration method during a treatment cycle, wherein the antibody comprises CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence shown in SEQ ID NO: 12, and CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence shown in SEQ ID NO:

8.

39. An antibody for use according to claim 38, wherein the antibody or the antigen-binding fragment thereof comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, all using EU numbering.

40. An antibody for use according to claim 38 or claim 39, wherein the antibody: (a) Administer once on day 1 of the administration cycle at a loading dose of: i. 2400 mg for patients weighing ≥40 to <60 kg, ii. 2700 mg for patients weighing ≥60 to <100 kg, or iii. 3000 mg for patients weighing ≥100 kg; and (b) on Day 15 of the administration cycle and every eight weeks thereafter at a maintenance dose of: i. Administer 3000 mg to patients weighing ≥40 to <60 kg, ii. 3300 mg for patients weighing ≥60 to <100 kg, or iii. Administer 3600 mg to patients weighing ≥100 kg.

41. The antibody for use according to claim 38, wherein the antibody is determined to be safe, tolerable, effective and sufficiently non-immunogenic following multiple IV doses in MG patients.

42. The antibody for use according to any one of claims 38 to 41, wherein the antibody is Ravolizumab.

43. A method of treating a human patient suffering from myasthenia gravis (MG), the method comprising administering to the patient an effective amount of an antibody or antigen-binding fragment thereof comprising the CDR1, CDR2 and CDR3 heavy chain sequences as shown in SEQ ID NOs: 19, 18 and 3, respectively, and the CDR1, CDR2 and CDR3 light chain sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively.

44. The method of claim 43, wherein the antibody or antigen-binding fragment thereof comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, all using EU numbering.

45. The method of claim 41 or claim 44, wherein the antibody or the antigen-binding fragment thereof: (a) Administer once on day 1 of the administration cycle at a loading dose of: i. 2400 mg for patients weighing ≥40 to <60 kg, ii. 2700 mg for patients weighing ≥60 to <100 kg, or iii. 3000 mg for patients weighing ≥100 kg; and (b) on Day 15 of the administration cycle and every eight weeks thereafter at a maintenance dose of: i. Administer 3000 mg to patients weighing ≥40 to <60 kg, ii. 3300 mg for patients weighing ≥60 to <100 kg, or iii Administer 3600 mg to patients weighing ≥100 kg.

46. ​​The method of any one of claims 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.

47. The method of any one of claims 43 to 46, wherein the antibody or the antigen-binding fragment thereof further comprises a heavy chain constant region of SEQ ID NO:

13.

48. The method of any one of claims 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.

49. The method according to any one of claims 43 to 48, wherein the antibody or the antigen-binding fragment thereof has a pH of 7.4 and 25°C at 0.1 nM ≤ K D Affinity dissociation constants (K) in the range of ≤1 nM D ) binds to human C5.

50. The method according to any one of claims 43 to 49, wherein the antibody or the antigen-binding fragment thereof is at a pH of 6.0 and 25° C. D ≥10nM binding to human C5.

51. The method according to any one of claims 43 to 50, wherein the antibody or the antigen-binding fragment thereof is administered to a patient weighing ≥40 to <60 kg: (a) administered once on day 1 of the administration cycle as a loading dose of 2400 mg; and (b) a maintenance dose of 3000 mg on day 15 of the administration cycle and every eight weeks thereafter.

52. The method according to any one of claims 43 to 50, wherein the antibody or the antigen-binding fragment thereof is administered to a patient weighing ≥60 to <100 kg: (a) administered once on day 1 of the administration cycle as a loading dose of 2700 mg; and (b) a maintenance dose of 3300 mg on day 15 of the administration cycle and every eight weeks thereafter.

53. The method according to any one of claims 43 to 50, wherein the antibody or the antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg: (a) administered once on day 1 of the administration cycle as a loading dose of 3000 mg; and (b) a maintenance dose of 3600 mg on day 15 of the administration cycle and every eight weeks thereafter.

54. The method of any one of claims 43 to 53, wherein the treatment maintains a serum trough concentration of the antibody or antigen-binding fragment thereof at 100 μg / mL or greater during the administration period.

55. The method of any one of claims 43 to 54, wherein the treatment maintains a serum trough concentration of the antibody or antigen-binding fragment thereof at 200 μg / mL or greater during the administration period.

56. The method of any one of claims 43 to 55, wherein the treatment maintains free antibody concentration at 0.309 to 0.5 μg / mL or less.

57. The method of any one of claims 43 to 56, wherein the antibody or the antigen-binding fragment thereof is administered at a dose of 3000 mg, 3300 mg or 3600 mg every eight weeks for up to two years after the administration cycle.

58. The method of any one of claims 43 to 57, wherein the antibody or the antigen-binding fragment thereof is formulated for intravenous administration.

59. The method of any one of claims 43 to 58, wherein the patient has not been previously treated with a complement inhibitor.

60. The method of any one of claims 43 to 59, wherein the administration cycle is a total of 26 weeks of treatment.

61. The method of any one of claims 43 to 60, wherein the treatment results in terminal complement inhibition.

62. The method of any one of claims 43 to 61, wherein the treatment causes the patient to experience a clinically meaningful improvement (reduction) in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score after 26 weeks of treatment.

63. The method of claim 62, wherein the clinically meaningful improvement experienced by the patient is a decrease in the patient's MG-ADL score of at least 3 points after 26 weeks of treatment.

64. The method of any one of claims 43 to 63, wherein the treatment results in a clinically meaningful improvement (reduction) in the quantitative myasthenia gravis (QMG) score after 26 weeks of treatment.

65. The method of claim 64, wherein the clinically meaningful improvement experienced by the patient is a decrease in the patient's QMG of at least 5 points after 26 weeks of treatment.

66. The method of any one of claims 43 to 65, wherein the treatment results in a clinically meaningful improvement (reduction) in the Myasthenia Gravis Composite (MGC) score after 26 weeks of treatment.

67. The method of any one of claims 43 to 65, wherein the treatment results in a clinically meaningful improvement (reduction) in quality of life as measured by the Myasthenia Gravis Quality of Life (MG-QOL15r) score after 26 weeks of treatment.

68. The method of any one of claims 43 to 66, wherein the treatment results in a clinically meaningful improvement (reduction) in neurological fatigue as measured by the Neurological QOL Fatigue score after 26 weeks of treatment.

69. The method of any one of claims 43 to 68, wherein the treatment results in a clinically meaningful improvement (reduction) in health status as measured by the European Quality of Life (EQ-5D-5L) health status score after 26 weeks of treatment.

70. The method of any one of claims 43 to 69, wherein the treatment results in a clinically meaningful improvement (reduction) in the Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Status (PIS) after 26 weeks of treatment.

71. The method of any one of claims 43 to 70, wherein the myasthenia gravis is generalized myasthenia gravis (gMG).

72. The method of claim 71, wherein the gMG patient is positive for anti-AChR antibodies.

73. The method of any one of claims 43 to 72, wherein the antibody is Ravolizumab.

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