EA046524B1 - DOSE AND ADMINISTRATION OF ANTI-C5 ANTIBODIES FOR THE TREATMENT OF GENERALIZED MYASTHENIAS GRAVIS - Google Patents

Description

State of the art

The complement system works in conjunction with the body's other immunological systems to protect against invading 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 protective functions by interacting in a series of complex but precise enzymatic cleavage and membrane binding events. The resulting complement cascade leads to the formation of products with opsonic, immunoregulatory and lytic functions.

Myasthenia gravis (MG) is a rare, debilitating acquired autoimmune neurological disease of the neuromuscular junction (NMJ) caused by a disorder of neuromuscular transmission that results from the binding of autoantibodies (auto-Abs) to proteins involved in signaling at the NMJ. These proteins include nicotinic acetylcholine receptors (AChRs) or, less commonly, muscle-specific tyrosine kinase (MuSK), which is involved in AChR clustering.

MG can cause life-threatening respiratory failure called myasthenic crisis. The prevalence of MG is 14-20 per 100,000 in the US, affecting approximately 60,000 Americans. It affects men and women equally, although incidence in women peaks in the 3rd decade, compared with men, whose peak age of onset is in the 6th or 7th decade. Approximately 15 to 20% of subjects will experience myasthenic crisis during the course of the disease, 75% within 2 years of diagnosis, requiring hospitalization and mechanical ventilation. The mortality rate from MG is approximately 4%, mainly due to respiratory failure.

Myasthenia gravis is clinically characterized by weakness and fatigue of voluntary skeletal muscles. MG may initially present with weakness of the eye muscles, affecting the movement of the eyes and eyelids, called ocular MG (oMG). In ten percent of subjects, the disease is limited to the eye muscles. Ninety percent of subjects have generalized MG with weakness of the neck, head, spine, bulbar, respiratory, or limb muscles. Bulbar weakness refers to muscles controlled by nerves coming from the bulbous part of the brainstem and manifests itself as difficulty speaking, chewing, swallowing, and controlling the head.

Patients with generalized myasthenia gravis (gMG) differ from the group of patients with ocular myasthenia gravis (oMG) in that the neuromuscular inflammation and clinical findings obtained are not limited only to the ocular muscles, but affect all voluntary muscle groups: bulbar, respiratory muscles, head, neck muscles , trunk or peripheral muscles with or without eye involvement. Profound weakness and devastating effects including slurred speech, dysarthria, dysphagia, blurred vision, shortness of breath (both active and at rest), upper and lower extremity weakness, impaired mobility, markedly decreased ability to perform activities of daily living (ADLs) , extreme fatigue and episodes of pulmonary failure requiring mechanical ventilation are the hallmark characteristics of gMG. Compared with patients with isolated oMG, patients with gMG have a higher incidence and higher disease burden. gMG is a rare disease with an estimated prevalence of 145 to 278 cases per million. Patients with gMG suffer from a devastating inflammatory neuromuscular disorder with limited therapeutic options.

Often, hospitalizations for exacerbations associated with gMG require respiratory support, including mechanical ventilation due to respiratory failure (eg, myasthenic crisis) and placement of a gastrointestinal tube for nutritional support and prevention of aspiration associated with dysphagia. In patients with more advanced gMG, mortality was reported to increase to 40% 10 years after diagnosis.

Although there is no cure for MG, there are therapies that reduce muscle weakness and improve neuromuscular function. Currently available treatments for myasthenia gravis are aimed at modulating neuromuscular transmission, suppressing the production or effects of pathogenic antibodies, or inhibiting inflammatory cytokines. Currently, specific treatments that target the underlying pathophysiology of NMJ injury, specifically the interaction of anti-AChR antibodies and AChRs leading to complement activation through the classical pathway and inflammation,

- 1 046524 which results in destruction of the NMJ is absent. There is no specific treatment aimed at correcting the autoimmune defect in MG. With immunosuppressive therapy (IST), the current standard of care, which typically combines cholinesterase inhibitors, corticosteroids, and immunosuppressive agents (most commonly azathioprine [AZA], cyclosporine, and mycophenolate mofetil [MMF]), most subjects with MG can achieve adequate control over your illness. However, these therapies may not be optimal for all patients, and there is a cohort of subjects who do not respond well to IST or cannot tolerate IST and those patients who require repeat treatments with plasmapheresis (PE) and/or intravenous immunoglobulin (IVIG). IVIg) to maintain clinical stability.

In difficult-to-control cases, patients with gMG experience unrelenting inflammation, tissue destruction, and resulting severe morbidity, including profound muscle weakness, impaired mobility, shortness of breath, pulmonary impairment, extreme fatigue, risk of aspiration, and marked impairment of ADLs. These patients are usually diagnosed in the prime of adulthood, with the average age of onset ranging from 36 to 60 years. As a result of the diseases associated with gMG, many patients are unable to work or have reduced productivity, have difficulty caring for themselves and others, and require assistance with talking, eating, moving, breathing, and performing ADLs.

Uncontrolled activation of the terminal complement complex has been implicated in experimental animal models of autoimmune gMG, as well as in other forms of human autoimmune neuropathy. Auto-Abs recognize target nerve or muscle tissues, including AChRs, leading to uncontrolled activation of the terminal complement complex on the surface of the nerve or muscle cell.

Autoantibody-driven uncontrolled activation of the terminal complement complex with membrane attack complex (MAC)-dependent lysis and activation, as well as C5a-dependent inflammation at the NMJ, causes AChR loss and failure of neuromuscular transmission. Consistent with this model, both complement component C3 fragments (C3a and C3b) and MAC C5b-9 were detected in the NMJ of MG patients.

Because there is no cure for MG and standard of care is not effective for all patients, there is a need for improved treatments for these patients.

The essence of the invention

The present invention provides compositions and methods for treating generalized myasthenia gravis (gMG) in a human patient, comprising administering to the patient an anti-C5 antibody or an antigen-binding fragment thereof, wherein the anti-C5 antibody or an antigen-binding fragment thereof is administered (or is intended to be administered) in accordance with a particular clinical condition. dosing regimen (i.e., in a specific dose amount and according to a specific dosing schedule).

Ravulizumab (also known as antibody BNJ441, ALXN1210 or Ultomiris™) contains heavy and light chains having the sequences shown in SEQ ID NO: 14 and 11, respectively, or antigen binding fragments and variants thereof. The terms BNJ441, ALXN1210, ravulizumab and Ultomiris™ may be used interchangeably throughout the invention, but they all refer to the same antibody. Accordingly, an exemplary antibody for use in the methods described herein is ravulizumab or an antibody containing the heavy and light chain complementarity determining regions (CDRs) or variable regions (VRs) of ravulizumab.

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

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

In some embodiments, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. , and a variant human Fc constant region that binds to the neonatal human Fc receptor (FcRn), wherein CH3

- 2 046524 human Fc variant constant region contains substitutions Met-429-Leu and Asn-435-Ser at residues corresponding to methionine 428 and asparagine 434, each of which is represented by EU numbering.

In some embodiments, the antibody competes for binding and/or binds to the same epitope on C5 as the aforementioned antibodies. In some embodiments, the antibody is at least about 90% identical to the amino acid sequence of the variable region of the aforementioned antibodies (e.g., at least about 90, 95, or 99% identical to the variable region of SEQ ID NO: 12 and SEQ ID NO: 8).

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

In some embodiments, patients treated in accordance with the methods described in this invention have been vaccinated against meningococcal infections 3 years before or at the time of initiation of treatment. In some embodiments, patients who received treatment less than 2 weeks after receiving the meningococcal vaccine also receive appropriate prophylactic antibiotics for 2 weeks after vaccination. In some embodiments, patients receiving treatment in accordance with the methods described in this invention are vaccinated against meningococcal serotypes A, C, Y, W135 and/or B.

In some embodiments, the dosage of the anti-C5 antibody or antigen-binding fragment thereof is based on the patient's body 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 antigen-binding fragment thereof is administered to a patient, depending on his body weight. In some embodiments, 2400 or 3000 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing >40 to <60 kg. In some embodiments, 2700 or 3300 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing >60 to <100 kg. In some embodiments, 3000 or 3600 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing >100 kg. In some embodiments, dosage regimens are adjusted to provide the optimal response required (eg, an effective response).

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 every 8 weeks thereafter. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof is administered once every 8 weeks following a dosing cycle for an additional period of up to two years (eg, at a dose of 3000, 3300, or 3600 mg).

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

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

Illustrative alternative complement inhibitors include, but are not limited to, antibodies or antigen binding fragments thereof, small molecules, polypeptides, polypeptide analogs

- 3 046524 dov, peptidomimetics, siRNA and aptamers. In some embodiments, the alternative complement inhibitor inhibits one or more complement components C1, C2, C3, C4, C5, C6, C7, C8, C9, factor D, factor B, properdin, MBL, MASP-1, MASP-2. or their biologically active fragments. In some embodiments, the alternative complement inhibitor inhibits one or both of the generation of C5a-associated anaphylatoxic activity and/or the assembly of the C5b-associated membrane attack complex. 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, Complemstatin, and K76 COOH.

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

In some embodiments, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and at a frequency that maintains antibodies per milliliter of the patient's blood at a level of at least 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, 195, 200, 205, 210, 215, 215, 215. 220, 225, 230, 235, 240, 245, 250, 255 or 260 mcg. In some embodiments, the anti-C5 antibody is administered to the patient in an amount and at a frequency that maintains the antibody per milliliter of the patient's blood at a level between 50 and 250 μg. In some embodiments, the anti-C5 antibody is administered to the patient in an amount and at a frequency that maintains the antibody per milliliter of the patient's blood at a level between 100 and 200 μg. In some embodiments, the anti-C5 antibody is administered to the patient in an amount and at a frequency that maintains the antibody per milliliter of the patient's blood at approximately 175 μg.

In some embodiments, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency that provides a minimum concentration of free C5. For example, in some embodiments, the anti-C5 antibody is administered to the patient in an amount and at a frequency that maintains the free C5 concentration at or below 0.2, 0.3, 0.4, 0.5 μg/mL. In some embodiments, the anti-C5 antibody is administered to the patient in an amount and frequency that provides a free C5 concentration of 0.309 to 0.5 μg/mL or lower. In some embodiments, the treatment described in this invention reduces the concentration of free C5 by more than 99% during the treatment period. In some embodiments, the treatment reduces the concentration of free C5 by more than 99.5% over the treatment period.

Antibodies to C5 or antigen binding fragments thereof can be administered to a patient by any suitable means. In some embodiments, the antibodies are formulated for intravenous administration.

The effectiveness of the treatment methods proposed in this invention can be assessed using any suitable means. In some embodiments, for a patient with gMG, treatment results in at least one therapeutic effect selected from the group consisting of, but not limited to, reduction or cessation of inflammation, tissue destruction, severe weakness, slurred speech, dysarthria, dysphagia, lack of clarity vision, shortness of breath (both active and at rest), weakness of the upper and lower extremities, impaired mobility, marked reduction in the ability to perform activities of daily living (ADL), extreme fatigue, and episodes of pulmonary failure requiring mechanical ventilation. In another embodiment, the patient has a clinically significant improvement (decrease) in one or more gMG severity indicators selected from the group consisting of MG-ADL, QMG, MG-QOL15r, nervous

- 4 046524 fatigue QOL, EQ-5D-5L, MGFA-PIS and/or MGC.

In some embodiments, the treatment results in inhibition of the terminal complement complex.

In some embodiments, the present invention provides a method comprising administering a therapeutically effective amount of ravulizumab to a patient, wherein the patient is positive for nicotinic acetylcholine receptor autoantibody binding (anti-AChR antibody) and exhibits severe generalized weakness or bulbar signs and symptoms of myasthenia gravis, and in which the patient is administered ravulizumab 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 chronic plasmapheresis or chronic IVIg administration to maintain clinical stability.

In some embodiments, a patient receiving treatment with the methods of this invention experiences a clinically significant improvement (decrease) in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale after 26 weeks of treatment. In some embodiments, the treatment effect will be assessed by the difference in means between the ravulizumab group and the placebo group in the change in MG-ADL total score from baseline at week 26, regardless of salvage therapy. A lower value of the corresponding score would indicate a positive treatment effect. In some embodiments, back-up therapy will be permitted when the patient's health is at risk, if back-up therapy has not been prescribed (eg, in emergency situations), or if the patient is experiencing clinical deterioration, as defined herein. In some embodiments, salvage therapy includes high doses of corticosteroids, PP/PE, or IVIg. In some embodiments, the clinically significant 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. In some embodiments, the treatment effect corresponding to a dichotomous 3-item MG-ADL response endpoint at week 26, regardless of salvage therapy, will be assessed by the odds ratio (OR) of the proportions of the corresponding endpoint in the ravulizumab group compared with the placebo.

In some embodiments, a patient receiving treatment with the methods of this invention experiences a clinically significant improvement (decrease) in the Quantitative Myasthenia Gravis (QMG) score after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to change from baseline in continuous endpoints will be assessed by the difference in means between the ravulizumab group and the placebo group in the change from baseline in QMG total score at week 26 regardless of salvage therapy. A lower value of the corresponding score would indicate a positive treatment effect. In some embodiments, the clinically significant improvement experienced by the patient is a decrease in the patient's QMG score of at least 5 points after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to the dichotomous 5-item QMG response endpoint at week 26, regardless of salvage therapy, will be estimated by the odds ratio (OR) of the proportions of the corresponding endpoint in the ravulizumab group compared with the placebo group.

In some embodiments, a patient receiving treatment with the methods of this invention experiences a clinically significant improvement (decrease) in the Myasthenia Gravis Composite (MGC) score after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to change from baseline in continuous endpoints will be assessed by the difference in means between the ravulizumab group and the placebo group in the change from baseline in MGC total score at week 26 regardless of salvage therapy. A lower value of the corresponding score would indicate a positive treatment effect.

In some embodiments, a patient receiving treatment with the methods of this invention experiences a clinically significant improvement (reduction in severity) in quality of life, as measured by the 15-item Myasthenia Gravis Quality of Life Scale-Revised (MG-QOL15r), after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to change from baseline in continuous endpoints will be assessed by the difference in means between the ravulizumab group and the placebo group in the change from baseline in MG-QOL15r total score at week 26 regardless of salvage therapy. . A lower value of the corresponding score would indicate a positive treatment effect.

In some embodiments, a patient receiving treatment with the methods of this invention experiences a clinically significant improvement (reduction) in neuronal fatigue, as measured by the QOL Neuronal Fatigue Scale, after 26 weeks of treatment. In some countries

- 5 046524 ant implementation, the treatment effect corresponding to the change from baseline in continuous endpoints will be assessed by the difference in means between the ravulizumab group and the placebo group in the change in total QOL fatigue score from baseline at week 26, regardless of backup therapy. A lower value of the corresponding score would indicate a positive treatment effect.

In some embodiments, a patient receiving treatment with the methods of this invention experiences a clinically significant improvement in health status, as measured by the EQ-5D-5L Health Status Scale, after 26 weeks of treatment. In some embodiments, a patient receiving treatment with the methods of this invention experiences a clinically significant improvement in health status, as measured by the EQ-5D-5L score, after 26 weeks of treatment. In some embodiments, a patient receiving treatment with the methods of this invention experiences a clinically significant improvement in health status, as measured by the VAS EQ-5D-5L score, after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to the change from baseline in continuous endpoints will be assessed by the difference in means between the ravulizumab group and the placebo group in the change from baseline in an EQ-5D-5L health outcome measure (e.g., an EQ-5D-5L score or VAS EQ-5D-5L score at week 26) regardless of reserve therapy. A lower value of the corresponding score would indicate a positive treatment effect.

In some embodiments, a patient receiving treatment with the methods of this invention experiences a clinically significant improvement in health status, as measured by the MGFA-PIS score, after 26 weeks of treatment. The treatment effect corresponding to the MGFA-PIS endpoint will be estimated by the proportional odds ratio (OR) of the cumulative proportions by ordinal category (best effect first) of that endpoint in the ravulizumab group compared with the placebo group at week 26, regardless of salvage therapy . An OR score >1 would indicate a positive treatment effect.

In some embodiments, a patient receiving treatment with the methods of this invention experiences a clinically significant improvement in health status, as measured by a decrease in the frequency of all-cause hospitalizations or clinical deterioration, as defined herein, after 26 weeks of treatment. In some embodiments, the treatment effect corresponding to the dichotomous endpoint of all-cause hospitalization or clinical worsening as defined herein, over 26 weeks regardless of salvage therapy, will be estimated using the odds ratio (OR) of the proportions of the corresponding endpoint in the ravulizumab group by compared to the placebo group. A score of OR<1 corresponding to the composite endpoint of hospitalization would indicate a positive treatment effect, similarly a score of OR>1 corresponding to the responder endpoint would indicate a positive treatment effect.

In some embodiments, the present invention 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 nicotinic acetylcholine receptor autoantibody binding (anti-AChR antibody) and exhibits severe generalized weakness or bulbar headaches. signs and symptoms of myasthenia gravis during treatment of myasthenia gravis, including cholinesterase inhibitor therapy and immunosuppressant therapy (IST), or requires chronic plasmapheresis or chronic IVIg to maintain clinical stability; wherein ravulizumab is administered using a phased dosing regimen as defined herein, and wherein the patient exhibits a clinically significant improvement (decrease) in at least one measure of severity of generalized myasthenia gravis selected from the group consisting of MG-ADL, QMG, MG- QOL15r, nervous fatigue QOL, EQ-5D-5L, MGFA-PIS and/or MGC.

In some embodiments, the present invention 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 nicotinic acetylcholine receptor autoantibody binding (anti-AChR antibody) and exhibits severe generalized weakness or bulbar headaches. signs and symptoms of myasthenia gravis during treatment of myasthenia gravis, including cholinesterase inhibitor therapy and immunosuppressant therapy (IST), and requires chronic plasmapheresis or chronic IVIg to maintain clinical stability; wherein ravulizumab is administered using a phased dosing regimen disclosed in this invention, and wherein the patient exhibits a clinically significant improvement (decrease) in at least two measures of severity of generalized myasthenia gravis selected from the group consisting of MG-ADL, QMG, MG- QOL15r, nervous fatigue QOL, EQ-5D-5L, MGFA-PIS and/or MGC.

In some embodiments, the present invention provides a method of treating gene

- 6 046524 treating myasthenia gravis in a patient in need thereof, comprising administering ravulizumab to the patient, wherein the patient is positive for nicotinic acetylcholine receptor autoantibody binding (anti-AChR antibody) and demonstrates severe generalized weakness or bulbar signs and symptoms of myasthenia gravis when treated myasthenia gravis, including cholinesterase inhibitor therapy and immunosuppressant therapy (IST), or requires chronic plasmapheresis or chronic IVIg to maintain clinical stability; wherein ravulizumab is administered using a phased dosing regimen disclosed in this invention, and wherein the patient exhibits a clinically significant improvement (reduction) in at least three measures of severity of generalized myasthenia gravis selected from the group consisting of MG-ADL, QMG, MG- QOL15r, nervous fatigue QOL, EQ-5D-5L, MGFA-PIS and/or MGC. In some embodiments, the patient has a clinically significant improvement (decrease) in four measures of severity of generalized myasthenia gravis selected from the group consisting of MG-ADL, QMG, MG-QOL15r, QOL fatigue, EQ-5D-5L, MGFA-PIS, and/ or MGC. In some embodiments, the patient has a clinically significant improvement (decrease) in five measures of severity of generalized myasthenia gravis, wherein the five measures of severity of generalized myasthenia gravis are MG-ADL, QMG, MG-QOL15r, Fatigue QOL, EQ-5D-5L, MGFA -PIS and/or MGC. In some embodiments, the patient has a clinically significant improvement (decrease) in five measures of severity of generalized myasthenia gravis, wherein the six measures of severity of generalized myasthenia gravis are MG-ADL, QMG, MG-QOL15r, Fatigue QOL, EQ-5D-5L, MGFA -PIS and/or MGC. In some embodiments, the patient has a clinically significant improvement (decrease) in five measures of severity of generalized myasthenia gravis, wherein the seven measures of severity of generalized myasthenia gravis are MG-ADL, QMG, MG-QOL15r, Fatigue QOL, EQ-5D-5L, MGFA -PIS and/or MGC.

In some embodiments, the present invention 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 variant of ravulizumab comprising a heavy chain amino acid sequence according to SEQ ID NO: 14 and the light chain amino acid sequence of SEQ ID NO: 11.

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

In some embodiments, the present invention provides a method of treating generalized myasthenia gravis in a patient in need thereof, comprising administering a therapeutically effective amount of ravulizumab to maintain its concentration at 50-100 μg/mL in the patient's serum.

In some embodiments, the present invention 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 one or more ISTs after at least 26 weeks of treatment.

In some embodiments, the present invention 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 experiences a decreased need for chronic plasmapheresis or chronic IVIg administration to maintain clinical stability after at least 26 weeks treatment.

In some embodiments, the present invention provides a method of treating gene

- 7 046524 to treat myasthenia gravis in a patient in need thereof, comprising administering a therapeutically effective amount of ravulizumab such that the patient no longer requires chronic plasmapheresis or chronic IVIg to maintain clinical stability after at least 26 weeks of treatment.

In some embodiments, the present invention 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 experiences a decreased need for chronic plasmapheresis or chronic IVIg administration to maintain clinical stability after at least 26 weeks treatment.

In some embodiments, the present invention 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 contains an antibody or antigen binding fragment thereof comprising CDR1, CDR2 and The heavy chain CDR3 shown in SEQ ID NOs: 19, 18 and 3, respectively, and the light chain CDR1, CDR2 and CDR3 sequences shown in SEQ ID NOs: 4, 5 and 6, respectively.

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

In some embodiments, the composition comprising the antibody or antigen-binding fragment thereof is administered (a) once on day 1 of the dosing cycle

2400 mg for a patient weighing >40 to <60 kg,

2700 mg in a patient weighing >60 to <100 kg, or

3000 mg for a patient weighing > 100 kg; and (b) on day 15 of the dosing cycle and every 8 weeks thereafter at a dose

3000 mg for a patient weighing >40 to <60 kg,

3300 mg in a patient weighing >60 to <100 kg, or

3600 mg for a patient weighing >100 kg.

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 .

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.

In some embodiments, the antibody or antigen binding fragment thereof binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) that is in the range of 0.1 hM < KD < 1 nM. In some embodiments, the antibody or antigen binding fragment thereof binds to human C5 at pH 6.0 and 25° with a KD>10 nM.

In some embodiments, the antibody or antigen-binding fragment thereof is administered to a patient weighing >40 to <60 kg (a) once on day 1 of the administration cycle at a loading dose of 2400 mg; and (b) on day 15 of the dosing cycle and every 8 weeks thereafter at a maintenance dose of 3000 mg.

In some embodiments, the antibody or antigen-binding fragment thereof is administered to a patient weighing >60 to <100 kg (a) once on day 1 of the administration cycle at a loading dose of 2700 mg; and (b) on day 15 of the dosing cycle and every 8 weeks thereafter at a maintenance dose of 3300 mg.

In some embodiments, the antibody or antigen-binding fragment thereof is administered to a patient weighing >100 kg (a) once on day 1 of the administration cycle at a loading dose of 3000 mg; and (b) on day 15 of the dosing cycle and every 8 weeks thereafter at a maintenance dose of 3600 mg.

In some embodiments, treatment with an antibody or antigen-binding fragment thereof maintains a minimum serum concentration of the antibody or antigen-binding fragment thereof at 100 μg/mL or greater during the administration cycle. In some embodiments, treatment with an antibody or antigen-binding fragment thereof maintains a minimum serum concentration of the antibody or antigen-binding fragment thereof at 200 μg/mL or greater during the administration cycle.

In some embodiments, treatment with an antibody or antigen-binding fragment thereof maintains the concentration of the free antibody or antigen-binding fragment thereof at

- 8 046524 level from 0.309 to 0.5 µg/ml or less.

In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 3000, 3300, or 3600 mg once every 8 weeks over a dosing cycle of up to two years.

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

In some embodiments, the patient receiving treatment with the antibody or antigen-binding fragment thereof has not previously received treatment with a complement inhibitor.

In some embodiments, the administration cycle is a total of 26 weeks of treatment.

In some embodiments, treatment with an antibody or an antigen-binding fragment thereof results in inhibition of the terminal complement complex.

In some embodiments, treatment with an antibody or antigen-binding fragment thereof results in the patient experiencing a clinically significant improvement (decrease) in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale after 26 weeks of treatment. In some embodiments, the clinically significant 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.

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

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

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

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

In some embodiments, treatment with an antibody or antigen-binding fragment thereof results in a clinically significant improvement in health status, as measured by the European Quality of Life Questionnaire (EQ-5D-5L) health status scale, after 26 weeks of treatment.

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

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

In some embodiments, the antibody is ravulizumab.

In some embodiments, a kit is provided for the treatment of myasthenia gravis (MG) in a human patient, 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 set forth in SEQ ID NO: 12, and light chain variable region domains CDR1, CDR2 and CDR3 having the sequence shown in SEQ ID NO: 8; and (b) instructions for use of the antibody or antigen-binding fragment thereof in the method of any of the preceding paragraphs.

In some embodiments, the antibody or antigen binding fragment of the kit comprises a variant human Fc constant region that binds to the neonatal human Fc receptor (FcRn), wherein CH3 of the variant human Fc constant region contains the substitutions Met-429-Leu and Asn-435 -Ser at residues corresponding to methionine 428 and asparagine 434, each represented according to EU numbering.

In some embodiments, the antibody or antigen-binding portion of the kit is administered to a patient weighing >40 to <60 kg (a) once on day 1 of the administration cycle at a loading dose of 2400 mg; and (b) on day 15 of the dosing cycle and every 8 weeks thereafter at a maintenance dose of 3000 mg.

In some embodiments, the antibody or antigen-binding portion of the kit is administered to a patient weighing >60 to <100 kg (a) once on day 1 of the dosing cycle at a dose of 2700 mg; And

- 9 046524 (b) on the 15th day of the administration cycle and every 8 weeks thereafter at a maintenance dose of 3300 mg.

In some embodiments, the antibody or antigen-binding portion of the kit is administered to a patient weighing >100 kg (a) once on day 1 of the dosing cycle at a dose of 3000 mg; and (b) on day 15 of the dosing cycle and every 8 weeks thereafter at a maintenance dose of 3600 mg.

In some embodiments, the antibody is ravulizumab.

In some embodiments, the present invention provides an antibody comprising heavy chain variable region CDR1, CDR2 and CDR3 domains having the sequence set forth in SEQ ID NO: 12 and light chain variable region CDR1, CDR2 and CDR3 domains having the sequence SEQ ID NO: : 8, for administration in the treatment cycle.

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

In some embodiments, the antibody is administered (a) once on day 1 of the dosing cycle

2400 mg for a patient weighing >40 to <60 kg,

2700 mg in a patient weighing >60 to <100 kg, or

3000 mg for a patient weighing >100 kg; and (b) on day 15 of the dosing cycle and every 8 weeks thereafter at a dose

3000 mg for a patient weighing >40 to <60 kg,

3300 mg in a patient weighing >60 to <100 kg, or

3600 mg for a patient weighing >100 kg.

In some embodiments, the antibody is determined to be safe, tolerable, effective, and sufficiently non-immunogenic after multiple IV doses for use in patients with MG.

In some embodiments, the antibody is ravulizumab.

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

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

In some embodiments, the antibody or antigen-binding fragment thereof is administered (a) once on day 1 of the dosing cycle

2400 mg for a patient weighing >40 to <60 kg,

2700 mg in a patient weighing >60 to <100 kg, or

3000 mg for a patient weighing >100 kg; and (b) on day 15 of the dosing cycle and every 8 weeks thereafter at a dose

3000 mg for a patient weighing >40 to <60 kg,

3300 mg in a patient weighing >60 to <100 kg, or

3600 mg for a patient weighing >100 kg.

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 .

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.

In some embodiments, the antibody or antigen binding fragment thereof binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) that is in the range of 0.1 hM < K _d < 1 nM. In some embodiments, the antibody or antigen-binding fragment thereof binds to human C5 at pH 6.0 and 25° with a K _D >10 nM.

In some embodiments, the antibody or antigen-binding fragment thereof is administered to a patient weighing >40 to <60 kg (a) once on day 1 of the dosing cycle at a dose of 2400 mg; and (b) on day 15 of the administration cycle and every 8 weeks thereafter at a dose of 3000 mg.

In some embodiments, the antibody or antigen-binding fragment thereof is administered

- 10 046524 for a patient with a body weight from >60 to <100 kg (a) 1 time on the 1st day of the administration cycle at a dose of 2700 mg; and (b) on day 15 of the administration cycle and once every eight weeks thereafter at a dose of 3300 mg.

In some embodiments, the antibody or antigen-binding fragment thereof is administered to a patient weighing >100 kg (a) once on day 1 of the dosing cycle at a dose of 3000 mg; and (b) on day 15 of the administration cycle and every 8 weeks thereafter at a dose of 3600 mg.

In some embodiments, treatment with an antibody or antigen-binding fragment thereof maintains a minimum serum concentration of the antibody or antigen-binding fragment thereof at 100 μg/mL or greater during the administration cycle. In some embodiments, treatment with an antibody or antigen-binding fragment thereof maintains a minimum serum concentration of the antibody or antigen-binding fragment thereof at 200 μg/mL or greater during the administration cycle.

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

In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 3000, 3300, or 3600 mg once every 8 weeks over a dosing cycle of up to two years.

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

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

In some embodiments, the administration cycle is a total of 26 weeks of treatment. In some embodiments, the treatment results in inhibition of the terminal complement complex.

In some embodiments, treatment with an antibody or antigen-binding fragment thereof results in the patient experiencing a clinically significant improvement (decrease) in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale after 26 weeks of treatment. In some embodiments, the clinically significant 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.

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

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

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

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

In some embodiments, treatment with an antibody or antigen-binding fragment thereof results in a clinically significant improvement in health status, as measured by the European Quality of Life Questionnaire (EQ-5D-5L) health status scale, after 26 weeks of treatment.

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

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

In some embodiments, the antibody is ravulizumab.

Moreover, the present invention covers any of the above embodiments used with any other of the above embodiments in any combination.

Brief description of graphic materials

In fig. Figure 1 is a flowchart depicting the design of the phase III clinical trial of ALXN1210-MG-306 in patients with gMG.

- 11 046524

In fig. 2 is a flowchart depicting the ravulizumab once-every-8-week dosing regimen versus the eculizumab once-every-two-week dosing regimen, including actual infusion days, for patients participating in the phase III ALXN1210-MG-306 study.

In fig. 3A, 3B and 3C show the European Quality of Life Questionnaire (EQ-5D-5L) health status scale used in the clinical study described in this invention.

In fig. Figure 4 shows the Columbia Suicidality Rating Scale (C-SSRS) measured at baseline/patient screening.

In fig. Figure 5 shows the Columbia Suicidality Rating Scale (C-SSRS), measured since the patient's last visit.

Detailed description of the invention

In the context of this invention, the term subject or patient means a human patient (eg, a patient having generalized myasthenia gravis (gMG)). In the context of this invention, the terms subject and patient are used interchangeably.

In the context of this invention, the phrase requires chronic plasmapheresis refers to the use of plasma exchange therapy in a patient on a regular basis to treat muscle weakness at least once every 3 months for the past 12 months.

In the context of this invention, the phrase requires chronic administration of IVIg refers to the patient's use of IVIg on a regular basis to treat muscle weakness at least once every 3 months for the past 12 months.

In the context of this invention, the term clinical deterioration refers to patients who are experiencing an MG crisis, which is defined as weakness resulting from MG that is severe enough to require intubation or to delay extubation after surgery, when respiratory failure occurs due to weakness of the respiratory muscles, severe bulbar (oropharyngeal) muscle weakness accompanies respiratory muscle weakness or is the predominant feature of the patient; or when there is a significant worsening of symptoms to a score of 3 or 2 from baseline on any of the individual MG Activities of Daily Living (MG-ADL) scale items other than double vision or drooping eyelids; or a patient, in the opinion of the investigator or the investigator's designated physician, is prescribed backup therapy whose health would be at risk if backup therapy were not provided (for example, in emergency situations).

In the context of this invention, the term effective treatment refers to treatment that produces a beneficial effect, for example, alleviation of at least one symptom of a disease or disorder. A positive effect may represent an improvement over baseline, i.e. an improvement compared to a measurement or observation made before initiation of therapy according to the method. Effective treatment may relate, for example, to alleviating at least one symptom of MG.

The term effective amount refers to the amount of agent that provides the desired biological, therapeutic and/or prophylactic result. This result may be the reduction, improvement, temporary attenuation, reduction, delay and/or normalization of one or more signs, symptoms or causes of disease or any other necessary change in the biological system. In one example, the effective amount is an amount of an anti-C5 antibody or antigen-binding fragment thereof useful, for example clinically proven, to relieve at least one symptom of MG. An effective amount may be administered in one or more administrations.

In the context of the present invention, the terms induction and induction phase are used interchangeably and refer to the first phase of the dosing regimen.

In the context of the present invention, 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 until clinical improvement is observed or until uncontrolled toxicity or disease progression occurs. The maintenance phase of ravulizumab can last from 6 weeks until the end of the patient's life. In some embodiments, the maintenance phase lasts 26-52, 26-78, 26-104, 26-130, 26-156, 26-182, 26-208 weeks, or more. In some embodiments, the maintenance phase lasts longer 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. In some embodiments, the maintenance phase lasts more than 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 years and more years. In some embodiments, the maintenance phase lasts for the rest of the patient's life.

In some embodiments, the multiphase ravulizumab dosing regimen includes a third phase. This third phase is used when the MG patient needs to undergo an emergency procedure to maintain clinical stability and includes plasma exchange/plasmapheresis (PE/PP) and/or dosing of IVIg. In this phase, after plasma exchange, a dose of ravulizumab is administered to replace the drug lost during plasma exchange/plasmapheresis.

- 12 046524

In some embodiments, a dose of an additional investigational drug, such as ravulizumab, is required if PE/PP or IVIg backup therapy is administered on non-drug days. In another embodiment, if the PE/PP or IVIg infusion is administered on the day of dosing, it should occur before the administration of the study drug. In some embodiments, if PE/PP is administered or IVIg is administered during unscheduled dosing visits, patients receiving PE/PP are given an additional dose 4 hours after completion of the PE/PP session. In another embodiment, patients receiving IVIg are given an additional dose 4 hours after completion of the last continuous IVIg administration session(s). In some embodiments, the number of additional doses may or may not vary depending on the PE/PP or IVIg (Tables 1 and 2). In some embodiments, if PE/PP is performed or IVIg is administered during scheduled dosing visits, regular dosing will be maintained 60 minutes after completion of PE/PP or IVIg administration. In some embodiments, an interval between the additional dose and the regularly scheduled dose is not required.

Table 1

Additional dose when administering PE/PP as backup therapy during unscheduled dosing visits

Study period Administration of a dose of ravalizumab or placebo Body weight (kg) ^{1 2 3} Ravulizumab dose (mg) Volume (ml) Ravulizumab Placebo Thinner (0.9¾ chloride solution sodium) Total Group with application ravulizumab Randomized controlled Loading dose (1st day) from >40 to <60 1200 120 0 120 240 from >60 to <100 1500 150 0 150 300 >100 1500 150 0 150 300 Maintenance dose (15th, 71st, 127th days) from >40 to <60 1500 150 0 150 300 from >60 to <100 1800 180 0 180 360 >100 1800 180 0 180 360 Open extended Masked dose ⁴ (day 183) from >40 to <60 600 60 0 60 120 from >60 to <100 600 60 0 60 120 >100 600 60 0 60 120 Open, extended, maintenance dose (from day 197 to day 869, 1 r./8 wk.) from > 40 to < 60 1500 150 0 150 300 from >60 to <100 1800 180 0 180 360 >100 1800 180 0 180 360 Placebo group Randomized controlled Loading dose (1st day) from >40 to <60 0 0 120 120 240 from > 60 to < 100 0 0 150 150 300 >100 0 0 150 150 300 Maintenance dose (15th, 71st, 127th days) from > 40 to < 60 0 0 150 150 300 from > 60 to < 100 0 0 180 180 360 >100 0 0 180 180 360 Open extended Masked loading dose’ (day 183) from >40 to <60 600 60 0 60 120 from >60 to <100 600 60 0 60 120 >100 600 60 0 60 120 Open, extended, maintenance dose (from day 197 to day 869, 1 r./8 weeks) from >40 to <60 1500 150 0 150 300 from >60 to <100 1800 180 0 180 360 >100 1800 180 0 180 360

¹ The dose regimen will be based on the patient's last recorded body weight at the previous study/screening visit.

² Masked dose on day 183 (week 26) for patients who were randomized to ravulizumab and entering the open-label extension period.

³ Masked loading dose on day 183 (week 26) for patients who were randomized to placebo and entering the open-label extension period.

- 13 046524

Table 2 Additional dose of intravenous immunoglobulin as backup therapy during unscheduled dosing visits_______

Study period Administration of a dose of ravalizumab or placebo Body weight (kg) ¹ Ravulizumab dose (mg) Volume (ml) Ravulizumab Placebo Thinner (0.9% chloride solution sodium) Total Ravulizumab group Randomized controlled Loading dose (1st day) from >40 to <60 600 60 0 60 12 0 from > 60 to < 100 600 60 0 60 12 0 >100 600 60 0 60 12 0 Maintenance dose (15th, 71st, 127th days) from >40 to <60 600 60 0 60 12 0 from > 60 to < 100 600 60 0 60 12 0 >100 600 60 0 60 12 0 Open extended Masked dose ^{2 3} (day 183) from >40 to <60 600 60 0 60 12 0 from > 60 to < 100 600 60 0 60 12 0 >100 600 60 0 60 12 0 Open-label, maintenance dose (from the 197th day to the 869th day, 1 r./8 weeks) from >40 to <60 600 60 0 60 12 0 from > 60 to < 100 600 60 0 60 12 0 >100 600 60 0 60 12 0 Placebo group Randomized controlled Loading dose (1st day) from >40 to <60 0 0 60 60 12 0 from > 60 to < 100 0 0 60 60 12 0 >100 0 0 60 60 12 0 Maintenance dose (15th, 71st, 127th days) from > 40 to < 60 0 0 60 60 12 0 from > 60 to < 100 0 0 60 60 12 0 >100 0 0 60 60 12 0 Open extended Masked loading dose’ (day 183) from >40 to <60 600 60 0 60 12 0 from > 60 to < 100 600 60 0 60 12 0 >100 600 60 0 60 12 0 Open-label, maintenance dose (from the 197th day to the 869th day, 1 r./8 weeks) from >40 to <60 600 60 0 60 12 0 from > 60 to < 100 600 60 0 60 12 0 >100 600 60 0 60 12 0

¹ The dose regimen will be based on the patient's last recorded body weight at the previous study/screening visit.

² Masked dose on day 183 (week 26) for patients who were randomized to ravulizumab and entering the open-label extension period.

³ Masked loading dose on day 183 (week 26) for patients who were randomized to placebo and entering the open-label extension period.

In the context of this invention, the term loading dose refers to the initial dose administered

- 14 046524 to the patient. The load may be, for example, 2400, 2700 or 3000 mg. Loading doses can be adjusted based on body weight.

In the context of this invention, the terms maintenance dose or maintenance phase refer to the dose administered to the patient after the loading dose.

For example, the loading dose may be 3000, 3300 or 3600 mg. Maintenance doses can be adjusted based on body weight.

In the context of this invention, the term residual serum level refers to the lowest concentration at which an agent (eg, an anti-C5 antibody or antigen-binding fragment thereof) or drug is present in the blood serum. In contrast, peak serum level refers to the highest serum concentration of the drug. Mean serum level refers to the average serum concentration of a drug over time.

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

In another embodiment, to obtain an effective response, the patient is administered an anti-C5 antibody or antigen-binding fragment thereof in an amount and frequency that provides the required minimum concentration of free C5. For example, in one embodiment, an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient in an amount and frequency to maintain a free C5 concentration of 0.2, 0.3, 0.4, 0.5 μg/ml or less. In another embodiment, the anti-C5 antibody or 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 in this invention reduces the concentration of free C5 by more than 99% during the treatment period. In another embodiment, the treatment reduces the concentration of free C5 by more than 99.5% during the treatment period.

The term antibody describes polypeptides containing at least one antigen binding site derived from an antibody (eg, VH/VL region or Fv, or CDR). Antibodies include known forms of antibodies. The antibody may be, for example, a human antibody, a humanized antibody, a bispecific antibody, a chimeric antibody, or a camel antibody. The antibody may also be a Fab, Fab'2, scFv, SMIP, affibody, nanobody, or single domain antibody. The antibody may also be any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD and IgE, as well as hybrid isotypes such as IgG2/4. The antibody may be a naturally occurring antibody or may be an antibody that has been modified by protein engineering techniques (eg, mutation, deletion, substitution, conjugation to a fragment other than the antibody). An antibody may include, for example, one or more variant amino acids (compared to a naturally occurring antibody) that alter a property (eg, a functional property) of the antibody. Numerous such changes are known in the art that affect, for example, the half-life, effector function and/or immune responses to the antibody in a patient. The term antibody also includes artificial or engineered polypeptide constructs that contain at least one antigen binding site derived from an antibody.

Antibodies to C5.

The anti-C5 antibodies described in this invention bind to complement component C5 (eg, human complement C5) and inhibit the cleavage of C5 into C5a and C5b fragments. Antibodies to

- 15 046524

C5 (or VH/VL domains or other antigen binding fragments derived from them) suitable for use in this invention can be prepared using methods known in the art. Anti-C5 antibodies recognized in the art can also be used. Antibodies that compete with any of these art-recognized antibodies for binding to C5 may also be used.

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

Ravulizumab (also known as BNJ441, ALXN1210 or Ultomiris®) is an anti-C5 antibody containing heavy and light chains having the sequences shown in SEQ ID NO: 14 and 11, respectively, or antigen binding fragments and variants thereof. Ravulizumab is described in PCT/US2015/019225 and US Patent No. 9079949, the teachings of which are incorporated herein by reference. Ravulizumab selectively binds to human complement protein C5, inhibiting its cleavage to C5a and C5b during complement activation. This inhibition prevents the release of the proinflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC) C5b-9, while preserving the proximal or early complement activation components (e.g., C3 and C3b) required for opsonization of microorganisms and clearance of immune complexes.

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

Another example of an anti-C5 antibody is BNJ421, which contains heavy and light chains having the sequences set forth in SEQ ID NOs: 20 and 11, respectively, or antigen binding fragments and variants thereof. BNJ421 is described in PCT/US2015/019225 and US Patent No. 9079949, all concepts of which are incorporated herein by reference.

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

The exact boundaries of the CDR have been determined in different ways depending on the different methods. In some embodiments, the positions of the CDRs or framework regions in the light or heavy chain variable domain may be as defined by Kabat et al. [(1991) Sequences of Proteins of Immunological Interest, NIH Publication No. 91-3242, U.S. Department of Health and Human Services, Bethesda, MD]. In such cases, the CDRs may be designated Kabat CDRs (eg, Kabat LCDR2 or Kabat HCDR1). In some embodiments, the light or heavy chain variable region CDR positions may be as defined by Chothia et al. (Nature, 342:877-83, 1989). Accordingly, these regions may be designated Chothia CDRs (eg, Chothia LCDR2 or Chothia HCDR3). In some embodiments, the CDR positions of the light and heavy chain variable regions may be as determined by the combined definition according to Kabat-Chothia. In such embodiments, these regions may be designated in combination

- 16 046524 numeric CDRs according to Kabat-Chothia (Thomas, T. et al., Mol. Immunol., 33:1389-401, 1996).

Another example of an anti-C5 antibody is antibody 7086, described in US 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 antibody 7086 (see US Pat. Nos. 8,241,628 and 8,883,158). In another embodiment, the antibody or antigen binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NO: 24, 25 and 26 respectively. In another embodiment, the antibody or antigen binding fragment thereof comprises a VH region of antibody 7086 having the sequence set forth in SEQ ID NO: 27 and a VL region of antibody 7086 having the sequence set forth in SEQ ID NO: 28.

Another example of an anti-C5 antibody is antibody 8110, also described in US 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 antibody 8110. In another embodiment, the antibody or antigen binding fragment thereof comprises the CDR1, CDR2 domains and heavy chain CDR3 having the sequences shown in SEQ ID NOs: 29, 30 and 31, respectively, and 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 an antibody 8110 VH region having the sequence set forth in SEQ ID NO: 35 and an antibody 8110 VL region having the sequence set forth in SEQ ID NO: 36.

Another example of an anti-C5 antibody is the 305LO5 antibody described in US2O16/O176954A1. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody. In another embodiment, the antibody or antigen binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NO: 40, 41 and 42 respectively. In another embodiment, the antibody comprises a 305LO5 antibody VH region having the sequence set forth in SEQ ID NO: 43 and a 305LO5 antibody VL region having the sequence set forth in SEQ ID NO: 44.

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 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.

Another example of an anti-C5 antibody is the H4H12166PP antibody described in PCT/US2017/037226 and US2017/0355757A1. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the H4H12166PP antibody. In another embodiment, the antibody or antigen binding fragment thereof comprises a VH region of an H4H12166PP antibody having the sequence set forth in SEQ ID NO: 47 and a VL region of an H4H12166PP antibody having the sequence set forth in SEQ ID NO: 48. In another embodiment, the antibody or the antigen binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 49 and a light chain comprising SEQ ID NO: 50.

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

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

QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGEILPGSGH

TEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSPNWYFDVWGQG

TLVTVSS (SEQ ID NO: 12).

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

DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVP

SRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIK (SEQ ID NO:8).

The anti-C5 antibody described in this invention may, in some embodiments, contain

- 17 046524 to produce a variant human Fc constant region that binds to the neonatal human Fc receptor (FcRn) with a higher affinity than the affinity of the native human Fc constant region from which the variant human Fc constant region is derived. The Fc constant region may contain, 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 . Substitutions can increase the binding affinity of an IgG antibody containing a variant constant Fc 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 constant Fc region of an antibody increase the affinity of the constant Fc region for FcRn at pH 6.0 (while maintaining the pH dependence of the interaction) are known in the art and are presented in worked examples (see, for example, PCT/US2015/019225 and US Patent No. 9079949, the disclosures of each of which are incorporated herein by reference in their entirety).

Substitutions that increase the binding affinity of the antibody Fc constant region to FcRn are known in the art and include, for example, (1) the triple substitution M252Y/S254T/T256E (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); and (3) substitutions N434A or T307/E380A/N434A (Petkova, S. et al., Int. Immunol., 18:1759-69, 2006).

Additional substitution pairs are also discussed herein, such as P257I/Q311I, P257I/N434H, and D376V/N434H (Datta-Mannan, A. et al., J. Biol. Chem., 282:1709-17, 2007).

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

In some embodiments, the variant Fc constant region includes 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 contains 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 contains a methionine at position 428 and an asparagine at position 434, each of which is identified by EU numbering. In some embodiments, the variant Fc constant region contains a 428L/434S double substitution, as described, for example, in US Pat. No. 8,088,376.

In some embodiments, the exact location of these mutations may be shifted from the position of the native human Fc constant region as a result of antibody engineering. The 428L/434S double substitution when used in a chimeric IgG2/4 Fc, for example, could correspond to 429L and 435S, as in the M429L and N435S variants found in BNJ441 (ravulizumab) and described in US Pat. No. 9,079,949, the disclosure of which is incorporated herein by links in full.

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 on the series at position 254; glutamic acid to arginine at position 255; aspartic acid, glutamic acid or glutamine to threonine at position 256; alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine or valine to proline at position 257; histidine to glutamic acid at position 258; alanine to aspartic acid at position 265; phenylalanine to aspartic acid at position 270; alanine or glutamic acid to asparagine at position 286; histidine to threonine at position 289; alanine to asparagine at position 297; glycine to serine at position 298; alanine to valine at position 303; alanine to valine at position 305; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan or tyrosine to threonine at position 307; alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine or threonine to valine at position 308; alanine, aspartic acid, glutamic acid, proline or arginine to leucine or valine at position 309; alanine, histidine or isoleucine to glutamine at position 311; alanine or histidine to aspartic acid at position 312, lysine or arginine to leucine at position 314; alanine or histidine to asparagine

- 18 046524 in position 315; alanine to lysine at position 317; glycine to asparagine at position 325; valine to isoleucine at position 332; leucine to lysine at position 334; histidine to lysine at position 360; alanine to aspartic acid at position 376; alanine to glutamic acid at position 380; alanine to glutamic acid at position 382; alanine to asparagine or serine at position 384; aspartic acid or histidine to glycine at position 385; proline to glutamine at position 386; glutamic acid to proline at position 387; alanine or serine to asparagine at position 389; alanine to serine at position 424; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan or tyrosine to methionine at position 428; lysine to histidine at position 433; alanine, phenylalanine, histidine, serine, tryptophan or tyrosine to asparagine at position 434; and histidine to tyrosine or phenylalanine at position 436, all of which are according to EU numbering.

Suitable anti-C5 antibodies for use in the methods described herein may comprise a heavy chain polypeptide containing the amino acid sequence of SEQ ID NO: 14 and/or a light chain polypeptide containing the amino acid sequence of SEQ ID NO: 11. Alternatively, antibodies to C5 for use in the methods described in this invention may contain a heavy chain polypeptide containing the amino acid sequence of SEQ ID NO: 20, and/or a light chain polypeptide containing the amino acid sequence of SEQ ID NO: 11.

In one embodiment, the antibody binds to C5 at pH 7.4 and 25°C (and otherwise under physiological conditions) with an affinity dissociation constant (KD) that is at least 0.1 nM (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. In some embodiments, the KD of the anti-C5 antibody or antigen-binding fragment thereof is no more than 1 (e.g., no more than 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0 ,2 nM).

In some embodiments, [(KD of anti-C5 antibody at pH 6.0 at 25°C)/(KD of anti-C5 antibody at pH 7.4 at 25°C)] is greater than 21 (e.g., greater than 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 15 00, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500 or 8000).

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

In the context of the present invention, the term k _a refers to the rate constant of association of an antibody with an antigen. The term kd refers to the rate constant for the dissociation of an antibody from the antibody/antigen complex. The term Kd refers to the equilibrium dissociation constant of the antibody-antigen interaction. The equilibrium dissociation constant is derived from the relation of the kinetic rate constants KD=k _a /kd. Such determinations are preferably carried out at 25 or 37°C. The kinetics of antibody binding to human C5 can be determined, for example, at pH 8.0, 7.4, 7.0, 6.5 and 6.0 by surface plasmon resonance (SPR) on a BIAcore 3000 instrument using the antibody capture method to Fc with antibody immobilization.

Methods for determining whether a particular antibody described in this invention inhibits C5 cleavage are known in the art. Inhibition of human complement component C5 may reduce the ability of complement to lyse cells in a subject's body fluids. Such a decrease in the ability of complement to lyse cells present in the body fluid(s) can be measured by methods known in the art, such as, for example, a conventional hemolysis assay, such as the hemolysis assay described by Kabat and Mayer (eds.), Experimental Immunochemistry, 2nd edition, 135-240, Springfield, IL, CC Thomas (1961), p. 135-139, or a conventional variant of this assay, such as the chicken erythrocyte hemolysis method (Hillmen, P. et al., N. Engl. J. Med., 350:552-9, 2004). Methods for determining whether a candidate compound inhibits the cleavage of human C5 into the C5a and C5b forms 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 fluid can be measured, for example, by methods known in the art. For C5b, hemolysis assays or soluble C5b-9 assays can be used, as discussed in this invention. Other assays known in the art may also be used. Using these or other suitable assays, candidate agents capable of inhibiting human complement component C5 can be screened.

- 19 046524

Immunological techniques, such as, but not limited to, ELISA, can be used to measure the concentration of C5 protein and/or its degradation products to determine the ability of an anti-C5 antibody or antigen-binding fragment thereof to inhibit the conversion of C5 to biologically active products. In some embodiments, the formation of C5a is measured. In some embodiments, C5b-9 neoepitope-specific antibodies are used to detect formation of the terminal complement complex.

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

To determine the effect of an anti-C5 antibody or antigen-binding fragment 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 a C5 polypeptide. The percentage of lysis is normalized by taking 100% lysis to be equal to the lysis that occurs in the absence of the inhibitor. In some embodiments, the alternative complement pathway is activated by lipopolysaccharide molecules, such as those used in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with anti-C5 antibody or its antigen-binding fragment in the presence of lipopolysaccharide. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring the fluorescence at the appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody or its antigen-binding fragment.

In some embodiments, C5 activity or inhibition thereof is quantified using a CH50eq assay. The CH50eq assay is a method of measuring total classical complement activity in serum. This test is a lysis assay that uses antibody-sensitized red blood cells as an activator of the classical complement pathway and various dilutions of test serum to determine the amount required to achieve 50% lysis (CH50). The percentage of hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect assessment of the formation of the terminal complement complex (TCC), since the TCC itself is directly responsible for the hemolysis measured. Briefly, to activate the classical complement pathway, undiluted blood serum samples (eg, reconstituted human serum samples) are added to microassay wells containing antibody-coated red blood cells, thereby generating TCCs. Activated serum samples are then diluted into microassay wells, which are coated with a capture reagent (eg, an antibody that binds to one or more TCC components). The TCC present in the activated samples binds to the monoclonal antibodies coating the surface of the microassay wells. The wells are washed and a detection reagent is added to each well, which is detectably labeled and recognizes bound TCC. The detectable label may be, for example, a fluorescent label or an enzyme label. Assay results are expressed in CH50 equivalent units per milliliter (CH50 eq/mL).

Inhibition, for example, which relates to the activity of the terminal complement complex, includes at least 5% (for example, at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60%) reduction in terminal complement complex activity, for example, in a hemolysis assay or CH50eq assay, compared with the effect of a control antibody (or antigen-binding fragment thereof) under similar conditions and at an equimolar concentration. Substantial inhibition in the context of this invention refers to inhibition of a given activity (e.g., terminal complement complex activity) by at least 40% (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95% or more). In some embodiments, an anti-C5 antibody,

- 20 046524 described in this invention contains one or more amino acid substitutions relative to the eculizumab CDR (i.e. SEQ ID NO: 1-6), but retains at least 30% (for example, at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%) of the complement inhibitory activity of eculizumab in the hemolysis assay or CH50eq assay.

The anti-C5 antibody described herein has a half-life in human serum of at least 20 days (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55 days) . In another embodiment, the anti-C5 antibody described in this invention has a half-life in human serum that is at least 40 days. In another embodiment, the anti-C5 antibody described herein has a half-life in human serum of approximately 43 days. In another embodiment, the anti-C5 antibody described in this invention has a half-life in human serum that ranges from 39 to 48 days. Methods for measuring the half-life of an antibody in serum 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%) greater than the serum half-life of eculizumab, e.g., as measured in one of the mouse model systems described in the working examples (eg, the C5/NOD/scid deficient mouse model system or the hFcRn transgenic mouse).

In one embodiment, the antibody competes for binding and/or binds to the same epitope on C5 as the antibody described in this invention. The term binds to the same epitope when applied to two or more antibodies means that the antibodies bind to the same segment of amino acid residues as determined by this method. Techniques for determining whether antibodies with the same epitope on C5 bind to the antibodies described in this invention include, for example, epitope mapping techniques such as X-ray crystal analyzes of antigen:antibody complexes, which provide atomic separation of the epitope, and mass spectrometry with hydrogen/deuterium exchange (HDX-MS). Other methods monitor antibody binding to peptide antigen fragments or mutated variants of the antigen, where loss of binding due to modification of an amino acid residue in the antigen sequence is often considered to be indicative of an epitope component. Computational combinatorial methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from phage display combinatorial peptide libraries. Antibodies having the same VH and VL sequences or the same CDR1, 2 and 3 sequences are expected to bind to the same epitope.

Antibodies that compete with another antibody for binding to a target refer to antibodies that inhibit (partially or completely) the binding of another antibody to a target. Do two antibodies compete with each other for binding to the target, i.e. whether and to what extent one antibody inhibits the binding of another antibody to its target can be determined using known competition experiments. In some embodiments, the antibody competes with another antibody and inhibits its binding to the target by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%. The level of inhibition or competition may vary depending on which antibody is the blocking antibody (ie, a cold antibody that is first incubated with the target). Competing antibodies may bind, for example, to the same epitope, overlapping epitope, or adjacent epitopes (eg, as evidenced by steric hindrance).

Antibodies to C5 or antigen binding fragments described in this invention used in the methods described in this invention can be obtained using a variety of techniques recognized in the field. Monoclonal antibodies can be produced by various techniques known to those skilled in the art. Briefly, spleen cells from an animal immunized with the desired antigen are immortalized, usually by fusion with a myeloma cell (Kohler, G. & Milstein, S., Eur. J. Immunol., 6:511-9, 1976). Alternative methods of immortalization include transformation with Epstein-Barr virus, oncogenes or retroviruses, or other methods well known in the art. Colonies arising from single immortalized cells are screened for the production of antibodies with the required specificity and affinity for the antigen, and the yield of monoclonal antibodies produced by such cells can be increased by various techniques, including injection into the peritoneal cavity of the vertebrate host. Alternatively, DNA sequences that encode a monoclonal antibody or a binding fragment thereof can be isolated by screening a DNA library from human B cells (Huse, W. et al., Science, 246:1275-81, 1989).

Compositions.

Pharmaceutical compositions containing ravulizumab are provided, either alone or in combination with prophylactic agents, therapeutic agents and/or pharmaceutically

- 21 046524 acceptable carriers. The present invention provides pharmaceutical compositions containing ravulizumab for use, for example, in the diagnosis, detection or monitoring of a disorder, in the prevention, treatment, control or alleviation of a disorder or one or more symptoms thereof and/or in research. Formulations of pharmaceutical compositions, alone or in combination with prophylactic agents, therapeutic agents and/or pharmaceutically acceptable carriers, are known in the art.

The present invention also provides compositions containing an anti-C5 antibody or an antigen-binding fragment thereof for use in the treatment methods described herein, wherein a patient is switched from treatment with one anti-C5 antibody (e.g., eculizumab) to treatment with another anti-C5 antibody (e.g., ravulizumab) during the course of treatment.

The composition may be formulated as a pharmaceutical solution, for example, for administration to a subject for the treatment or prevention of MG. The pharmaceutical composition may contain a pharmaceutically acceptable carrier. As used herein, the term pharmaceutically acceptable carrier refers to and includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The composition may contain a pharmaceutically acceptable salt, for example, an acid addition salt or a base addition salt, sugars, carbohydrates, polyols and/or tonicity modifiers.

The composition can be formulated by known methods (Gennaro (2000), Remington: The Science and Practice of Pharmacy, 20th edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999), Pharmaceutical Dosage Forms and Drug Delivery Systems , 7th edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000), Handbook of Pharmaceutical Excipients American Pharmaceutical Association, 3rd edition (ISBN: 091733096X)). In some embodiments, the composition may be formulated, for example, as a buffered solution of suitable concentration and suitable for storage at 2-8°C (eg, 4°C). In some embodiments, the composition may be formulated for storage at temperatures below 0°C (eg, -20 or -80°C). In some embodiments, the composition may be formulated to be stored for up to 2 years (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 months, 1, 11/2, or 2 years) at 2 -8°C (for example, 4°C). Thus, in some embodiments, the compositions described in this invention are stable when stored for at least 1 year at 2-8°C (eg, 4°C).

Pharmaceutical compositions can be in various forms. These forms include, for example, liquid, semi-solid and solid dosage forms such as liquid solutions (eg, injections and infusions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends in part on the intended route of administration and therapeutic use. Compositions containing a composition intended for systemic or local delivery may, for example, be in the form of injections or infusions. The compositions may be formulated for parenteral administration (eg, intravenous, subcutaneous, intraperitoneal, or intramuscular injection). Parenteral administration, parenterally administered and other grammatically equivalent phrases, in the context of this invention, refer to routes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid and intrathoracic injection or infusion. In one embodiment, the antibodies are formulated for intravenous administration.

An exemplary non-limiting range for a therapeutically or prophylactically effective amount of ravulizumab or other anti-C5 antibodies, such as eculizumab, BNJ 421, 7086, 8110, SKY59 and H4H12166PP, provided in this invention is 600-5000 mg, for example 900-2000 mg. It should be noted that dosage values may vary depending on the type and severity of the condition being alleviated. It should also be understood that for any particular subject, specific dosage regimens may be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges provided in this invention are illustrative only and are not intended to limitations on the scope or practice of the claimed methods.

Combination therapy.

The anti-C5 antibody of this invention may also be administered with one or more additional drugs or therapeutic agents useful in the treatment of MG. The additional agent may be, for example, a therapeutic agent recognized in the art for the treatment of MG. The combination may also contain more than one additional agent, for example two or three additional agents. Binding agent

- 22 046524 in various embodiments is administered with an agent that is a protein, peptide, carbohydrate, drug, small molecule, or genetic material (eg, DNA or RNA). In various embodiments, the agent is one or more cholinesterase inhibitors, one or more corticosteroids, and/or one or more immunosuppressive agents (most commonly azathioprine [AZA], cyclosporine, and/or mycophenolate mofetil [MMF]).

Ways.

The present invention provides methods for treating complement associated disorder(s) (e.g., MG, e.g., gMG, e.g., when the patient is anti-AChR antibody positive) in a human patient, comprising administering to the patient an anti-C5 antibody or antigen-binding antibody thereof. fragment, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered (or intended to be administered) in accordance with a particular clinical dosing regimen (ie, in a particular dosage amount and in accordance with a particular dosing regimen).

In some embodiments, the MG includes gMG. In some embodiments, gMG is characterized as including subjects or patients who are positive for AChR autoantibody binding and who continue to demonstrate significant general 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 require chronic plasmapheresis or chronic IVIg to maintain clinical stability.

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 every 8 weeks thereafter. In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered once every 8 weeks following a dosing cycle for an additional period of up to two years (eg, at a dose of 3000, 3300, or 3600 mg).

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

In another embodiment, the patient switches from taking one C5 inhibitor to another C5 inhibitor during a course of treatment. Different anti-C5 antibodies can be administered during separate treatment periods. For example, in one embodiment, a method is provided for treating a human patient having a complement-associated disorder (eg, MG) who is receiving treatment with eculizumab, the method comprising discontinuing treatment with eculizumab and switching the patient to treatment with an alternative complement inhibitor. In another embodiment, a method is provided for treating a human patient having a complement-associated disorder who is receiving treatment with ravulizumab, the method comprising discontinuing treatment with ravulizumab and switching the patient to treatment with an alternative complement inhibitor.

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

Examples of alternative anti-C5 antibodies include, but are not limited to, (i) eculizumab;

(ii) an antibody or antigen binding fragment thereof comprising heavy chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 24, 25 and 26 respectively;

(iii) an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising SEQ ID NO: 27 and a light chain variable region comprising SEQ ID NO: 28;

(iv) an antibody or antigen binding fragment thereof comprising heavy chain CDR1, CDR2 and CDR3 domains containing SEQ ID NOs: 29, 30 and 31, respectively, and light chain CDR1, CDR2 and CDR3 domains containing SEQ ID NOs: 32, 33 and 34 respectively;

(v) an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising SEQ ID NO: 35 and a light chain variable region comprising SEQ ID NO: 36;

(vi) an antibody or antigen binding fragment comprising the heavy chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 37, 38 and 39, respectively, and the light chain CDR1, CDR2 and CDR3 domains

- 23 046524 chains containing SEQ ID NO: 40, 41 and 42, respectively;

(vii) an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising SEQ ID NO: 43 and a light chain variable region comprising SEQ ID NO: 44; and (viii) an antibody or antigen binding fragment thereof comprising a heavy chain comprising SEQ ID NO: 45 and a light chain comprising SEQ ID NO: 46.

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

In one embodiment, the anti-C5 antibody is administered (or intended to be administered) in accordance with a specific clinical dosing regimen (eg, in a specific dosage amount and/or in accordance with a specific dosing regimen). In one embodiment, the anti-C5 antibody is administered at a fixed dose, which is fixed regardless of the patient's body weight. In the context of this invention, the terms fixed dose, constant dose and constant fixed dose are used interchangeably and refer to a dose that is administered to a patient without taking into account the body weight or body surface area (BSA) of the patient. Thus, a fixed or constant dose is provided not as a dose in mg/g, but as an absolute amount of anti-C5 antibody or antigen-binding fragment thereof.

In one embodiment, the anti-C5 antibody is administered at a fixed dose of 10, 20, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450 , 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1100, 1200 , 1300 , 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3 400,

3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100,5200,

5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900,7000,

7100, 7200, 7300, 7400, 7500, 7600, 7700, 7800, 7900, 8000, 8100, 8200, 8300, 8400, 8500, 8600, 8700,8800,

8900, 9000, 9100, 9200, 9300, 9400, 9500, 9600, 9700, 9800, 9900, 10000, 10100, 10200, 10300, 10400, 10500, 10600, 10700, 1 0800, 10900 or 11000 mg without taking into account the patient's body weight.

In some embodiments, the dosage of the anti-C5 antibody is based on the patient's body weight. In one embodiment, 10, 20, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1100, 1200, 1300, 1400, 150 0, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 370 0, 3800, 3900, 4000, 4100, 4200, 4300,

4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000,6100,

6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 7400, 7500, 7600, 7700, 7800,7900,

8000, 8100, 8200, 8300, 8400, 8500, 8600, 8700, 8800, 8900, 9000, 9100, 9200, 9300, 9400, 9500, 9600,9700,

9800, 9900, 10000, 10100, 10200, 10300, 10400, 10500, 10600, 10700, 10800, 10900 or 11000 mg of anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing >40 to <60 kg.

In another embodiment, 10, 20, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1100, 1200, 1300, 1400, 150 0, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 370 0, 3800, 3900, 4000, 4100, 4200,

4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900,6000,

6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 7400, 7500, 7600, 7700,7800,

7900, 8000, 8100, 8200, 8300, 8400, 8500, 8600, 8700, 8800, 8900, 9000, 9100, 9200, 9300, 9400, 9500,9600,

9700, 9800, 9900, 10000, 10100, 10200, 10300, 10400, 10500, 10600, 10700, 10800, 10900 or 11000 mg of anti-C5 antibody or antigen-binding fragment is administered to a patient with a body weight of >60 to <10 0 kg.

In another embodiment, 10, 20, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1100, 1200, 1300, 1400, 150 0, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 370 0, 3800, 3900, 4000, 4100, 4200,

4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900,6000,

6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 7400, 7500, 7600, 7700,7800,

7900, 8000, 8100, 8200, 8300, 8400, 8500, 8600, 8700, 8800, 8900, 9000, 9100, 9200, 9300, 9400, 9500,9600,

9700, 9800, 9900, 10000, 10100, 10200, 10300, 10400, 10500, 10600, 10700, 10800, 10900, or 11000 mg is administered to a patient weighing >100 kg. In some embodiments, dosage regimens are adjusted to provide the optimal response required (eg, an effective response).

In another embodiment, the anti-C5 antibody is administered at a dose of milligrams per kilogram (mg/kg). In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of

- 24 046524

0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 2.75, 3, 0, 3.25, 3.50, 3.75, 4.0, 4.25, 4.50, 4.75, 5.0, 5.25, 5.50, 5.75, 6.0, 6.25, 6.50, 6.75, 7.0, 7.25, 7.50, 7.75, 8.0, 8.25, 8.50, 8.75, 9.0, 9, 25, 9.50, 9.75, 10.0,

11.25, 11.50, 11.75, 12.0, 12.25, 12.50, 12.75, 13.0, 13.25, 13.50, 13.75, 14.0, 14, 25, 14.50, 14.75, 15.0, 15.25,

15.50, 15.75, 16.0, 16.25, 16.50, 16.75, 17.0, 17.25, 17.50, 17.75, 18.0, 18.25, 18, 50, 18.75, 19.0, 19.25, 19.50,

19.75, 20.0, 20.25, 20.50, 20.75, 21.0, 21.25, 21.50, 21.75, 22.0, 22.25, 22.50, 22, 75, 23.0, 23.25, 23.50, 23.75,

24.0, 24.25, 24.50, 24.75 or 25.0 mg/kg.

In one embodiment, the anti-C5 antibody is administered 1 time per week, 2 times per week, 3 times per week, 4 times per week, 5 times per week, 6 times per week, or 1 time per day. In another embodiment, the anti-C5 antibody is administered 2 times daily. In another embodiment, the anti-C5 antibody is administered once every 2 weeks, once every 3 weeks, once every 4 weeks, twice every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, Once every 9 weeks, once every 10 weeks, once every 11 weeks or once every 12 weeks. In another embodiment, the anti-C5 antibody is administered at a loading dose on day 1, then another maintenance dose on day 15, and every 8 weeks thereafter.

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

In some embodiments, patients treated in accordance with the methods described in this invention were vaccinated against meningococcal diseases 3 years before or at the time of initiation of the study drug. In one embodiment, patients who begin treatment less than two weeks after receiving the meningococcal vaccine are treated with appropriate prophylactic antibiotics for two weeks after vaccination. In another embodiment, patients receiving treatment in accordance with the methods described in this invention are vaccinated against meningococcal serotypes A, C, Y, W135 and/or B.

Results.

In some embodiments, treating MG includes normalizing or improving one or more symptoms associated with MG. Symptoms associated with MG include muscle weakness and fatigue. The muscles that are primarily affected by MG include the muscles that control eye and eyelid movement, facial expression, chewing, speaking, swallowing, breathing, neck movements, and limb movements.

In some embodiments, treating MG includes improving a clinical marker of MG progression. These markers include MG-ADL scores, QMG disease severity, MGC, NIF, forced vital capacity, post-MGFA status, and other quality of life measures. In some embodiments, the MG-ADL is the primary assessment for measuring MG improvement.

The MG-ADL is an 8-item questionnaire that focuses on relevant symptoms and functional performance of activities of daily living (ADL) in subjects with MG (Table 3). The 8 MG-ADL items were derived from the symptom-oriented components of the original 13-item QMG to assess disability secondary to ocular impairment (2 items), bulbar symptoms (3 items), respiratory symptoms (1 item), and gross motor skills. or limbs (2 items) associated with MG effects. In this functional status instrument, each response is scored from 0 (normal) to 3 (most severe). The MG-ADL total score range is 0-24. A clinically significant improvement in a patient's MG-ADL in one embodiment is, for example, a decrease in score of 3 or more points after 26 weeks of treatment.

The current QMG scoring system consists of 13 items: ocular (2 items), facial (1 item), bulbar symptoms (2 items), gross motor symptoms (6 items), axial symptoms (1 item), and respiratory symptoms (1 item). ; each of them was scored from 0 to 3 points, with 3 points corresponding to the most severe condition (Table 4). The QMG total score range is 0-39. The QMG scoring system is an objective assessment of MG therapy and is based on quantitative testing of indicator muscle groups. The MGFA Working Group recommended the use of the QMG score in prospective studies of MG therapy (Benatar, M. et al., Muscle Nerve, 45:909–17, 2012). A clinically significant improvement in a patient's QMG in one embodiment is, for example, a decrease in score of 5 points or more after 26 weeks of treatment.

- 25 046524

Table 3

Profile MG-ADL

Items Degree 0 Degree 1 Degree 2 Degree 3 Point (0,

1,2,3)

1. Conversation Norm Intermittent Constant Speech, complex slurred or nasal speech slurred or nasal speech, but can be understandable for understanding 2. Chewing Norm Fatigue from solid food Fatigue from soft food Gastric probe 3. Swallowing Norm Rare episode of stuck throat Frequent cases getting stuck in throat requiring dietary changes Gastric probe 4. Breathing Norm Shortness of breath when voltage Dyspnea at rest need for a ventilator 5. Violation ability to brush teeth or comb hair No Extra effort but no rest periods required Required rest periods Cannot perform one of these functions 6. Violation ability to get up from a chair No Minor, sometimes with the help of HANDS Moderate, always with hands Heavy, needs help 7. Double vision No Happens, but not daily Every day, but not all the time Constantly 8. Drooping eyelids No Happens, but not daily Every day, but not all the time Constantly

- 26 046524

Table 4

Disease severity score according to the QMG scale

QUANTITATIVE FORM OF MYASTHENIAS GRAVIS TESTING

Patient name:------------------------------------------------ -Patient No.:-----Date:

No. MR:DOB:Gender:__Height (inches):-----------------Body weight (kg):________________

Evaluator: Dominant hand: Dominant leg: Study time:

Anticholinesterase substance: .................................................... .......................

Comments

WEAKNESS ACCORDING TO STUDY MISSING WEAK MODERATE STRONG SCORE POINTS T I DEGREE 0 1 2 3 Double vision (when viewed from the side) sec. 60 11-59 1-10 Spontaneous Ptosis (upward gaze) sec.. 60 11-59 1-10 Spontaneous Facial muscles Normal eyelid closure Full, weak, some resistance Complete, without resistance Incomplete Swallowing 4 ounces water (1/2 cup) Normal Minimal coughing or sore throat Severe coughing, choking, or nasal regurgitation. Inability to swallow (not tested) Speech after counting out loud from 1 to 50 (beginning of dysarthria) Absent at No. 50 Dysarthria with No. 30-49 Dysarthria with No. 10-29 Dysarthria with No. 9 Right arm extended (90°, in a sitting position) sec. 240 90-239 10-89 0-9 Left arm extended (90°, in a sitting position) sec. 240 90-239 10-89 0-9 Forced vital capacity >80% 65-79% 50-64% <50% Right hand grip: man (kg) : woman >45 >30 15-44 10-29 5-14 5-9 0-4 0-4 Left hand grip: man (kg) : woman >35 >25 15-34 10-24 5-14 5-9 0-4 0-4 Elevated head (45%, supine position) sec. 120 30-119 1-29 0 Right leg extended (45-50%, in a supine position) sec. 100 31-99 1-30 0 Left leg extended (45-50%, in a supine position) sec. 100 31-99 1-30 0

Overall MG score.

The MGC is a validated assessment tool for measuring the clinical status of subjects with MG (16). The MGC assesses 10 important functional areas most commonly affected by MG, and scales are weighted by clinical relevance, which includes subject-reported outcomes (Table 5; Bums, T. et al., Muscle Nerve, 54:1015–22, 2016). MGC is given at the time of screening, day 1, 1-4, 8, 12, 16, 20 and 26 weeks or ET (1-6, 8, 10, 12, 14 - and 17th visits or ET). A clinically significant improvement in a patient's MGC in one embodiment is, for example, a score reduction of 3 or more points after 26 weeks of treatment.

Table 5

Combined MG scale

Ptosis, upward gaze (PE) > 45 seconds 0 11-45 seconds 1 1-10 seconds 2 Slowly 3 Double vision, when viewed from the side, left or right (RE) >45 seconds 0 11-45 seconds 1 1-10 seconds 2 Not slowly 4 Eye closure (RE) Normal 0 Slight weakness (can be opened with force) 0 Moderate weakness (open easily) 1 Severe weakness (inability to keep eyes closed) 2 Conversation (Pt) Normal 0 Intermittent slurred or nasal speech 2 Constantly slurred or nasal speech, but may be understandable 4 Speech difficult to understand 6

- 27 046524

Chewing (Pt) Normal 0 Fatigue from solid foods 2 Fatigue from soft foods 4 Gastric tube 6 Swallowing (Pt) Normal 0 A rare episode of getting stuck in throat 2 Frequent episodes (diet changes) 5 Gastric tube 6 Breath Normal 0 SOB at voltage 2 SOB at rest 4 Need for mechanical ventilation 9 Neck flexion/extension (weakest RE) Normal 0 Lung 1 Moderate (~50% weak condition +/-15%) 3 Strong 4 Shoulder abduction (RE) Normal 0 Lightweight 2 Moderate (~50% weak condition +/-15%) 4 Strong 5 Hip flexion Normal 0 Lung 2 Moderate (~50% weak condition +/-15%) 4 Strong 5 0 15 33 50

The 15-item Myasthenia Gravis Quality of Life Scale-Revised (MG-QOL15r) is a health-related quality of life instrument specific to patients with MG (Table 6). The MG-QOL15r was designed to provide information on patients' perceptions of impairment and disability, measure tolerance of disease manifestations, and be easy to administer and interpret. MG-QOL15r is completed by the patient. Higher scores indicate greater severity and dissatisfaction with MG-related dysfunction. A clinically significant improvement in a patient's MG-QOL15 is a decrease in scores after 26 weeks of treatment.

Table 6

Updated MG-QOL15r scale

Please indicate how true each statement was (per Not at all 0 To some extent 1 Very much 2 1. I'm upset about my MG. 2. I have eye problems due to my MG (eg double vision) 3. I have eating problems because of my MG. 4. I have limited my social activities because of my MG. 5. My MG limits my ability to enjoy ho bon n entertainment. 6. I have trouble meeting my family's needs because of my MG. 7. I have to make plans with my education in mind. 8. I am concerned about restrictions in doing my job (including working from home) due to my MG. 9. It's hard for me to talk because of my MG. 10. I have lost some personal independence due to my activities (eg, driving, shopping, running errands) I. I'm depressed because of my MG 12. I have trouble walking because of MG. 13. I have problems moving in public places because of my MG. 14. I feel overwhelmed by my MG. Ooshy aall on the scale MGQOL-R

The QOL Nervous Fatigue Questionnaire is a reliable and validated 19-item short fatigue questionnaire completed by the subject or patient. Higher scores indicate higher fatigue and greater impact of MG on activity (Table 7; Gershon, R. et al.,

- 28 046524

Qual. Life Res., 21:475-86, 2012). A clinically significant improvement in the patient's QQL fatigue score is reflected in a decrease in the score after 26 weeks of treatment.

Table 7

QOL Nervous Fatigue Scale

In the last 7 days... Never Rarely Sometimes Often Always I felt exhausted □ □ □ □ □ NQFTG13 1 2 3 4 5 □ □ □ □ □ NQFTG11 I felt like I had no energy 1 2 3 4 5 □ □ □ □ □ NQFTG15 I felt tired 1 2 3 4 5 □ □ □ □ □ NQFTG06 I was too tired to do my household chores 1 2 3 4 5 □ □ □ □ □ NQFTG07 I was too tired to leave the house 1 2 3 4 5 I was disappointed because I was too tired □ □ □ □ □ NQFTG10 to do what I wanted to do 1 2 3 4 5 □ □ □ □ □ NQFTG14 I felt tired 1 2 3 4 5 I had to limit my social activities due to... □ □ □ □ □ NQFTG02 for the fact that 1 2 3 4 5 I'm tired I needed help doing my usual tasks □ □ □ □ □ NQFTG01 because of my fatigue 1 2 3 4 5 □ □ □ □ □ NQFTG03 During the day I needed sleep 1 2 3 4 5 I had difficulty starting anything because I was □ □ □ □ □ NQFTG04 too tired 1 2 3 4 5 I had difficulty finishing anything because □ □ □ □ □ NQFTG05 was too tired 1 2 3 4 5 □ □ □ □ □ NQFTG08 I'm too tired to take a short walk 1 2 3 4 5 □ □ □ □ □ NQFTG09 I was too tired to eat 1 2 3 4 5 I was so tired that I needed to rest during the day □ □ □ □ □ NQFTG12 1 2 3 4 5 □ □ □ □ □ NQFTG16 I felt weak in everything 1 2 3 4 5 I needed help doing my usual tasks □ □ □ □ □ NQFTG17 due to weakness 1 2 3 4 5 I had to limit my social activities due to... □ □ □ □ □ NQFTG18 for the fact that 1 2 3 4 5 I was physically weak NQFTG20 I had to force myself to get up and do something, □ □ □ □ □ because I was physically too weak 1 2 3 4 5

The European Quality of Life Questionnaire (EQ-5D-5L) is a self-report health-related QoL questionnaire (Figures 3A, 3B and 3C). The EQ-5D-5L consists of two pages: the EQ-5D descriptive scale (Figure 3B) and the EQ visual analogue scale (EQ VAS) (Figure 3C). The scale measures quality of life on a five-item scale, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each level is rated on a scale that describes the degree of problems in that area (for example, I have no problems walking, minor problems, mental

- 29 046524 real problems, serious problems or I can’t 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 dimensions. This solution results in a single-digit number that expresses the level chosen for that measurement. The digits of the five dimensions can be combined into a five-digit number that describes the patient's health status. Clinically significant improvement in a patient's EQ-5D is reflected by a decrease in scores in each category after 26 weeks of treatment. This instrument also has an overall health status scale (EQ VAS), where the rater selects a number from 1 to 100 to describe their health status, with 100 representing the best possible value. The EQ VAS records a patient's self-rated health on a vertical visual analogue scale, with endpoints labeled Best Health You Can Imagine and Worst Health You Can Imagine. VAS can be used as a quantitative measure of health status, reflecting the patient's own opinion. Clinically significant improvement in a patient's EQ VAS is reflected in an increase in scores after 26 weeks of treatment. Convergent validity was demonstrated by the correlation between the EQ-5D-5L and World Health Organization 5 questionnaire measures (r=0.43, p<0.001) (see Janssen, M. et al., Qual. Life Res., 22:1717- 27, 2013). The EQ-5D-5L approach is reliable, with average test-retest reliability using interclass coefficients with averages of 0.78 and 0.73 (Brooks, R., Health Policy, 37:53-72, 1996; Chaudhury, C. et al., Biochemistry, 45:4983-90, 2006).

Subjects who progress to severe MG may suffer from potentially fatal respiratory complications, including significant respiratory muscle weakness. Respiratory function is closely monitored for the presence of respiratory failure in MG subjects, and ventilator support is recommended in the event of a consistent decrease in serial forced vital capacity (FVC) or NIF measurements, compromised upper airway integrity (difficulty processing oral secretions, swallowing, etc.) .d. or conversation) or against the background of emerging respiratory failure. The FVC assessment, as one of the test items in the QMG, is performed when the QMG assessment is performed. NIF assessment was performed using a NIF meter.

The clinical status of MG is assessed using the MGFA Post-Intervention Status (MGFA-PIS). Changes in the status categories Improvement, No Change, Worsening, Exacerbation and Death from MG, as well as Minimal Manifestation (MM) can be assessed (Table 8).

Table 8

MGFA-PIS

Complete stable remission (CSR) The patient has had no symptoms or signs of MG for at least 1 year and

Pharmacological remission (PR)

Minimum manifestations (MM)

MM-0 received no treatment for MG during this time. Upon careful examination by a neuromuscular disease evaluator, there is no weakness in any muscles. Isolated weakness when closing the eyelids is acceptable.

Same criteria as for CSR, except that the patient remains on some form of therapy for MG. Patients taking cholinesterase inhibitors are excluded from this category because their use presupposes the presence of weakness.

The patient has no symptoms of functional limitations in the MG, but has some weakness on examination of some muscles. This class recognizes that some patients who would otherwise meet the definition of CSR or PR do have weakness that can only be detected by careful examination.

The patient had not received treatment for MG for at least 1 year.

- 30 046524

MM-1 The patient continues to receive some form of immunosuppression, but without cholinesterase inhibitors or other symptomatic MM-2 therapy. The patient received only low doses of cholinesterase inhibitors (<120 mg MM-3 pyridostigmine/day) for at least 1 year. The patient received cholinesterase inhibitors or other symptomatic therapy Change of status and some forms of immunosuppression within the last year. Improvement (I) Significant reduction in pre-treatment clinical symptoms or sustained significant reduction in medications used to treat MG, as defined in the protocol. In prospective studies this should be No change (U) defined as a specific decrease in QMG score. No significant change in pre-treatment clinical symptoms or reduction in MG medication use as defined in the protocol. In prospective studies this should be defined in terms of Deterioration (W) maximum change in QMG score. Significant increase in clinical manifestations before treatment or Exacerbation (E) essential increasing the use of medications for the treatment of MG, as defined in Death due to MG (D MG) protocol. In prospective studies, this should be defined as a specific increase in QMG score. Patients who met criteria for CSR, PR, or MM, but who

Subsequently, clinical results appeared higher than acceptable according to these criteria.

Patients who died from MG, complications of MG therapy, or within 30 days of thymectomy. Indicate the cause (see Morbidity and Mortality Table).

Patients treated with ravulizumab experienced a decrease in MG-ADL scores. In some embodiments, subjects have an initial MG-ADL score greater than 6. In some embodiments, subjects have an initial MG-ADL value 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 points. In some embodiments, after a course of treatment with ravulizumab, the subject's MG-ADL score is reduced to less than 6 points. In some embodiments, 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 at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 16 points, at least 17 points, at least 18 points, at least 19 points, at least 20 points, at least 21 points, at least 22 points, at least 23 points or at least 24 points after treatment with ravulizumab. In some embodiments, a patient's MG-ADL score decreases by at least 1 point after a course of treatment with ravulizumab. In some embodiments, the patient's MG-ADL score 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 after treatment with ravulizumab.

In some embodiments, the course of treatment with ravulizumab lasts 26 weeks. In some embodiments, the course of treatment lasts 26-52, 26-78, 26-104, 26-130, 26-156, 26-182, 26-208 weeks, or more. 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. In some embodiments, the course of treatment lasts more than 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, and more than years. In some embodiments, the course of treatment lasts for the rest of the subject's life.

In some embodiments, during a course of treatment, one or more symptoms or scores associated with MG improve during the course of treatment and are maintained at an improved level throughout the course of treatment. The MG-ADL score may improve, for example, after 26 weeks of treatment with a therapeutic antibody that specifically binds to C5, and then remain at an improved level throughout the treatment period, which is 52 weeks of treatment with a therapeutic antibody that specifically binds to C5. One of

- 31 046524 examples of a therapeutic antibody that binds to C5 is ravulizumab.

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

In some embodiments, the MG includes refractory gMG. In some embodiments, refractory gMG is characterized as including subjects or patients characterized by positive AChR autoantibody binding results who continue to demonstrate significant general 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 chronic plasmapheresis or chronic IVIg to maintain clinical stability. In some embodiments, refractory gMG is characterized to include subjects or patients who continue to demonstrate severe generalized weakness or bulbar signs and symptoms of myasthenia gravis while receiving current standard of care for MG, such as cholinesterase inhibitor therapy and IST, or who require chronic plasmapheresis or chronic IVIg for maintaining clinical stability.

Kits and single dosage forms.

The present invention also provides kits that contain a pharmaceutical composition containing an anti-C5 antibody or an antigen-binding fragment thereof, such as ravulizumab, and a pharmaceutically acceptable carrier in a therapeutically effective amount adapted for use in the previous methods. The kits may also optionally contain instructions, for example containing administration schedules, allowing a practitioner (eg, doctor, nurse or patient) to administer the composition contained therein for administering the composition to a patient having MG. The kit may also contain a syringe.

The kits may optionally contain multiple packages of single-dose pharmaceutical compositions, each of which contains an effective amount of an anti-C5 antibody or antigen-binding fragment thereof for a single administration in accordance with the methods described above. Instruments or devices necessary for administering the pharmaceutical composition(s) may also be included in the kits. The kit may contain one or more pre-filled syringes containing an amount of anti-C5 antibody or antigen-binding fragment thereof.

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

Examples

Example. A randomized, double-blind, placebo-controlled, multicenter, phase 3 study to evaluate the safety and efficacy of ravulizumab in complement inhibitor-naive adult patients with generalized myasthenia gravis.

A randomized, double-blind, placebo-controlled, multicenter, phase 3 trial is being conducted to evaluate the safety and efficacy of ravulizumab administered by intravenous (IV) infusion to adult patients with gMG. The study design for ALXN1210-MG-306 is shown in FIG. 1.

1. Rationale for the study.

Ravulizumab specifically binds to the terminal component of human complement (C5) with high affinity, inhibiting the enzymatic cleavage of C5 and thereby preventing the formation of the proinflammatory/prothrombotic complement activation products, C5a, and the cytolytic and proinflammatory/prothrombotic membrane attack complex, C5b-9, which are responsible for mediating antibodies destroy the NMJ, loss of acetylcholine receptors and disruption of neuromuscular transmission associated with gMG. Eculizumab is approved for the treatment of, for example, gMG under the trade name Soliris®.

Similar to eculizumab, ravulizumab also provides almost immediate and complete C5 inhibition, but ravulizumab additionally provides sustained complement inhibition over an extended dosing interval; it was specifically designed (and subsequently proven) to have an increased half-life compared to eculizumab. Thus, ravulizumab requires less frequent infusions (once every 8 weeks [Q/8 weeks]) than eculizumab (infusions every 2 weeks [Q/2 weeks]). Given that gMG is a chronic disease requiring significant treatment, the relative convenience of the ravulizumab dosing regimen may improve

- 32 046524 patient satisfaction and adherence and ultimately lead to improved health outcomes.

The improved pharmacokinetic (PK)/pharmacodynamic profile of ravulizumab, with fewer residual PK concentrations than eculizumab, may improve therapeutic efficacy while maintaining a safety profile similar to that of eculizumab. Dose regimen: 1 r./8 weeks. minimizes the risk of incomplete complement inhibition. The frequency of infusions is relatively low (6 infusions per year) (Fig. 2), which provides the opportunity to improve quality of life (QoL) due to fewer days missed from work or school, better adherence to treatment, and greater accessibility. Ravulizumab offers convenient dosing and immediate onset of action with effective and complete inhibition of the terminal complement complex at the end of the first infusion. The ravulizumab dosing schedule was optimized to reduce differences in exposure across the adult body weight range by using a weight-based dosing paradigm that provides immediate, complete, and sustained C5 inhibition throughout the dosing interval. Thus, ravulizumab minimizes the risk of inflammation, including C5a recruitment and inflammatory cell activation, as well as direct damage to the motor neural end plate caused by the MAC complex (Kusner, L. et al., Expert Rev. Clin. Immunol., 4:43 -52, 2008).

2. Risk-benefit assessment.

Ravulizumab provides patients and physicians with the option of less frequent dosing, which provides greater access to care for those patients who may not initiate treatment with eculizumab, may discontinue eculizumab due to dosing frequency, or who are currently receiving eculizumab every 2 weeks.

Neisseria meningitides.

Increased susceptibility to Neisseria meningitidis (N. meningitidis) infection is a known risk associated with complement inhibition. The main risk associated with ravulizumab is the risk of meningococcal infections. Specific risk mitigation measures are used to eliminate this risk, as described in this invention.

Immunogenicity.

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

Of 261 patients with paroxysmal nocturnal hemoglobinuria (PNH) who were treated with ravulizumab in clinical trials of IV ravulizumab, 1 patient developed ADAs during treatment. Treatment-induced ADAs were observed in 3 healthy subjects receiving subcutaneous (SC) ravulizumab and 1 healthy subject receiving IV ravulizumab in the ALXN1210-HV-104 study. All positive ADA titers were low and negative for eculizumab cross-reactivity. There was no obvious effect of immunogenicity on the PK or PD of ravulizumab.

Immunogenicity monitoring for this study was performed as described in Table. 10 and 11 and as described elsewhere in this invention.

Local and systemic reactions.

Protein drugs administered intravenously may cause local (injection site reactions) and systemic reactions (infusion-associated reactions). Administration site reactions are reactions localized to the site of IV drug administration and may include reactions such as erythema, itching, and bruising.

Infusion-associated reactions are reactions that are systemic in nature and may be immune or non-immune-mediated, typically occurring within a few hours of drug administration. Immune-mediated reactions may include allergic reactions (eg, anaphylaxis), whereas non-immune-mediated reactions are nonspecific (eg, headache, dizziness, nausea). Monitoring of these reactions is carried out as part of the routine safety assessments for this study described in this invention.

3. Goals.

The primary objective of the study is to evaluate the effectiveness of ravulizumab versus placebo in the treatment of gMG based on improvement in MG-ADL score profile. The secondary objective of the study is to evaluate the effectiveness of ravulizumab versus placebo in the treatment of gMG based on improvement in total QMG score.

The research objectives of this study are as follows:

(1) evaluate the PK/PD and immunogenicity of ravulizumab in gMG throughout the study;

- 33 046524 (2) evaluate the effectiveness of ravulizumab versus placebo in the treatment of gMG based on the incidence of all-cause hospitalization or clinical worsening;

(3) evaluate the effectiveness of ravulizumab compared with placebo in the treatment of gMG based on measures of quality of life improvement; and (4) evaluate the efficacy of ravulizumab in the treatment of gMG based on other efficacy endpoints throughout the study.

The purpose of the safety study is to characterize the overall safety of ravulizumab in the treatment of gMG.

4. Endpoints.

The study's primary efficacy endpoint is change from baseline in MG-ADL total score at week 26 of the randomized controlled period.

The study's secondary efficacy endpoint is change in QMG total score from baseline at week 26.

The study's exploratory efficacy endpoints include the following:

changes in the concentration of ravulizumab in blood serum over time;

changes in the concentration of free C5 in blood serum over time;

the frequency of antibodies to the drug arising as a result of treatment over time;

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

change from baseline in myasthenia gravis quality of life 15-item (MG-QOL15r) score at week 26;

change from baseline in the QOL fatigue score at week 26;

an improvement of at least 3 points in MG-ADL total score from baseline at week 26;

an improvement of at least 5 points in QMG total score from baseline at week 26;

change from baseline in Myasthenia Gravis Composite (MGC) score at week 26;

Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Score (PIS) at week 26;

change from baseline on the European Quality of Life Questionnaire (EQ-5D-5L) health status scale at week 26.

The safety endpoints of this study are (1) the incidence of adverse events and serious adverse events over time; and (2) deviations from baseline in vital signs and laboratory assessments.

The goals and end points of the study are presented in Table. 9 in this invention.

Table 9

Goals and endpoints of study ALXN1210-MG-306

Goals Endpoints Primary To evaluate the effectiveness of ravulizumab compared with placebo in the treatment of gMG based on improvement in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score profile. Change from baseline in MG-ADL total score at week 26 of the randomized controlled period. Secondary To evaluate the effectiveness of ravulizumab compared with placebo in the treatment of gMG based on improvement in the global quantitative myasthenia gravis (QMG) score. Change from baseline in QMG total score at 26 weeks. Research

- 34 046524

• Assess the PK/PD and immunogenicity of ravulizumab in gMG throughout the study. • To assess the effectiveness of ravulizumab compared with placebo in the treatment of gMG based on the incidence of all-cause hospitalization or clinical worsening. • To evaluate the effectiveness of ravulizumab compared with placebo in the treatment of gMG based on measures of improvement in quality of life. • Assess the efficacy of ravulizumab in the treatment of gMG based on other efficacy endpoints throughout the study. • Change in ravalizumab concentration in blood serum dynamics. • Change in the concentration of free C5 in blood serum dynamics. • Frequency of antibodies to the drug resulting from treatment over time. • Rates of all-cause hospitalization or clinical deterioration during the 26-week randomized controlled period. • Change from baseline in Myasthenia Gravis Quality of Life 15-item (MG-QOL15r) score at week 26. • Change from baseline in the QOL fatigue score at 26 weeks. • At least a 3-point improvement in MG-ADL total score from baseline at 26 weeks. • At least a 5-point improvement in QMG total score from baseline at 26 weeks. • Change from baseline in Myasthenia Gravis Composite (MGC) score at 26 weeks. • Myasthenia Gravis Foundation of America (MGFA) Post Intervention Score (PIS) at 26 weeks. • Change from baseline in the European Quality of Life Questionnaire (EQ-5D-5L) health status scale at 26 weeks. Safety To characterize the overall safety of ravalizumab in the treatment of gMG. • Frequency of adverse events and serious adverse events over time. • Changes in vital signs and laboratory assessments from baseline.

5. General design.

ALXN1210-MG-306 is a randomized, double-blind, placebo-controlled, multicenter, parallel-group, phase 3 study to evaluate the safety and efficacy of ravulizumab for the treatment of patients with gMG. The ALXN1210MG-306 study design is shown in FIG. 1. Approximately 160 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.

This study had 3 periods: a screening period, a randomized control period, and an open-label extension (OLE) period.

After a 26-week randomized controlled period and assessments at day 183 (week 26), patients in the placebo group received a masked loading dose of ravulizumab, and patients in the ravulizumab group received a masked loading dose of ravulizumab at 900 mg. Beginning with

- 35 046524

At week 28, all patients began taking open-label maintenance doses of ravulizumab once a day/8 weeks. For patients in the ravulizumab group, a masked dose of ravulizumab was selected at 900 mg to ensure complete C5 inhibition until the next scheduled maintenance dose at week 28 (day 197).

Eight weeks after the last dose of study drug, all enrolled patients returned for an end-of-study (EOS) visit (visit 30) at week 132 (±2 days), at which final study assessments were performed. If a patient left the study or completed the study early (before visit 29; week 124), for example, if ravulizumab was registered or approved (according to country regulations) before visit 29, the patient was advised to return for an early termination visit (ET)/EOS 8 weeks (±2 days) after the day of the last dose of study drug at which the final planned safety assessments described in this invention were performed. Attempts were made to monitor all patients for safety for 8 weeks from the date of the last dose of study drug.

Patients who are treated with an IST at the screening visit may continue to receive the original IST during the randomized controlled and OLE periods. However, the IST dose should not be changed, and no new ISTs could be added or withdrawn during the randomized controlled study period unless deemed medically necessary by the investigator. Throughout the study, back-up therapy (eg, high-dose corticosteroids, plasmapheresis/plasma exchange, or intravenous immunoglobulin) is permitted if the patient experiences clinical deterioration as defined in the study protocol. Reserve therapy used for a particular patient is at the discretion of the investigator.

Throughout the study, back-up therapy (eg, high-dose corticosteroids, PP/PE, or IVIg) is permitted if the patient experiences clinical deterioration as defined herein. The reserve therapy used for a particular patient is at the discretion of the investigator.

The primary endpoint for this study is measured at week 26 (day 183). Endpoints were measured and analyzed regardless of salvage therapy. For those patients who completed the study as defined in the protocol, the EOS visit was defined as the patient's last visit during the (up to) 2-year OLE period. Including the 8-week safety study follow-up period, which begins after the patient's last dose of study drug, the total study duration for an individual patient is estimated to be up to 132 weeks (from study enrollment to the end of the safety study follow-up period). The period of active patient participation is estimated at 132 weeks (from study enrollment to EOS visit).

Schedules of intervention (SOA) for the randomized controlled period and OLE period are presented in Table. 10 and 11 respectively.

Screening period (2-4 weeks to 1st day).

At the screening visit, after obtaining informed consent, the patient is screened for study eligibility through a review of medical history, demographic data, and laboratory evaluations. Medical history review includes confirmation of diagnosis of MG as defined in the inclusion criteria for this protocol, history of previous MG treatment(s) (eg, thymectomy, IST including corticosteroids, IVIg and PE/RR), history of exacerbation or crisis of MG including duration of each exacerbation/crisis, medication taken during each exacerbation/crisis, and treatment for each exacerbation/crisis.

If all inclusion criteria and none of the exclusion criteria were met, patients were vaccinated against N. meningitidis if they had not already been vaccinated 3 years before their inclusion in the study. Patients who initiated study drug treatment less than 2 weeks after meningococcal vaccine administration were treated with appropriate prophylactic antibiotics for 2 weeks after vaccination.

If a patient experienced clinical deterioration or MG crisis during the screening period, the sponsor was notified. After discussion with the sponsor, a decision was made as to whether the patient could continue to participate in the study.

Number of patients.

Patients were screened until enough patients were recruited to reach a total of 160 patients, approximately 80 patients per group.

Randomization.

At the time of randomization, all patients were re-evaluated for eligibility and exclusion criteria. All vaccinated patients who continue to meet all inclusion criteria and none of the exclusion criteria at randomization

- 36 046524

[day 1]), and eligible for randomization by the investigator, were randomized 1:1 to 1 of 2 treatment groups:

(1) ravulizumab infusion; or (2) placebo infusion.

Patients were randomized centrally using interactive response technology. Randomization was stratified by region (North America, Europe, Asia-Pacific, and Japan).

Throughout the study, authorized therapy (eg, high-dose corticosteroids, PP/PE, or IVIg) is permitted when the patient's health would be at risk if backup therapy is not provided (eg, in emergency situations), or if the patient experiences clinical deterioration health conditions as defined in this protocol. Reserve therapy used for a particular patient is at the discretion of the investigator.

Patients were informed of the potential signs and symptoms of clinical worsening or MG crisis and instructed on how to contact the investigator for evaluation within 48 hours of notifying the investigator of the onset of symptoms. During the assessment visit, the investigator or designee performed assessments as specified in this protocol. The investigator or designee determined whether the patient met the definition of clinical deterioration as defined herein and treated the patient accordingly.

The primary endpoint for this study was measured at week 26 (day 183), regardless of salvage therapy.

Patients randomized to the ravulizumab group received a masked loading dose of ravulizumab on day 1, then a masked maintenance dose of ravulizumab on day 15 (week 2) and 1 day/8 weeks thereafter for a total of 18 weeks of treatment. . Patients randomized to placebo received a masked placebo dose on day 1, then a masked placebo dose on day 15 (week 2), and 1 time/8 weeks thereafter for a total of 18 weeks. Both ravulizumab and placebo were administered intravenously.

After a 26-week randomized controlled period and assessments at day 183 (week 26), patients in the placebo group received a masked loading dose of ravulizumab, and patients in the ravulizumab group received a masked dose of ravulizumab 900 mg; the 900 mg dose was chosen to provide complete C5 inhibition until the next scheduled maintenance dose at week 28 (day 197). Beginning at week 28, all patients began taking open-label maintenance doses of ravulizumab once a day/8 weeks.

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 the drug was registered or approved (according to country-specific regulations) , whichever comes first.

The schedule for screening activities until the end of the randomized controlled period is shown in Table. 10, and the extended period is shown in table. eleven.

Table 10

Intervention schedule: selection until the end of the randomized controlled period

Period/phase Screening Randomized controlled period Clinical 1 deterioration Research visit 1 2 3 4 5 6 7 8 9 10 eleven 12 13/ET Research day D1 D8 D15 D22 D29 D57 D71 D85 D99 D127 D155 D183 Window (day) + 2 + 2 + 2 + 2 + 2 + 2 + 2 + 2 + 2 + 2 + 2 weeks From -4th to -2nd week H1 H2 NZ H4 H8 H10 H12 H14 H18 H22 H26 Informed consent X Evaluation of criteria inclusions/exclusions X X Medical history X History of MG X

- 37 046524

Clinical 3 MGFA classification X X Body mass X X X X X X Height X Testing for presence of HIV- (1 and 2) X Vital signs functions and 4 pulse oximetry X X X X X X X X X X X X X X Physical examination X X X Abbreviated physical _ 5 examination X X X X X X X X X X X Concomitant medication X X X X X X X X X X X X X X Non-medicinal therapy X X X X X X X X X X X X X X MG therapy status X X X X X X X X X X X X X X Hospitalization status X X X X X X X X X X X X X Adverse event X X X X X X X X X X X X X X MG-QOL15T X X X X X X X X X X X X X X Nervous fatigue QOL X X X X X X X X X X X X X X EQ-5D-5L X X X X X X X X X X X X X X MG-ADL ³ ' ⁶ X X X X X X X X X X X X X X 3 7 QMG' X X X X X X X X X X X X X X 3 7 MGC' X X X X X X X X X X X X X X MGFA-PIS ³ X X X X X X X X C-SSRS Baseline/screening version X C-SSRS since version of last visit X X X

- 38 046524

ECG X X AB to AChR X X X X Clinical laboratory 8 research X X X X X X X _ _ 9 Pregnancy test X X X X X X RK, free C5 ¹⁰ V/R T/R T/R T/R T X

10 ADA X X X X X Vaccine against N 7 ¹¹ meningitidis X Map informational 12 patient consent X X X X X X X X X X X X 13 Randomization X Infusion of the test subject medicinal 14 facilities X X X X

¹ Assessment of clinical deterioration is performed as quickly as possible within 48 hours of notifying the investigator of the onset of symptoms. Additional assessment visits are scheduled at the discretion of the investigator.

² If a patient leaves the study prematurely during the randomized controlled period, an early termination visit is performed.

³ See, for example, table. 3.

⁴ Vital signs and pulse oximetry include systolic and diastolic blood pressure (millimeters of mercury [mmHg]), pulse oximetry (oxygen saturation [SO ₂ ]), heart rate (beats/minute), and temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). On dosing days, vital signs are measured before study drug administration and after the patient has rested for at least 5 minutes.

⁵ If necessary, performed based on the patient’s health status and the clinical judgment of the investigator.

⁶ The MG Activities of Daily Living (MG-ADL) assessment is performed by an appropriately trained clinical assessor, preferably the same assessor, throughout the study. The recall period for MG-ADL is the previous 7 days or since the last visit if the interval between visits is less than 7 days.

⁷ If the patient is taking a cholinesterase inhibitor, the dose is discontinued at least 10 hours before assessment.

⁸ Clinical laboratory tests are carried out in a central laboratory.

⁹ Pregnancy tests are carried out on all patients of childbearing age within the specified time frame. During screening, a serum pregnancy test is performed; Urine pregnancy tests are performed at all other required time points. A negative urine test result is required before administering ravulizumab to patients of childbearing potential at these visits. Additional pregnancy tests (urine or serum) may also be performed at any visit at the discretion of the investigator.

¹⁰ Blood samples for serum PK at baseline concentration (B) and residual concentration (T) of free C5 (PD) and ADA are collected predose (within 30 min before the start of the study drug infusion). Blood samples at peak concentration (P) for PK/PD serum samples are collected within 30 minutes after completion of the study drug infusion. T-samples are collected through a venous access set up for dose infusion prior to dosing. P-samples are taken from the patient's contralateral arm without infusion. At day 183 (week 26), the T-sample is considered the randomized controlled period evaluation and the P-sample is considered the extension period evaluation. All collection dates are recorded in the eCRF. In the event of clinical deterioration, blood samples are collected for serum PK/PD analysis and ADA if additional dosing is described in this invention.

- 39 046524 ¹¹ To reduce the risk of meningococcal disease (N. meningitidis), all patients are vaccinated against meningococcal diseases 3 years before or at the time of starting the study drug. Patients who initiated study drug treatment less than 2 weeks after meningococcal vaccine administration were treated with appropriate prophylactic antibiotics for 2 weeks after vaccination.

¹² Patients are provided with a Patient Safety Information Sheet before the first dose of study drug is administered. At each study visit, study staff will ensure that the patient has a Patient Safety Information Card.

¹³ All patients who continue to meet all inclusion criteria and none of the exclusion criteria and are accepted for randomization by the investigator are randomized centrally using interactive response technology (IRT).

¹⁴ The study drug is administered by intravenous infusion after completion of all other tests and procedures except peak blood sampling for PK/PD, free C5, and ADA.

Abbreviations.

Ab to AChR=anti-acetylcholine receptor antibody;

ADA=drug antibody;

B=sample at baseline;

C5=complement component 5;

C-SSRS=Columbia Suicidality Rating Scale (C-SSRS);

D=day;

ECG=electrocardiogram;

EQ-5D-5L=European Quality of Life Questionnaire;

ET=early termination;

HIV=human immunodeficiency virus;

MG=myasthenia gravis;

MG-ADL=Myasthenia Gravis Activities of Daily Living Scale profile;

MGC=Myasthenia Gravis Combined Grading Scale;

MGFA=Myasthenia Gravis Foundation of America;

MGFA-PIS=post-MGFA intervention status;

N. meningitidis=Neisseria meningitidis;

P=sample at peak concentration;

PK/PD=pharmacokineticsα/pharmacodynamics;

QMG = scale for quantitative assessment of disease severity in myasthenia gravis;

QoL=quality of life;

T=sample at residual concentration;

N=week(s).

Table 11

Event schedule: extended period

Period Open extended Research visit 13 14 15 16 17 18 19 20 21 Research days D183 D197 D211 D253 D267 D281 D309 D365 D421 weeks H26 H28 ISO H36 H38 H40 H44 H52 H60 Window (day) ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 Body mass X Vital signs functions and pulse oximetry Physical examination Abbreviated Physical Examination Related medicine X X X Non-medicinal therapy ^X X MG therapy status X X Hospitalization status X X X Adverse events X X X

Clinical deterioration 22 23 24 25 26 27 28 29 thirty D477 D533 D533 D645 D701 D757 D813 D869 D925 /ET /EOS 1168 H76 H76 H92 H100 H108 H116 H124 H132 ± 2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

- 40 046524

MG-QOL15r X X X X X X X X X X X Nervous fatigue QOL X X X X X X X X X X X X X X EQ-5D-5L X X X X X X X X X X X X X X MG-ADL ^6- ' X X X X X X X X X X X X X X QMG ⁶ > ⁸ X X X X X X X X X X X X X X X X X MGC ⁶ > ⁸ X X X X X X X X X X X X X X X X X MGFA-PIS ⁶ X X X X X X X X C-SSRS since the latest version visit X X X X X X X X ECG X Ab to AChR X X X X X X X X Clinical laboratory tests X X X X X X Pregnancy test X X X X X X X X X X X X X RK, free C5 R T/R T/R T/R G/R T/R T/R T/R T/R T/R T/R T/R T/R T/R X ADA ¹ X X X X X X X X X X X X X Patient Information Consent Card X X X X X X X Ravulizumab infusion X X X X X X X X X X X X X

¹ Assessment of clinical deterioration is performed as quickly as possible within 48 hours of notifying the investigator of the onset of symptoms. Additional assessment visits are scheduled at the discretion of the investigator.

² The extended period begins with the start of dosing on day 183 (week 26).

³ If a patient leaves the study prematurely during the extension period, an early termination visit is performed.

⁴ Vital signs and pulse oximetry include systolic and diastolic blood pressure (millimeters of mercury [mmHg]), pulse oximetry (oxygen saturation [SO ₂ ]), heart rate (beats/minute), and temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). On dosing days, vital signs are measured before study drug administration and after the patient has rested for at least 5 minutes.

⁵ If necessary, performed based on the patient’s health status and the clinical judgment of the investigator.

⁶ See, for example, table. 3.

⁷ The MG-ADL assessment is performed by an appropriately trained clinical assessor, preferably the same assessor, throughout the study. The recall period for MG-ADL is the previous 7 days or since the last visit if the interval between visits is less than 7 days.

⁸ If the patient is taking a cholinesterase inhibitor, the dose is discontinued at least 10 hours before assessment.

⁹ Clinical laboratory tests are carried out in a central laboratory.

¹⁰ Pregnancy tests are carried out on all patients of childbearing age within the specified time frame. For screening, serum pregnancy tests are performed at day 925/ET/EOS; Urine pregnancy tests are performed at all other required time points. A negative urine test result is required before administering ravulizumab to patients of childbearing potential at these visits. Additional pregnancy tests (urine or serum) may also be performed at any visit at the discretion of the investigator.

¹¹ Blood samples for serum PK at residual concentration (T) of free C5 (PD) and ADA are collected predose (within 30 minutes before the start of the study drug infusion). Blood samples at peak concentration (P) for serum PK/PD are collected within 30 minutes after completion of the study drug infusion. T-samples are collected through a venous access set up for dose infusion prior to dosing. P-samples are taken from the patient's contralateral arm without infusion. At day 183 (week 26), the T-sample is considered the randomized controlled period evaluation and the P-sample is considered the extension period evaluation. All collection dates are recorded in the eCRF. In the event of clinical deterioration, a blood sample is obtained for serum PK/PD analysis and ADA if additional dosing is described in this invention.

¹² Patients are provided with a Patient Safety Information Sheet before the first dose of study drug is administered. At each study visit, staff will ensure that the patient has a Patient Safety Information Card.

- 41 046524

6. Standard protocol definitions.

Table 12

Abbreviations and definitions for the study and follow-up period

Abbreviation or special term Explanation AB Antibody AChR Acetylcholine receptor AE Adverse event aHUS Atypical hemolytic-uremic syndrome ANCOVA Analysis of Covariance AZA Azathioprine VR Blood pressure C5 Complement protein 5 SMAH Maximum concentration CMIN Minimum concentration eCRF Electronic individual registration card C-SSRS Scale for assessing the severity of suicidal tendencies Columbia University ECG Electrocardiogram EDC Electronic data recording system ESH In utero exposure EOI Phenomenon of interest EOS End of study EQ-5D EuroQoL ET Early termination EU European Union F.A.S. Full sample for analysis FVC Forced vital capacity GCP Good Clinical Practice gMG Generalized myasthenia gravis ANAS Human antibody to human antibody HCG Human chorionic gonadotropin HR Heart rate I.B. Explorer Brochure ICF Informed consent form ICH International Conference on Harmonization

- 42 046524

ICU Intensive Care Unit IEC Independent Ethics Committee IVIg Intravenous immunoglobulin G IP Investigational drug IRB Institutional Review Board 1ST Immunosuppressive therapy b/b Intravenous IVIg Intravenous immunoglobulin IXRS Interactive voice or web communication system mAb Monoclonal antibody MedDRA Medical dictionary of terminology for regulatory activities MG Myasthenia gravis MG-ADL Activity profile during activities of daily living in MG M.G.C. Myasthenia Gravis Combined Rating Scale MGFA Myasthenia Gravis Foundation of America MM Minimum manifestation MMF Mycophenolate mofetil MMT Manual muscle test MTX Methotrexate MuSK Muscle-specific receptor tyrosine kinase NIF Negative inspiratory force NMJ Neuromuscular junction oMG Ocular myasthenia gravis P.D. Pharmacodynamics P.E. Plasmapheresis or plasma exchange P.I. Chief Investigator PIS Status after intervention P.K. Pharmacokinetics PNH Paroxysmal nocturnal hemoglobinuria PP Population according to protocol QOL The quality of life QMG Myasthenia gravis quantification scale R.R. Breathing rate RSI Security Reference SAE Serious adverse event SAP Statistical analysis plan SFEMG Single-fiber electromyography SOC Class of organ systems TEAE Adverse events during treatment TESAE SAE during treatment USA USA VAS Visual analogue scale WHODrug World Health Organization Drug Dictionary

- 43 046524

Clinical deterioration.

In this protocol, clinical deterioration is defined as follows.

1. Patients who experience MG crisis, weakness resulting from MG, which is defined as weakness resulting from MG that is severe enough to require intubation or delay extubation after surgery. Respiratory failure due to weakness of the respiratory muscles. Severe bulbar (oropharyngeal) muscle weakness often accompanies respiratory muscle weakness or is the predominant feature in some patients; or

2. Significant worsening of symptoms to a score of 3 or 2 from baseline on any of the individual MG Activities of Daily Living (MG-ADL) items other than double vision or drooping eyelids; or

3. Prescribing reserve therapy to a patient, in the opinion of the investigator or the physician appointed by him, whose health would be at risk if reserve therapy were not carried out (for example, in emergency situations).

Unplanned visits.

In exceptional cases, additional (unscheduled) visits beyond the scope of these visits are permitted, at the discretion of the researcher. Procedures, tests and assessments are performed at the discretion of the investigator and efforts are made to correlate relevant data with the appropriate visit.

An appropriately trained clinical assessor.

Appropriately trained clinical assessors are research personnel certified to perform MG-ADL, QMG, and MGC assessments. Only properly trained clinical assessors perform these assessments. The appropriately trained clinical evaluator is a neurologist, physical therapist, or other member of the research team designated by the investigator. Only the investigator or neurologist performs the manual muscle test (MMT), MGC assessment components, MGFA-PIS, and Myasthenia Gravis Foundation of America (MGFA) classification. Training and certification of clinical assessors for this protocol is provided either at an investigator meeting or through a sponsor-designated online training portal.

Responsibilities when evaluating myasthenia gravis.

Responsibilities for MG assessment are listed in Table. 13. Throughout the study, MG assessments are completed at approximately the same time of day by an appropriately trained clinical assessor and preferably by the same assessor.

Table 13

MG Grades and Responsibilities

Grade Appraiser MG-ADL A properly trained clinical assessor QMG A properly trained clinical assessor M.G.C. A properly trained clinical assessor MGC (MMT components) Researcher or neurologist MGFA-PIS Researcher or neurologist MGFA classification Researcher or neurologist

Abbreviations.

MG-ADL=Myasthenia Gravis Activities of Daily Living Scale profile;

MGC=myasthenia gravis composite score;

MGFA=Myasthenia Gravis Foundation of America;

MGFA-PIS=Myasthenia Foundation of America Post-Intervention Status;

MMT=manual muscle test;

QMG = scale for quantitative assessment of disease severity in myasthenia gravis.

Scientific rationale for the study design.

Published data support the profile of the MG-ADL score as a well-established, sensitive and objective assessment of treatment response over time in patients with gMG (Howard, J. et al., Muscle Nerve, 56:328–30, 2016).

The safety indicators assessed are routinely used in clinical trials in accordance with International Council for Harmonization (ICH) and Good Clinical Practice (GCP) guidelines.

Placebo is selected as a control and patients are allowed to continue stable therapy using the standard of care (eg, IST) throughout the study, thereby allowing comparison of the safety and effectiveness of ravulizumab when administered in addition to treatment

- 44,046,524 patients, standard of care in accordance with current standards of care for gMG patients.

Given the heterogeneity of the disease and variations in symptom severity, there is no single accepted international standard of care, and targeted treatment 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. A placebo-controlled study evaluates the treatment effect and uses a double-blind design; this is an important research condition that must be maintained when considering endpoints, including neurological scales, which are known to be particularly susceptible to placebo effects. The placebo-controlled portion of the study is limited to 26 weeks, after which all patients are switched to open-label ravulizumab for up to 2 years during the OLE period. At all points in the study, clinicians are encouraged to prioritize patient safety, and if patients experience clinical deterioration, a full range of back-up therapies is permitted.

Rationale for dose.

Ravulizumab is currently being studied in phase 3 clinical trials in patients with PNH and aHUS, with PK/PD data being carefully collected from all studies. Ravulizumab dosing regimens for these indications are selected based on comprehensive modeling and simulation analysis of phase 1 and 2 PK/PD data in healthy volunteers and PK/PD efficacy (lactate dehydrogenase) and safety data in patients with PNH, and are considered optimal to achieve immediate, complete , sustained inhibition of terminal complement complex activity at each dosing interval and throughout the course of treatment in all patients. A weight-based phase 3 dosing regimen (Table 14) was tested in gMG patients in the current study.

Table 14

Dosing of ravulizumab based on body weight

Weight (kg) Loading dose (mg) Maintenance dose (mg) (administered 1 day/8 weeks) from > 40 to < 60 2400 3000 from >60 to <100 2700 3300 > 100 3000 3600

Reduction.

r./8 weeks=1 time every 8 weeks.

According to the approved labeling of eculizumab for the treatment of adult and pediatric patients with aHUS and adult patients with gMG, an additional 50% dose of ravulizumab (rounded if not a whole amount of 300 mg, depending on vial configuration) is administered in the setting of RR backup therapy. /RE. Adult patients with gMG were given an additional dose of ravulizumab (600 mg) with concomitant backup therapy in the form of IVIg. An additional dose of ravulizumab 600 mg per week was selected based on PK simulations, taking into account published data describing the effect of co-administration of IVIg on the PK/PD of eculizumab (Tables 1, 2; Fitzpatrick, A. et al., J. Peripher. Nerv. Syst. , 16:84-91, 2011).

An additional dose of study drug (or placebo) was required if PE/PP or IVIg backup therapy was administered on non-dose days; An additional dose of study drug (or placebo) was not required if PE/PP or IVIg infusion was administered on the day of dosing but occurred before study drug administration. If PE/PP was performed or IVIg was administered during scheduled dosing visits, regular dosing was maintained 60 m after completion of PE/PP or IVIg administration. If PE/PP is performed or IVIg is administered during unscheduled visits, for patients receiving PE/PP: an additional dose is administered 4 hours after completion of the PE/PP session; For patients receiving IVIg: an additional dose is administered 4 hours after completion of the last continuous IVIg administration session(s) as described in this invention.

The favorable benefit/risk profiles of ravulizumab from recently completed phase 3 studies in patients with PNH support immediate (after the first dose or loading dose), complete (free C5 <0.5 μg/mL) and sustained (throughout active treatment) inhibition terminal complement complex within the dosing regimen studied above.

After a 26-week randomized controlled period and assessments at day 183 (week 26), patients in the placebo group received a masked loading dose of ravulizumab, and patients in the ravulizumab group received a masked dose of ravulizumab 900 mg; the 900 mg dose was chosen to provide complete C5 inhibition until the next scheduled maintenance dose at week 28 (day 197). Beginning at week 28 (day 197), all patients began taking open-label maintenance doses of ravulizumab once a day/8 weeks.

The proposed dosage regimen of 1 r./8 weeks facilitates the study of a number of RK effects of drugs

- 45 046524 means suitable for 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, including those expected under the proposed dosing regimens for gMG, in healthy volunteers and patients.

Determination of the end of the study.

A patient is considered to have completed the study if the patient has completed all study periods, including the last OLE visit of the period; or if the study is completed early, the patient has completed all applicable study periods, including the EOS visit;

the patient completed the study early (and completed the EOS visit) because the study drug was registered or approved (in accordance with national regulations).

Measurement of the primary endpoints is completed after the last visit of the last patient in the randomized controlled period. EOS is defined as the date of the last visit of the last patient in the study or the last scheduled procedure shown in the activity schedule (see Tables 10 and 11) for the last patient in the study worldwide. The study end date corresponds to the last visit at which the last patient in the study was examined or provided with a procedure for the primary or secondary endpoints and AEs.

7. Study group of patients.

Deemed protocol approval of deviations from study recruitment and inclusion criteria, also known as protocol waivers, will not be permitted.

Inclusion criteria.

Patients can only be included in the study if all of the following criteria are met.

Age.

1. Male and female patients aged >18 years at the time of signing the informed consent.

Patient type and disease characteristics.

2. The diagnosis of MG was made at least 6 months (180 days) before the date of the screening visit, as confirmed by the protocol criteria (see below).

3. Diagnosis of MG is performed using the following tests:

a) positive serological test for antibodies to AChR, confirmed by screening; And

b) one of the following:

history of abnormal neuromuscular transmission test demonstrated by single fiber electromyography or repetitive nerve stimulation;

history of a positive anticholinesterase test (eg, edrophonium chloride test);

As assessed by the treating physician, MG symptoms have been demonstrated to improve with oral cholinesterase inhibitors.

4. Clinical classification of myasthenia gravis according to the Myasthenia Foundation of America, corresponding to class II-IV, during screening.

5. MG-ADL scale profile >6 at screening and randomization (day 1).

6. Patients receiving treatment with one of the following components are treated and receive a stable dose for the periods of time indicated below until the date of the screening visit:

azathioprine (AZA): taking AZA for >6 months (180 days) and on a stable dose for >2 months (60 days);

immunosuppressive medications (eg, mycophenolate mofetil [MMF], methotrexate [MTX], cyclosporine [CYC], tacrolimus [TAC], or cyclophosphamide [CY]) are on IST for >3 months (90 days) and are on a stable dose at for >1 month (30 days);

oral corticosteroids, given at a stable dose for >4 weeks (28 days);

cholinesterase inhibitor at the screening visit, take a stable dose for >2 weeks (14 days).

7. To reduce the risk of meningococcal disease (N. meningitidis), all patients are vaccinated against meningococcal diseases 3 years before or at the time of starting study drug. Patients who initiated study drug treatment less than 2 weeks after meningococcal vaccine administration were treated with appropriate prophylactic antibiotics for 2 weeks after vaccination.

Body mass.

8. Body weight >40 kg at the time of screening.

Pregnancy and contraception.

9. Patients of childbearing potential and patients with potential partners of childbearing potential use contraception to prevent pregnancy during treatment and for 8 months after the last dose of study drug.

- 46 046524

Informed consent.

10. Opportunity to give signed informed consent.

As part of the informed consent, the researcher or his/her representative explains the nature of the study to the patient or his/her legal representative and answers all questions regarding the study;

patients are informed that their participation is voluntary; patients or their legal representatives must sign an informed consent statement that complies with 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act requirements, where applicable, and the IRB/IEC or study site;

the medical record includes a statement that written informed consent was obtained prior to patient enrollment in the study and the date written consent was obtained; the authorized person who received the informed consent also signs the ICF;

patients re-consent according to the most current version of Informed Consent Forms (ICF) at the time of their participation in the study; a copy of the ICF is provided to the patient;

the researcher retains the original version of the signed ICF(s); a copy of the signed ICF(s) is provided to the patient;

a rescreened patient is not required to sign a different ICF if an updated ICF is not available.

Exclusion criteria.

Patients are excluded from the study if any of the following criteria apply.

Medical conditions.

1. Any active or untreated thymoma. History of thymic carcinoma or thymic malignancy unless considered cured by adequate treatment without evidence of recurrence >5 years prior to screening.

2. History of thymectomy 12 months before examination.

3. History of hypersensitivity to any ingredient contained in the study medicinal product, including hypersensitivity to murine proteins.

4. History of N. meningitidis infection.

5. Human immunodeficiency virus (HIV) infection (as evidenced by antibody titers to HIV-1 or HIV-2).

6. Known medical or psychological condition(s) or risk factor that, in the opinion of the investigator, prevented the patient from full participation in the study, poses any additional risk to the patient, or impairs the patient's assessment or study outcome.

7. History of hospitalization for >24 hours for any reason in the 4 weeks (28 days) before screening;

8. Clinical signs that, in the opinion of the investigator, are consistent with MG crisis/exacerbation or clinical deterioration at the screening visit or at any time before randomization.

9. Patients planning pregnancy, pregnant or breastfeeding.

10. Patients with a positive pregnancy test result at screening or on day 1. Pre-/concomitant therapy.

11. Application of the following for the period of time specified below:

IVIg 4 weeks (28 days) before randomization (day 1);

use of PE 4 weeks (28 days) before randomization (day 1);

use of rituximab 6 months (180 days) before screening.

12. Patients who have previously received treatment with complement inhibitors (for example, eculizumab).

Previous/related clinical research experience.

13. Participation in another interventional treatment study or use of any investigational therapy within 30 days prior to the start of the study drug on Day 1 in that study or during the period corresponding to 5 half-lives of the study drug, whichever there are more values.

Persons who have not passed the screening.

Unscreened individuals are defined as patients who agreed to participate in a clinical trial but were subsequently not randomized to treatment. A minimum set of information on unscreened individuals is required to ensure transparent reporting of unscreened patients, consistent with the publication requirements of the Consolidated Trial Reporting Standards, and to respond to regulatory requests. Minimum information includes demographics, details of those not screened, eligibility criteria, and any serious adverse events (SAEs).

Individuals who do not meet the criteria for participation in this study (individual not screened) may be re-screened once based on discussion and agreement between the investigator and the medical monitor.

- 47 046524

A patient who experiences clinical deterioration or exacerbation/crisis of gMG during the screening period will be considered to have failed the screening. According to the investigator, such patients may be rescreened with sponsor approval once they have received treatment and are medically stable. Clinical stability must have existed for at least 28 days before inclusion in the study. A patient must meet all inclusion criteria and none of the exclusion criteria at the time of rescreening to be included in the study.

8. Investigational drug.

Investigational medicinal products used.

Ravulizumab is formulated at pH 7.0 and supplied in single-use 30 ml vials. Each vial of ravulizumab contains 300 mg ravulizumab (10 mg/mL) in 10 mM sodium phosphate, 150 mM sodium chloride, 0.02% polysorbate 80 and water for injection. The reference drug is a suitable sterile, clear, colorless solution with the same buffer components but without the active ingredient. Additional information is presented in table. 15.

Table 15

Study drug administered

Drug name Ravulizumab Placebo Dosage form Concentrated sterile aqueous solution without preservatives (10 mg/ml) in disposable bottles of 30 ml. Sterile aqueous solution without preservatives in single-use bottles of 30 ml. Route of administration Intravenous infusion Intravenous infusion Instructions for dose administration Refer to pharmacy manual for dosing instructions. Refer to pharmacy manual for dosing instructions. Packaging and labeling Glass bottles are sealed with a butyl rubber stopper. aluminum lid and hinged cap. The investigational drug will be supplied in kits. Glass vials are sealed with a butyl rubber stopper with an aluminum cap and hinged cap. The investigational drug will be supplied in kits. Physical Description The liquid solution is practically The liquid solution is practically contains particles. contains particles. Manufacturer Alexion Pharmaceuticals, Inc. Or contract manufacturing organization Alexion Pharmaceuticals, Inc. or contract manufacturing organization

Source: description of the drug.

The study drug is administered as indicated in Table. 16.

During the randomized controlled period, patients in the ravulizumab or placebo treatment groups received a weight-based loading dose of ravulizumab or placebo, respectively, on day 1 (visit 2). At Visit 4 (Week 2), patients in the ravulizumab or placebo treatment groups received weight-based maintenance doses of ravulizumab or placebo, respectively, every 8 weeks until the end of the randomized controlled period (see Table 16). After completion of the randomized controlled period, patients enter the OLE period.

After a 26-week randomized controlled period and assessments at day 183 (week 26), patients in the placebo group received a masked loading dose of ravulizumab, and patients in the ravulizumab group received a masked dose of ravulizumab 900 mg; the 900 mg dose was chosen to provide complete C5 inhibition until the next scheduled maintenance dose at week 28 (day 197). Beginning at week 28, all patients began taking open-label maintenance doses of ravulizumab once a day/8 weeks.

- 48 046524

Table 16

Reference table for dosing based on body weight

Study period Ravulizumab or Placebo Dose administration Gel weight (kg) ¹ Ravulizumab Dose (mg) Volume of ravulizumab (ml) Placebo Volume (ml) Diluent (0.9% sodium chloride solution) Volume (ml) Total Volume (ml) Ravulizumab group Randomized controlled Loading dose (1st day) from > 40 to < 60 2400 240 0 240 480 from > 60 to < 100 2700 270 0 270 540 > 100 3000 300 0 300 600 Maintenance dose (15th, 71st, 127th days) from >40 to <60 3000 300 0 300 600 from >60 to <100 3300 330 0 330 660 > 100 3600 360 0 360 720 Open extended Masked dose ² (day 183) from >40 to <60 900 90 150 240 480 from >60 to <100 900 90 180 270 540 > 100 900 90 210 300 600 Open extended, maintenance dose (from the 197th day to the 869th day, 1 r./8 weeks) from >40 to <60 3000 300 0 300 600 from >60 to <100 3300 330 0 330 660 > 100 3600 360 0 360 720 Placebo group Randomized controlled Loading dose (1st day) from >40 to <60 0 0 240 240 480 from >60 to <100 0 0 270 270 540 > 100 0 0 300 300 600 Maintenance dose (15th, 71st, 127th days) from >40 to <60 0 0 300 300 600 from >60 to <100 0 0 330 330 660 > 100 0 0 360 360 720 Open extended Masked loading dose’ (day 183) from > 40 to < 60 2400 240 0 240 480 from >60 to <100 2700 270 0 270 540 > 100 3000 300 0 300 600 Open extended, maintenance dose (from the 197th day to the 869th day, 1 r./8 weeks) from > 40 to < 60 3000 300 0 300 600 from >60 to <100 3300 330 0 330 660 > 100 3600 360 0 360 720

The dosage regimen is based on the patient's last recorded body weight at the previous study/screening visit.

Masked dose on day 183 (week 26) for patients who were randomized to ravulizumab and entering the open-label extension period.

Preparation/handling/storage/reporting.

The investigational drug is provided to the study site after receipt of all necessary basic documents in accordance with federal, state and local laws.

Only patients enrolled in the study receive the investigational drug, and only authorized site personnel provide or administer the investigational drug. All investigational medicinal products are stored in a secure, environmentally controlled and monitored (manually or automatically) area in accordance with designated storage conditions, with access limited to the investigator and authorized study site personnel.

Preparation of the study drug.

The study drug is prepared and administered by a trained member of the study team. The study drug is administered only to enrolled patients who are found to be eligible for participation.

Doses of ravulizumab and placebo are prepared according to local study site standards by qualified and trained pharmaceutical personnel.

Handling and preparation of materials used for the preparation and administration of the investigational medicinal product is carried out using aseptic techniques for sterile preparations. All study patients, study site personnel, sponsor personnel, sponsor designees, and all personnel directly involved in the conduct of the study are blinded to patient treatment assignment.

More detailed information about the preparation and dosing of the study medicinal product, as well as the disposition of the study medicinal product, is contained in the Pharmacy Guide.

Storage.

The Investigator or designee confirms that during transport, all genders

- 49 046524 tested investigational medicinal products are maintained at appropriate temperature conditions and that any discrepancies are reported and corrected before use of the investigational medicinal product.

Upon arrival at the study site, the study drug is immediately removed from the shipping refrigerator and stored refrigerated at 2 to 8°C (36 to 46°F). The pharmacist immediately records receipt of the investigational drug and notifies the distributor if the vials are damaged and/or temperature changes occur during transport. The study drug is stored in a secure, restricted access facility and the temperature is monitored daily.

Store diluted test drug solutions at 2 to 8°C (36 to 46°F) for 24 hours before administration. Before administration, the solution is allowed to warm to room temperature.

The mixed drug is kept at room temperature before administration. The material is not heated (for example, by a microwave oven or other heat source) by sources other than ambient air temperature.

Packaging and labeling.

The primary packaging of ravulizumab consists of a 30 ml vial (type I borosilicate glass) with stopper and seal. Secondary packaging is a cardboard box with one bottle. Both primary (bottle) and secondary (carton) packaging include a booklet label with relevant information. Additional information is presented in table. 13 and in the pharmacy manual. Placebo has an appearance identical to that of ravulizumab.

Reporting.

When a drug shipment arrives at the study site, the pharmacist inspects the contents, signs the packaging invoice included with the shipment, and stores the original for review by the study site monitor in the pharmacy folder. In addition, receipt of the investigational drug (as well as the status of the investigational drug at the time of receipt) is reported to the IRT system to allow for randomization, replenishment, assessment, and monitoring of drug shelf life.

Unless otherwise noted, empty vials and vials with residual materials are retained for review and reporting by the study site monitor until they are destroyed or processed in accordance with local pharmacy standard operating procedures for clinical trial medicinal products. Disposal of used and unused vials, both locally and centrally, is properly documented. Drug reporting is managed through the IRT system, and detailed instructions for managing the IRT drug reporting module are included in the IRT User Guide. The IRT module performs reporting in two stages, where study site personnel complete an initial reporting record in the system, after which the study site monitor verifies that the study site has correctly entered the appropriate status for all study drugs. The pharmacist or designee maintains accurate records showing the dates and quantities of investigational medicinal product received, to whom it was dispensed (personal records), and accounts of any investigational medicinal product accidentally or intentionally destroyed. These drug liability records are available upon request and are reviewed throughout the study.

Each kit has a label and space for the pharmacist to write down the patient's number and initials.

A monitor at the research center reviews the inventory during the study. In addition, inventory records are always available to regulators, local regulators or independent auditors.

See your pharmacy guide for more information.

Handling and disposal.

All clinical trial material provided to the investigator is stored in a secure location and is housed and distributed by appropriately trained personnel. Detailed records of the quantities of study medicinal product received, distributed and destroyed are maintained.

To satisfy regulatory requirements for drug reporting, all remaining ravulizumab inventory is reconciled and destroyed or returned to Alexion at the end of the study in accordance with applicable regulations.

See your pharmacy guide for more information.

Randomization.

Patients are randomized on day 1 after the investigator confirms that they meet the selection criteria. Patients are stratified by region (North America, Europe, Asia-Pacific, and Japan) and randomized 1:1 to either IV ravulizumab infusion or IV placebo infusion. Patients are randomized centrally using IRT.

- 50 046524

Disguise.

All study site personnel, sponsor staff, sponsor-designated employees, study personnel directly involved in the conduct of the study, and all patients are blinded to the patient's treatment assignment. Double-blindness is maintained by using identical study drug sets and labels for ravulizumab and placebo. Placebo has an appearance identical to that of ravulizumab. Random code is supported by the IRT vendor. After a 26-week randomized controlled period and assessments at day 183 (week 26), patients in the placebo group received a masked loading dose of ravulizumab, and patients in the ravulizumab group received a masked loading dose of ravulizumab at 900 mg. Beginning at week 28, all patients began taking open-label maintenance doses of ravulizumab once a day/8 weeks. For patients in the ravulizumab group, a masked dose of ravulizumab was selected at 900 mg to ensure complete C5 inhibition until the next scheduled maintenance dose at week 28 (day 197).

Consideration of unmasking should only be considered for patient safety reasons. If deemed necessary, the investigator will make a reasonable attempt to contact the sponsor to discuss the possibility of unmasking. After a reasonable attempt has been made, the investigator unmasks the patient's treatment assignment using IRT. The researcher notes the date, time and reason for unmasking. The investigator also informs the medical monitor that the patient is unmasked; however, it does not disclose patient treatment allocation to the medical monitor.

When an adverse event (AE) is unexpected or related and serious, the mask is opened only for that specific patient. Masking is maintained for those responsible for the ongoing conduct of the study (such as management, monitors, investigators, etc.), as well as for those responsible for analyzing the data and interpreting the results at the conclusion of the study, such as biometrics personnel. Public information is available only to those required to participate in safety reporting to health authorities, independent ethics committees (IECs), and/or institutional review boards (IRBs).

Any patient who was not masked during the study is excluded from the study.

Researchers receive only masked information unless obtaining unmasked information is deemed necessary for security reasons.

Concomitant therapy.

Previous medications (including vitamins and herbal medications), including those discussed in the exclusion criteria and procedures (any therapeutic intervention such as surgery/biopsy or physical therapy), the patient is taking or undergoing within 28 days of screening before the first doses of the study drug are recorded. In addition, a meningococcal vaccination history is collected 3 years before the first dose of study drug.

All medications and procedures undertaken during the study are recorded. These include all prescription drugs, herbal products, vitamins, minerals, over-the-counter drugs and any other current medications. Concomitant medications are recorded from the first infusion of study drug until 8 weeks after the patient's last dose of study drug. Any changes in the use of concomitant medications are also recorded. Any concomitant medications considered necessary for routine patient care during the study or for the treatment of any AE, along with any other medications other than those listed as prohibited medications as defined herein, are at the discretion of the investigator. . However, the investigator is responsible for recording detailed information about all medicinal products.

Compliance with study drugs.

The investigational medicinal product is administered under controlled conditions under the supervision of the investigator or designee to ensure compliance with the study medicinal product.

Palliative and supportive care.

Palliative and supportive care was allowed during the study for underlying conditions.

Approved medicines.

The drugs described in the following sections are permitted under certain circumstances and restrictions.

Cholinesterase inhibitors.

For study patients receiving a cholinesterase inhibitor at screening, the dose and regimen of the cholinesterase inhibitor remain stable throughout the randomized controlled period and the OLE period unless there is an urgent medical need. Increased cholinesterase therapy, which is required in

- 51 046524 as a result of a concomitant illness or other medical cause of deterioration, is permitted, but dosing is returned to study entry dose levels as soon as possible and the sponsor is notified of the change.

1. Treatment with a cholinesterase inhibitor is discontinued at least 10 hours before the QMG and MGC tests are performed.

2. If reduction in cholinesterase inhibitor levels is considered based on clinical assessment, sponsor approval is obtained prior to dose changes for the patient to continue the study.

Immunosuppressants.

The following immunosuppressive drugs were allowed during the study: corticosteroid, AZA, MMF, MTX, TAC, CYC, or CY. The immunosuppressant(s) and appropriate dose level to be used for an individual patient is at the discretion of the treating physician/investigator.

1. Corticosteroid. For study patients taking oral corticosteroids, such as prednisone, the dose/schedule remains unchanged throughout the double-blind study period (ie, the randomized control period). If steroid dose reduction or tapering is considered during the randomized controlled period based on clinical judgment, the patient will be given sponsor approval before changes are made to the study. If the dose level is subsequently increased, the increase in dose level does not exceed the dose level specified at baseline (at the start of randomized treatment).

2. High dose steroids are intended for patients who are experiencing clinical deterioration as defined in this invention. Every effort is made to notify the sponsor within 24 hours of administration if the patient requires backup therapy due to clinical deterioration.

3. AZA, MMF, MTX, TAC, CYC or CY. For patients who participate in a study taking the above-mentioned immunosuppressive drugs, the dosing regimen of the immunosuppressive drug remains unchanged throughout the randomized controlled period. If a dose change is considered due to known toxicity or side effects associated with a given immunosuppressant, the patient will be given sponsor approval to continue in the study before the dose change. No other immunosuppressive agent was added or changed during the 26-week randomized controlled period.

Plasma exchange/plasmapheresis/intravenous immunoglobulin.

The use of PE/PP or IVIg is approved for patients who are experiencing clinical deterioration as defined in this invention. Reserve therapy used for a particular patient is at the discretion of the investigator. Every effort is made to notify the sponsor within 24 hours if the patient requires backup therapy.

An additional dose of study drug (or placebo) is required if PE/PP back-up therapy or IVIg is administered on non-drug days; If PE/PP or IVIg infusion is administered on the day of dosing, this should occur before administration of the study drug.

1. If PE/PP is administered or IVIg is administered during unscheduled dosing visits.

a) Patients receiving PE/PP: an additional dose is administered 4 hours after completion of the PE/PP session.

b) Patients receiving IVIg administration: an additional dose is administered 4 hours after completion of the last continuous IVIg administration session(s).

c) The amount of additional dose may or may not vary depending on PE/PP or IVIg (Tables 1 and 2).

2. If PE/PP is administered or IVIg is administered during scheduled dosing visits.

Regular dosing was observed 60 minutes after completion of PE/PP or IVIg administration.

3. An interval between the additional dose and the regularly scheduled dose is not required.

Prohibited drugs.

The following concomitant medications are prohibited during the study: rituximab;

eculizumab (or other complement inhibitors)

A patient's use of rituximab or eculizumab (or other complement inhibitors) at any stage of the study will result in the patient being excluded from the study.

Reserve therapy.

Backup therapy (eg, high-dose corticosteroids, PP/PE, or IVIg) is permitted when the patient's health is at risk, if backup therapy will not be administered (eg, in emergency situations), or if the patient experiences clinical deterioration as defined in this invention . Reserve therapy used for a particular patient is at the discretion of the investigator. The date and time of taking the backup therapy drug are recorded, and

- 52 046524 also the name and mode of administration of the reserve therapy drug dose.

If the patient requires backup therapy, every effort is made to notify the sponsor within 24 hours.

Activities after the end of the study.

Upon completion of participation in the study, patients return to their physician.

9. Discontinuation of participation in the study and completion of the study of patients/exclusion of the patient. Stopping participation in the study.

The patient may withdraw from the study at any time at his/her own request or may be withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or administrative reasons. If a patient discontinues study treatment, the investigator attempts to complete (if the patient consents) the assessments specified for the ET visit or, if this is not possible, contacts by telephone 8 weeks after the last dose of study drug (Tables 10 and 11). Attempts were also made to monitor all patients for safety for a total of 8 weeks from the date of the last dose of study drug. The sponsor and site monitor are notified as quickly as possible. If a patient withdraws from the study or withdraws consent, no further data will be collected. Patients who dropped out of the study cannot be replaced.

Patients stop taking the study drug if any of the following events occur during the study:

1) a serious hypersensitivity reaction (for example, bronchospasm with wheezing or the need for mechanical ventilation support, symptomatic hypotension or serum sickness-like reactions occurring 1-14 days after administration of the study drug;

2) severe uncontrolled infection;

3) pregnancy or planned pregnancy; or

4) the sponsor believes that this is in the best interests of the patient;

5) use of rituximab, eculizumab (or other complement inhibitors). The investigator contacts the medical monitor before the patient stops taking the study drug. If the patient discontinues treatment, the patient is advised to return for an ET visit (Tables 10 and 11) 8 weeks after the last dose of study drug.

The reason for discontinuation of treatment (eg, patient withdrawal of consent, patient refusal of procedures, physician decision, AE, or other reason specified in the eCRF) is recorded.

If a patient permanently discontinues study drug due to pregnancy, the investigator will make a reasonable attempt at follow-up in accordance with local laws and regulations until the outcome of the pregnancy is known.

If the patient revokes consent for future disclosures, the sponsor will retain and continue to use all data collected prior to such withdrawal of consent.

If a patient refuses to participate in the study, the patient may request the destruction of any samples taken and not tested, and the investigator will record this in the study site's records and inform the supervisor and sponsor.

Patients lost to follow-up.

A patient is considered lost to follow-up if the patient repeatedly fails to return for scheduled visits and is unable to contact the study site.

If the patient is unable to return to the clinic for a required study visit, the following actions should be taken.

1. The study site attempts to contact the patient and reschedule the missed appointment as quickly as possible, counsels the patient on the importance of maintaining scheduled appointments, and determines whether the patient wishes and/or should continue to participate in the study.

2. Before a patient is considered lost to follow-up, the investigator or designee will make every effort to re-establish contact with the patient (if possible, 3 telephone calls and, if necessary, certified mail to the patient's last known mailing address or local equivalent communication methods). These contact attempts are recorded in the patient's medical record.

3. If the patient remains unavailable, the patient is deemed to have withdrawn consent and future missed appointments are not considered protocol deviations.

10. Assessments and research procedures.

Performance assessments.

G hospitalization.

Information related to hospitalization for any reason is collected after the patient signs the ICF during the OLE period. Hospitalizations are defined as all medical admissions

- 53 046524 institution, regardless of the underlying relationship to MG. Dates of admission/discharge, reasons for admission, attitude towards MG and other relevant information are collected.

Hospitalization includes the following:

1) emergency department visits for MG with or without hospitalization, regardless of duration;

2) unplanned hospitalization to a medical facility, regardless of attitude towards MG;

3) inpatient infusion/treatment for MG in a hospital setting (eg, IVIg, PP, PE, ventilator).

Hospitalization does not include the following:

1) routine administration of the study drug;

2) rehabilitation institution;

3) hospice;

4) nursing home/nursing home/long term care facility;

5) outpatient clinics;

6) planned hospitalization for treatment of a pre-existing condition (ie, a condition that began before informed consent was obtained);

7) planned/unplanned outpatient surgery (eg, used as surgical equipment);

8) non-MG emergency department visit without hospitalization;

9) outpatient infusion/inpatient treatment (eg, IVIg, PP).

Clinical deterioration.

Information related to clinical deterioration, as defined in this invention, is collected from the time the patient signs the ICF during the OLE period. A visit to assess clinical deterioration occurs as quickly as possible within 48 hours of notifying the investigator of the onset of symptoms. Additional unscheduled visits, as defined herein, are scheduled at the discretion of the investigator. During this visit, the following tests and procedures are performed:

1) measurement of vital signs and pulse oximetry, including assessment of systolic and blood pressure (BP), temperature (°C or °F), oxygen saturation (SO2) and heart rate (HR);

2) a record of any new medications or changes in concomitant medications, including all MG treatments;

3) assessment and recording of any new AEs or changes in AEs since the previous visit;

4) assessment of the MG-ADL scale by an appropriately trained rater, preferably the same rater, throughout the study. The recall period is the previous 7 days or since the last visit, whichever occurs first;

5) conducting clinical evaluations of QMG and MGC; they are performed at approximately the same time of day by a properly trained evaluator, preferably the same evaluator, throughout the study;

6) collection of a blood sample for AChR autoantibody testing;

collection of a blood sample for clinical laboratory testing (Table 17); tests presented in detail in table. 17, carried out by the central laboratory; protocol requirements for inclusion or exclusion of patients are described in detail in this invention; additional tests are carried out at any time during the study;

8) if medically indicated to assess clinical deterioration, additional tests are performed at the discretion of the investigator;

9) taking PK/PD samples at or during a visit due to clinical deterioration:

a) collect 1 blood sample for PK and free C5 tests if study drug is not administered;

b) if study drug is administered during a visit due to clinical deterioration, according to the protocol schedule, collect 2 blood samples, at trough and peak concentrations, [1] 5-90 minutes before study drug infusion and [2] within 30 minutes after completion of the study drug infusion;

c) if the patient is receiving PP/PE or IVIg during clinical deterioration, an additional dose of study drug is administered. Collect blood samples for PK analysis and free C5 analysis [1] 5-90 min before PP/PE or IVIg, [2] after PP/PE or IVIg and before study drug infusion, and [3] within 30 min after completion infusion of the study drug.

- 54 046524

Table 17

Laboratory safety assessments according to protocol

Laboratory assessments Indicators Clinical blood analysis Platelet content Contents RBC Hemoglobin Hematocrit RBC indicators: Leukocyte (WBC) formula: Distribution width Average erythrocyte volume Avg, amount of hemoglobin in erythrocyte % reticulocytes Neutrophils Lymphocytes Monocytes Eosinophils Basophils Biochemical blood analysis BUN C-reactive protein Creatinine Chlorine Potassium Bicarbonate of soda Glucose (not on an empty stomach) AST/SGOT ALT/SGPT Alkaline phosphatase, gamma-glutamyltransferase Total and direct bilirubin Total protein Albumen Uric acid Coagulation international normalization ratio, partial thromboplastin time, prothrombin time General urine analysis Appearance, color, specific gravity, pH, glucose, protein, creatinine, blood, ketones, bilirubin, urobilinogen, nitrite, microscopic examination (if blood or protein is abnormal) Other screening tests Serum/urine pregnancy test for beta-hCG (if necessary for patients of childbearing potential) Serum follicle-stimulating hormone test (if necessary for patients who consider themselves to be postmenopausal) Antibodies to HIV-1 and HIV-2 The results of each test must be entered into the eCRF. Activity complement Free C5

Abbreviations.

ALT=alanine aminotransferase;

AST=aspartate aminotransferase;

BUN=blood urea nitrogen;

C5=complement component 5;

eCRF=electronic individual registration card;

hCG=human chorionic gonadotropin;

HU-1=human immunodeficiency virus type 1;

HU-2=human immunodeficiency virus type 2;

RBC=red blood cells;

SGOT=serum glutamic acid oxalacetic transaminase;

SGPT=serum glutamic acid pyruvic transaminase;

WB C=white blood cells.

Safety assessments.

Physical examination.

Physical examination includes assessment of the following body organs/systems: skin, head, ears, eyes, nose, throat, neck, lymph nodes, pulse, chest, heart, abdomen, extremities; musculoskeletal and general neurological examination. The abbreviated physical examination consists of an examination related to the body system, based on the assessment of the examiner and the patient's symptoms. For consistency, every effort is made to ensure that medical examinations are performed by the same qualified research personnel.

Vital signs and pulse oximetry.

Vital signs and pulse oximetry are measured at each visit and include assessment of systolic and diastolic BP (mmHg), temperature (°C or °F), _SO2

- 55 046524 and HR (beats/minute). Vital signs are measured after the patient has been lying supine or sitting for at least 5 minutes. Ideally, each patient's HR is measured on one arm. Electrocardiogram

One 12-lead electrocardiogram (ECG) is obtained according to the intervention schedule (Tables 10 and 11) using an ECG machine that automatically calculates HR and measures PR, QRS, QT and QTc intervals. Patients lie supine for approximately 5-10 minutes before the ECG is taken and remain supine but awake during the ECG.

The investigator or designee is responsible for reviewing the ECG to assess whether the ECG is within normal limits and to determine the clinical significance of the findings.

Laboratory assessments of clinical safety.

Laboratory assessments are verified at a central laboratory. Any clinically significant abnormalities are monitored until resolution or stabilization.

All laboratory evaluations required by the protocol as defined in this invention are performed in accordance with the laboratory manual and activity schedule (Tables 10 and 11).

The investigator reviews the laboratory report, documents this review, and records any clinically significant changes that occur during the study. Laboratory reports are attached to the primary documents.

Clinically significant laboratory abnormalities associated with the underlying disease are not considered AEs unless the investigator considers them to be more severe than expected for the patient's condition.

If such values do not return to normal/baseline values within a period of time deemed reasonable by the investigator, the etiology is determined and the sponsor is notified.

General urine analysis and biochemical urine analysis.

Urine samples are analyzed according to the parameters given in table. 17. Microscopic examination of urine samples is carried out if the results of macroscopic analysis deviate from the norm.

Urine samples are also analyzed to measure protein and creatinine to calculate the urine protein:creatinine ratio.

Serological analysis of viruses.

Before inclusion in the study, all patients must be tested for human immunodeficiency virus HIV-1 and HIV-2. Patients who are HIV positive are not included in the study.

Immunogenicity assessment.

Before administration of the study drug, blood samples are collected to check for the presence of ADA to ravulizumab in the serum. If necessary, further characterize antibody responses, including antibody binding and neutralization, PK/PD, safety and activity of ravulizumab. Antibodies to ravulizumab are assessed in serum samples collected from all patients according to the intervention schedule (Tables 10 and 11). Serum samples are screened for antibodies that bind to ravulizumab, and the titer of confirmed positive samples is reported. Detection and characterization of antibodies to ravulizumab are performed using an assay validated by or under the supervision of the sponsor. Monitoring Suicide Risk

Columbia University Suicidal Tendency Scale.

The Columbia Suicidality Rating Scale (C-SSRS; Figures 4 and 5) is a validated questionnaire widely used in primary care, clinical practice, surveillance, research, and institutions to assess suicidal ideation and behavior (Posner. K. et. al., Am J Psychiatry, 168:1266-77, 2011). The C-SSRS score is assigned by the investigator or an appropriately trained designee. The C-SSRS is assessed according to the intervention schedule (Tables 10 and 11). The C-SSRS score is used to ensure that patients who experience suicidal ideation or behavior are appropriately recognized and adequately managed.

Adverse events and serious adverse events.

The patient (or, as appropriate, the patient's guardian, surrogate, or legal designee) reports adverse events to the investigator or designee.

The investigator or designees are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE and are responsible for the follow-up of serious events considered to be related to the investigational medicinal product or investigational procedures; or because the patient stopped taking the study drug.

Time period and frequency of collection of information on adverse events and serious adverse events.

All AEs are collected from the time the ICF is signed until 8 weeks after the last dose of study drug.

- 56 046524

Medical events that began before the start of the study drug, but after obtaining informed consent, are recorded.

All SAEs are recorded and reported to the sponsor or designee within 24 hours. The Investigator sends all SAE updates to the sponsor within 24 hours of receipt of the information.

Researchers are not required to actively seek out AEs or SAEs after completion of study participation. However, if the investigator becomes aware of any SAE, including death, at any time after the patient has been withdrawn from the study, whether the event is related to the study drug or not, the investigator will promptly notify the sponsor.

Method for detecting adverse events and serious adverse events.

When AE and/or SAE are detected, efforts are made not to introduce systematic error. Non-time-limited and non-provocative verbal questioning of the patient is the preferred method of ascertaining the occurrence of AE.

Follow-up for adverse events and serious adverse events.

After the initial report of AE/SAE, the investigator should actively follow up each patient at subsequent visits/contacts. All SAEs will be monitored until resolution, stabilization, until the event is otherwise explained, or until the patient is lost to follow-up contact (as defined herein).

Regulatory reporting requirements for serious adverse events.

The investigator notifies the sponsor of the SAE within 24 hours of first becoming aware of the event.

The sponsor has the legal responsibility to notify local regulatory authorities and other regulatory authorities about the safety of the investigational medicinal product in clinical trials. The sponsor complies with country-specific regulatory requirements regarding safety reporting to the regulatory agency, IRB/IEC, and investigators.

Council for International Organizations of Medical Sciences (CIOMS) or MedWatch reports are prepared for suspected unexpected serious adverse reactions (SUSARs) in accordance with local regulatory requirements and sponsor policies and sent to investigators as appropriate. Alexion's procedures for reporting SUSAR comply with Title 21 CFR 312.32 and European Union Clinical Trials Directive 2001/20/EC and associated details.

Guidance documents or national regulatory requirements in participating countries, and IRB/IEC, where applicable.

An investigator who receives an investigator safety report describing an SAE or other specific safety information (e.g., summary or list of SAEs) from a sponsor reviews and validates the report and notifies the IRB/IEC as appropriate in accordance with local requirements.

Pregnancy.

Patients of childbearing potential undergo a serum pregnancy test (i.e., beta human chorionic gonadotropin) at the time of screening and at EOS/ET. My pregnancy tests are carried out at all other required time points, as indicated in the schedule of events (Tables 10 and 11). Patients of childbearing potential must have a negative pregnancy test before prescribing ravulizumab.

If pregnancy is reported, the investigator informs the sponsor within 24 hours of learning of the pregnancy.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, and ectopic pregnancy) are considered SAEs and are recorded.

Prevention with vaccines and antibiotics.

As with any terminal complement antagonist, the use of ravulizumab increases the patient's susceptibility to meningococcal disease (N. meningitidis). To reduce the risk of meningococcal disease, all patients are vaccinated against meningococcal disease 3 years before or at the time of starting the study drug. Patients who initiated study drug treatment less than 2 weeks after meningococcal vaccine administration were treated with appropriate prophylactic antibiotics for 2 weeks after vaccination.

Vaccines against serotypes A, C, Y, W135, and B, when available, are recommended to prevent the development of common pathogenic meningococcal serotypes. Patients are vaccinated or revaccinated according to current national vaccination guidelines or local practice for complement inhibitor vaccination (eg, eculizumab).

Vaccination may not be sufficient to prevent meningococcal disease. Official guidelines and local practices for the appropriate use of antibacterial agents should be considered. All patients are monitored for early signs of meningococcus

- 57 046524 infection are immediately assessed if infection is suspected and treated with appropriate antibiotics if necessary.

To increase awareness of the risks and facilitate the rapid identification of any potential signs or symptoms of infection that patients experienced during the study, patients are provided with a safety card that they can carry with them at all times. Additional discussion and explanation of potential risks, signs, and symptoms occurs at each visit as part of the patient safety chart discussion, as described in the intervention schedule (Tables 10 and 11). Vaccination(s) against N meningitidis fixes.

Reactions to the administration of the study drug.

Local and systemic reactions.

Administration site reactions are reactions localized to the site of intravenous administration of the study drug and include reactions such as erythema, itching, and bruising. Infusion-associated reactions are reactions that are systemic in nature and may be immune or non-immune-mediated, typically occurring within a few hours of administration of the study drug. Immune-mediated reactions include allergic reactions (eg, anaphylaxis), whereas non-immune-mediated reactions are nonspecific (eg, headache, dizziness, nausea). These reactions are monitored as part of routine safety assessments for this study.

Infusion-associated reactions.

Infusion-associated reactions are defined as systemic AEs (eg, fever, chills, flushing, changes in HR and BP, shortness of breath, nausea, vomiting, diarrhea, and generalized skin rash) occurring during or within 24 hours after initiation of i.v. infusions that the investigator assesses as possibly, likely, or definitely related to the study drug.

Adverse events of particular interest.

Meningococcal infections are collectively considered adverse events of special interest (AESI) for this study.

Pharmacokinetics.

Blood samples are collected to assess serum ravulizumab concentrations before and after treatment at the time points and windows specified in the intervention schedule (see Tables 10 and 11). Samples obtained outside the designated windows are considered protocol deviations. Unused samples are stored for up to 5 years for further evaluation if necessary.

Pharmacodynamics.

Blood samples are collected to assess serum free C5 before and after treatment at the time points and windows specified in the intervention schedule (see Tables 10 and 11). Samples obtained outside the designated windows are considered protocol deviations. Unused samples are stored for up to 5 years for further evaluation if necessary.

Biomarkers.

Blood samples for assessment of auto-Ab to AChR are taken at the time points specified in the intervention schedule (Tables 10 and 11).

Health resource utilization and health economics.

Health resource utilization and health economics data associated with health care utilization are collected by the investigator or designee for all patients throughout the study. The data is recorded. Protocol-required procedures, tests and meetings are excluded.

Data collected are used to conduct exploratory economic analysis and include the number and duration of health care encounters, including surgical procedures and other selected procedures (inpatient and outpatient);

length of hospitalization (total number of days or length of stay, including length of stay in wards (eg, intensive care unit);

number and type of diagnostic and treatment tests and procedures;

outpatient medical examinations and treatments (including doctor or emergency room visits, tests and procedures, and medications).

11. Statistical aspects.

The statistical methods described in this invention will be described in more detail in a separate SAP. SAP is being developed and refined until the database is closed. Analyzes are performed using SAS® statistical software version 9.4 or later. Statistical analysis includes summary tables, analysis results, patient lists, and figures. Inference from the efficacy analysis is based on a two-sided Type I error (α)=5%. Summary statistics for continuous variables include, at a minimum, n, mean, standard deviation, minimum, median, and maximum. Frequencies and percentages are presented for categorical variables.

- 58 046524

The baseline value for analysis and reporting is based on the last non-missing measurement at the time of administration or before the first dose of study drug. Treatment groups for analysis and reporting are based on the conventions outlined in Table 1 . 18. The Total panel is designed to report demographics, baseline characteristics, and other preliminary information such as SAE in prior studies, medical history, or prior medications. Details for substituting performance data are described in SAP. Missing safety data is not supplied.

Statistical hypotheses.

Primary hypothesis.

The primary hypothesis of this study is that ravulizumab is superior to placebo in improving MG-ADL total score at week 26.

The treatment effect based on the primary endpoint was assessed by the mean difference between the ravulizumab group and the placebo group in the change in MG-ADL total score from baseline at week 26, regardless of salvage therapy. A lower value of the corresponding score indicates a positive treatment effect.

Secondary hypothesis.

The following secondary hypothesis is included in the adjustment for multiple studies (provided that the null hypothesis for the primary endpoint is rejected) and as provided in this invention.

Ravulizumab is superior to placebo in improving QMG total score at 26 weeks.

Hypotheses related to effectiveness research objectives.

1. Ravulizumab is superior to placebo in reducing all-cause hospitalization or clinical worsening over 26 weeks.

2. Ravulizumab is superior to placebo in improving MG-QOL15r total score at 26 weeks.

3. Ravulizumab is superior to placebo in improving QOL Nerve Fatigue Total Score at 26 weeks.

4. Ravulizumab is superior to placebo in improving total MGC score at 26 weeks.

5. Ravulizumab is superior to placebo in QMG 5-point response (>5 point improvement from baseline in QMG total score) at week 26.

6. Ravulizumab is superior to placebo in MG-ADL 3-point response (>3 point improvement from baseline in MG-ADL total score) at week 26.

7. Ravulizumab is superior to placebo on the MGFA-PIS at 26 weeks.

8. Ravulizumab is superior to placebo in improving EQ-5D-5L score at 26 weeks.

9. Ravulizumab is superior to placebo in improving EQ-5D-5L VAS scores at week 26.

The treatment effect corresponding to the change from the original continuous endpoints is assessed in the same way as the primary endpoint.

The treatment effect for the following dichotomous endpoints is assessed using the odds ratio (OR) of the proportions of the corresponding endpoint in the ravulizumab group compared with the placebo group:

a) incidence of any-cause hospitalization or clinical deterioration over 26 weeks regardless of therapy;

b) response on a 5-point QMG scale at week 26, regardless of reserve therapy;

c) response on the 3-point MG-ADL scale at week 26, regardless of reserve therapy.

A score of OR<1 corresponding to the composite endpoint of hospitalization indicates a positive treatment effect, similarly a score of OR>1 corresponding to the responder endpoint indicates a positive treatment effect.

The treatment effect corresponding to the MGFA-PIS endpoint is estimated by the proportional OR of the cumulative proportions by ordinal category (best effect first) of that endpoint in the ravulizumab group compared with the placebo group at week 26, regardless of salvage therapy. An OR score >1 indicates a positive treatment effect.

Determining sample size.

Approximately 160 patients are randomized to receive ravulizumab or placebo in a 1:1 ratio (ravulizumab:placebo), stratified by region (North America, Europe, Asia-Pacific and Japan) to ensure at least 90% nominal power to reject the null hypothesis of no treatment difference for the primary and secondary endpoints based on two-sided type I error (α)=5%. Assumptions related to statistical power calculations are based on the ECU-MG-301 study. Details are presented as defined in this invention.

- 59 046524

Table 18

ALXN1210-MG-306 Study Analysis Samples

Description patient groups Randomized All randomized patients are grouped according to randomization totality treatment group (to report distribution, demographics, and baseline characteristics). PK Analysis Set (PKAS) All patients treated with ravulizumab with data available for at least one concentration for PK analysis after baseline. Full Analysis Set (FAS) Totality according to protocol (PPS) All randomized patients receiving at least 1 dose of study drug are grouped into randomized treatment arm (for reporting efficacy data). Subset of FAS without any major deviations from protocol ¹ during the randomized controlled period, grouped by randomized treatment arm (to represent primary efficacy data). Safety Analysis Set (SS) All patients receiving at least 1 dose of study drug, grouped by actual treatment received (to report exposure and safety data). In order for a patient to be analyzed according to the treatment actually received rather than according to the randomization schedule, the patient will need to receive that treatment for the entire randomized controlled period. Aggregate for open extended period All patients who received at least 1 dose of ravlizumab starting at week 26 (to represent all OLE period data).

¹ Determination of applicable major protocol deviations for this purpose will be made prior to database closure and study unblinding.

Statistical analysis.

Study inclusion and allocation.

The number of patients screened, screened failures, and patients randomized is presented. Study inclusion information is presented grouped by stratification factor and treatment group. The number of patients who discontinued treatment, with reasons, in the randomized controlled period, the OLE period, and the entire study is summed.

Demographics, baseline characteristics, inclusion and exclusion criteria, and protocol deviations.

All demographic information and baseline characteristics are presented by treatment group and overall. There is no statistical test for homogeneity among treatment groups.

The number and percentage of patients not meeting specific inclusion or exclusion criteria are summed. Similar overall results are presented for major protocol deviations based on predefined categories.

Medical/surgical history, physical examination, and history of myasthenia gravis.

Medical and surgical history is summarized in the Medical Dictionary of Terminology for Regulatory Activities (MedDRA) version 20.1 or later by system organ class (SOC) and preferred term. MG and pathological physical examination are also summarized.

Preceding and concomitant medications.

For analysis and reporting purposes, any drug that is started before the first dose of the study drug is considered a precursor drug; and medications started during or after the first dose of study drug are considered concomitant medications. All prior and concomitant medications are summarized, including MG-specific medications and salvage therapy during the study, if any.

- 60 046524

Efficiency analysis.

Primary effectiveness analysis.

A mixed-effects model with repeated measures (MMRM) is used to estimate the primary efficacy endpoint (change from baseline in MG-ADL total score at week 26) using all available longitudinal data (full or partial), whether whether patients received backup therapy. Backup therapy includes high-dose corticosteroids, PP/PE, or IVIg. It is permitted when the patient's health is at risk, unless back-up therapy is provided (eg in emergency situations) or if the patient experiences clinical deterioration. Missing data are not imputed for the primary analysis. The model includes change in MG-ADL score from baseline at each prespecified time point as the response variable, fixed categorical effects of treatment, study visit, and a treatment-by-study visit interaction by region; and a fixed covariate of baseline MG-ADL total score. Treatment effect is assessed by contrasting the treatment term with respect to the 26-week visit. An unstructured covariance matrix is used to model correlations between repeated measurements within each patient. Other covariance structures are applied if convergence is an issue (see SAP for details). To estimate the degrees of freedom of the denominator, the Kenward-Rogers method is used.

Sensitivity analysis for the primary endpoint.

Two sensitivity analyzes are performed for the primary efficacy endpoint to examine the robustness of the MMRM results to the primary efficacy analysis.

1. Placebo-based sensitivity analysis.

The placebo-based sensitivity analysis examines the missing non-random (MNAR) mechanism for missing data, where it is assumed that patients who stop ravulizumab prematurely follow a trajectory of outcomes similar to that of the placebo group after stopping ravulizumab, given observed values until you stop taking it.

2. Sensitivity analysis of turning points.

This approach assumes that patients who discontinue treatment with ravulizumab experience worsening as measured by a prespecified adjustment of the primary efficacy endpoint.

Analysis of secondary and exploratory endpoints.

All continuous secondary and exploratory endpoints associated with deviation from baseline were analyzed in the same way as primary endpoints.

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

The responder endpoints of the 5-point QMG scale and the 3-point MG-ADL scale are analyzed using a mixed-effects repeated measures model. The model includes the response variable at each prespecified time point as the dependent variable, fixed categorical effects of treatment, study visit, and an interaction between study visit and region; and a fixed covariate of baseline QMG or MG-ADL total score (depending on the response variable). Treatment effect is assessed by contrasting the treatment term with respect to the 26-week visit. An unstructured covariance matrix is used to model correlations between repeated measurements within each patient. Other covariance structures are applied if convergence is an issue (see SAP for details).

The MGFA-PIS endpoint at week 26 is considered an ordinal scale. Logistic regression of cumulative odds (accumulated across categories, starting with the best outcome) is performed using treatment as a categorical fixed effect and adjustment for region.

Long-term effectiveness data are summarized descriptively based on the OLE sample.

Multiplicity adjustment for primary and secondary endpoints.

The study was designed to strictly control for an overall two-sided Type I error of α=0.05. The primary null hypothesis is tested first at α=0.05. If there is statistical significance, the secondary effectiveness hypothesis is tested at α=0.05.

Per-protocol analysis for primary and secondary endpoints.

Additional per-protocol analyzes for primary and secondary endpoints are performed on a per-protocol pooled (PPS) basis in the same manner as for FAS.

- 61 046524

Safety analyses.

The safety and tolerability of ravulizumab are assessed based on adverse effects, clinical laboratory data, vital signs, and ECG abnormalities. Safety analyzes are performed on the safety cohort and OLE sample based on the study period considered.

Analysis of adverse events.

Analysis and reporting of AEs are based on treatment-emergent adverse events (TEAEs), including treatment-emergent serious adverse events (TESAEs), defined as AEs at initiation or after the first dose of ravulizumab in the randomized controlled period. Treatment-emergent adverse events and TESAEs are summarized using SOC and MedDRA preferred term, by severity and by study drug. The adjusted event rate in patient-years is calculated to characterize the long-term safety profile.

Analysis of clinical laboratory parameters, vital signs and electrocardiogram parameters.

Laboratory measurements, as well as their changes from baseline at each visit and deviation from baseline, if applicable, are summarized descriptively. Significant ECG, vital signs, and pulse oximetry findings are also summarized using descriptive analysis.

Other safety analyses.

The number and percentage of patients in each of the C-SSRS categories and bias analysis are obtained. The results of pregnancy tests are summarized.

Analysis of pharmacokinetics and pharmacodynamics.

Pharmacokinetic parameters such as peak and trough serum concentrations of ravulizumab are reported and summarized. A population-based PK analysis of ravulizumab is performed to characterize the PK of ravulizumab in patients with gMG using sparse PK data. Key pharmacokinetic parameters of ravulizumab, such as clearance, volume of distribution and terminal half-life, are assessed using population pharmacokinetic analysis. The potential influence of intrinsic and extrinsic factors on the PK of ravulizumab is also assessed. Pharmacodynamic data (free C5 before and after treatment) are presented and summarized. Correlations between PK and PD are examined. Additional tests are considered if necessary.

Immunogenicity assay.

The presence of ADA in serum with ravulizumab is assessed throughout the study. Immunogenicity results are analyzed by summing the number and percentage of patients who develop detectable ADAs. The association of ADA with ravulizumab concentration, PD parameters, efficacy and TEAE is assessed.

Analysis of research biomarkers.

Levels of acetylcholine receptor antibody titers and their changes from baseline at each visit are summarized descriptively.

Interim analyses.

There are no interim analyzes planned for the ALXN1210-MG-306 study during the randomized controlled period. The primary analysis occurs when the last patient completes the randomized controlled period, the database is closed, and the study randomization schedule is unmasked. Periodic analysis and reporting is performed during the OLE period in accordance with regulatory requirements. The final analysis and report is carried out upon completion of the study.

Learn more about determining sample size.

Power calculations are based on longitudinal change in total scale scores.

MG-ADL from baseline observed in the ECU-MG-301 study. A simulation-based approach is adopted to calculate power based on the model-based treatment effect on the MG-ADL scale. A total of 160 patients were required to ensure at least 90% power to reject the null hypothesis of no treatment effect based on change from baseline in MG-ADL total score at week 26. See SAP for more details.

More information about the sensitivity analysis for the primary endpoint.

To assess the strength of the primary analysis, the following sensitivity analyzes are planned, based on assumptions that are sufficiently unfavorable for the ravulizumab arm to constitute a compelling stress test of the primary analysis.

Placebo-based sensitivity analysis.

A placebo-based sensitivity analysis examines the MNAR mechanism for missing data, where it is assumed that patients who discontinue prematurely in the ravulizumab group follow a trajectory of outcomes similar to that observed in the placebo group after discontinuation

- 62 046524 ravulizumab, taking into account observed values before discontinuation (Little, R. & Yau, L., Biometrics, 52:1324-33, 1996; Ratitch, B. et al., Pharm. Stat., 12:337 -47, 2013). Patients who discontinue placebo prematurely are expected to have unobserved outcomes similar to those of placebo-treated patients who continue to receive the randomized treatment. The assumption that the efficacy profiles of dropout patients following ravulizumab discontinuation are similar to those of patients in the placebo group provides an estimate of the efficacy attributable to patients in the ravulizumab group if obtained at the time point of interest, while limiting efficacy after early discontinuation compared with those of the placebo groups.

Sensitivity analysis of turning points.

Additional sensitivity analysis is performed based on the delta-adjusted stress testing method (critical point analysis). This approach assumes that patients who discontinue active treatment experience worsening, as measured by a prespecified adjustment (delta) in the primary efficacy endpoint compared with the observed efficacy estimate of patients who continue the study to the next visit (O'Kelley M RB, Statistics in Practice, 1 ed., Chichester, West Sussex, UK: John Wiley & Sons, Ltd; 2014. pp. 257-368). Because a negative change in QMG total score indicates improvement, the predefined delta value is a non-negative fixed value. For each delta value, a treatment effect is determined, and the delta value for which the nominal two-sided p value crosses 0.05 is considered a tipping point in the sense that the positive conclusion drawn from the primary analysis is reversed when dropouts are expected to experience this is a fixed deterioration after the cancellation visit. Once such a tipping point is identified, a clinical assessment of the plausibility of the assumptions underlying that tipping point is applied. This methodology is expected to provide information on what needs to be done to challenge study conclusions based on various assumptions about missing data. A delta value of zero is considered equivalent to the primary analysis.

Brief information about sequences

SEQ ID NO:1

GYIFSNYWIQ

SEQ ID NO:2

EILPGSGSTEYTENFKD

SEQ ID NO:3

YFFGSSPNWYFDV

SEQ ID NO:4

GASENIYGALN

SEQ ID NO:5

GATNLAD

SEQ ID NO:6

QNVLNTPLT

SEQ ID NO:7

QVQLVQSGAEVKKPGASVKVSCKASGYIFSNYWIQWVRQAPGQGLEWMGEILPGSGSTEYTENF

KDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSSPNWYFDVWGQGTLVTVSS

- 63 046524

SEQ ID NO:8

DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIK

SEQ ID NO:9

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKD TLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDW LNG KEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSL SLSLGK

SEQ ID NO:10

QVQLVQSGAEVKKPGASVKVSCKASGYIFSNYWIQWVRQAPGQGLEWMGEILPGSGSTEYTENF KDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSSPNWYFDVWGQGTLVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSNFGT QTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO:11

DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIKPTVAAPSVFPFPPSPEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVY ACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO:12

QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGEILPGSGHTEYTENF KDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSSPNWYFDVWGQGTLVTVSS SEQ ID NO:13

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKD TLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDW LNG KEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHSHYTQKSL SLSLGK

SEQ ID NO:14

QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGEILPGSGHTEYTENF KDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSSPNWYFDVWGQGTLVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSNFGTQ TYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES

- 64 046524

NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHSHYTQKSLSLSLGK SEQ ID NO:15

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKD TLYITREPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKPREEQFNSTFRWSVLTWHQDW LNGKEYK CKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK

SEQ ID NO:16

QVQLVQSGAEVKKPGASVKVSCKASGYIFSNYWIQWVRQAPGQGLEWMGEILPGSGSTEYTENF KDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSPNWYFDVWGQGTLVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VTSSNFGTQ TYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLYITR EPEVTCVWDVSHEDPEVQFNWYVDGMEVHNAKTKPREEQFNSTFRWSVLTWHQDWLNGKEY KCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTT PPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

SEQ ID NO:17

GASENIYHALN

SEQ ID NO:18

EILPGSGHTEYTENFKD

SEQ ID NO:19

GHIFSNYWIQ

SEQ ID NO:20

QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGEILPGSGHTEYTENF KDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSSPNWYFDVWGQGTLVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSNFGTQ TYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES

- 65 046524

NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

SEQ ID NO:21

SYAIS

SEQ ID NO:22

GIGPFFGTANYAQKFQG

SEQ ID NO:23

DTPYFDY

SEQ ID NO:24

SGDSIPNYYVY

SEQ ID NO:25

DDSNRPS

SEQ ID NO:26

QSFDSSLNAEV

SEQ ID NO:27

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISVWRQAPGQGLEWMGGIGPFFGTANYAQKF

QGRVTITADESTSTAYMELSSLRSEDTAVYYCARDTPYFDYWGQGTLVTVSS

SEQ ID NO:28

DIELTQPPSVSVAPGQTARISCSGDSIPNYYVYWYQQKPGQAPVLVIYDDSNRPSGIPERFSGS

NSGNTATLTISGTQAEDEADYYCQSFDSSLNAEVFGGGTKLTVL

SEQ ID NO:29

NYIS

SEQ ID NO:30

IIDPDSYTEYSPSFQG

SEQ ID NO:31

- 66 046524

YEYGGFDI

SEQ ID NO:32

SGDNIGNSYVH

SEQ ID NO:33

KDNDRPS

SEQ ID NO:34

GTYDIESYV

SEQ ID NO:35

EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYISWVRQMPGKGLEWMGIIDPDDSYTEYSPSFQ

GQVTISADKSISTAYLQWSSLKASDTAMYYCARYEYGGFDIWGQGTLVTVSS

SEQ ID NO:36

SYELTQPPSVSVAPGQTARISCSGDNIGNSYVHWYQQKPGQAPVLVIYKDNDRPSGIPERFSGS

NSGNTATLTISGTQAEDEADYYCGTYDIESYVFGGGTKLTVL

SEQ ID NO:37

SSYYVA

SEQ ID NO:38

AI YTGSGATYKASWAKG

SEQ ID NO:39

DGGYDYPTHAMHY

SEQ ID NO:40

QASQNIGSSLA

SEQ ID NO:41

GASKTHS

SEQ ID NO:42

- 67 046524

QSTKVGSSYGNH

SEQ ID NO:43

QVQLVESGGGLVQPGGSLRLSCAASGFTSHSSYYVAWVRQAPGKGLEWVGAIYTGSGATYKASW AKGRFTISKDTSKNQWLTMTNMDPVDTATYYCASDGGYDYPTHAMHYWGQGTLVTVSS

SEQ ID NO:44

DWMTQSPSSLSASVGDRVTITCQASQNIGSSLAWYQQKPGQAPRLLIYGASKTHSGVPSRFSG SGSGTDFTLTISSLQPEDVATYYCQSTKVGSSYGNHFGGGTKVEIK

SEQ ID NO:45

QVQLVESGGGLVQPGRSLRLSCAASGFTVHSSYYMAWVRQAPGKGLEWVGAIFTGSGAEYKAEW AKGRVTISKDTSKNQWLTMTNMDPVDTATYYCASDAGYDYPTHAMHYWGQGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELRRGPKVFLFPPKPKDT LMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHAHYTRKELS LSP

SEQ ID NO:46

K VYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO:47

QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYNPSLK SRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTVSS

SEQ ID NO:48

AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFAG RGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIK

SEQ ID NO:49

- 68 046524

QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNYNPSLK SRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVTVSSASTKGPSV IFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO :50

AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFAG RGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSG TASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV Y ACEVTHQGLSSPVTKSFNRGEC

Claims (37)

1. Use of a composition for the treatment of myasthenia gravis (MG) in a human patient, wherein said treatment comprises administering to the patient an effective amount of the composition, wherein the composition contains an antibody or antigen binding fragment thereof comprising the heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 19, 18 and 3, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 4, 5 and 6, respectively, wherein said antibody or antigen binding fragment thereof is administered in an administration cycle comprising administration(s) 1 once every day 1 at a loading dose of (i) 2400 mg to a patient weighing >40 to <60 kg, (ii) 2700 mg to a patient weighing >60 to <100 kg, or (iii) 3000 mg to a patient with body weight > 100 kg; and (b) on day 15 and every 8 weeks thereafter at a maintenance dose of (i) 3000 mg in a patient weighing >40 to <60 kg, (ii) 3300 mg in a patient weighing >60 to <100 kg, or (iii) 3600 mg in a patient weighing >100 kg. 2. Use of a composition according to claim 1, wherein the antibody or antigen-binding fragment thereof contains a human variant constant Fc region that binds to the neonatal human Fc receptor (FcRn), wherein CH3 of the human variant constant Fc region contains substitutions Met-429- Leu and Asn-435-Ser at residues corresponding to methionine 428 and asparagine 434, each represented according to EU numbering. 3. Use of a composition according to any of the preceding claims, wherein said 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. 4. Use of a composition according to any of the previous claims, wherein said antibody or antigen-binding fragment thereof further comprises a heavy chain constant region of SEQ ID NO: 13. 5. Use of a composition according to any of the preceding claims, wherein said antibody or antigen binding fragment thereof comprises a heavy chain polypeptide containing the amino acid sequence of SEQ ID NO: 14 and a light chain polypeptide containing the amino acid sequence of SEQ ID NO: 11. 6. Use of a composition according to any of the previous paragraphs, wherein said antibody or antigen-binding fragment thereof binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (K _D ), which is in the range of 0.1 hM<K _d <1 nM. 7. Use of a composition according to any of the previous paragraphs, wherein said antibody or antigen-binding fragment thereof binds to human C5 at pH 6.0 and 25°C with a K _D >10 nM. 8. Use of a composition according to any of the previous claims, wherein said antibody or antigen-binding fragment thereof is included in a composition for intravenous administration. 9. Use of a composition according to any one of claims 1 to 8, wherein said myasthenia gravis is generalized myasthenia gravis (gMG). 10. Use of the composition according to claim 9, wherein said gMG patient is characterized by positive results for antibodies to AChR. 11. Use of a composition according to any of the previous paragraphs, in which said antibody - 69 046524 is ravulizumab. 12. A kit for the treatment of myasthenia gravis (MG) in a human patient, comprising (a) a dose of an antibody or antigen binding fragment thereof containing the CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and light chain variable region domains CDR1, CDR2 and CDR3 having the sequence set forth in SEQ ID NO: 8; and (b) instructions for use of the antibody or antigen-binding fragment thereof according to any of the preceding paragraphs. 13. A kit for use according to claim 12, wherein said antibody or antigen-binding fragment thereof contains a human variant constant Fc region that binds to the neonatal human Fc receptor (FcRn), wherein CH3 of the human variant constant Fc region contains Met substitutions -429-Leu and Asn-435-Ser at residues corresponding to methionine 428 and asparagine 434, each represented according to EU numbering. 14. The kit according to claim 12 or 13, wherein said antibody is ravulizumab. 15. Use of an antibody for the treatment of myasthenia gravis (MG) in a human patient, wherein said antibody comprises the CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 variable domains light chain region having the sequence set forth in SEQ ID NO: 8, wherein said antibody or antigen binding fragment thereof is administered in an administration cycle comprising administering (a) once on day 1 a loading dose of (i) 2400 mg to a patient with weight body weight >40 to <60 kg, (ii) 2700 mg to a patient weighing >60 to <100 kg, or (iii) 3000 mg to a patient weighing >100 kg; and (b) on day 15 and every 8 weeks thereafter at a maintenance dose of (i) 3000 mg in a patient weighing >40 to <60 kg, (ii) 3300 mg in a patient weighing >60 to <100 kg, or (iii) 3600 mg in a patient weighing >100 kg. 16. Use of an antibody according to claim 15, wherein said antibody or antigen-binding fragment thereof comprises a human variant constant Fc region that binds to the neonatal human Fc receptor (FcRn), wherein CH3 of the human variant constant Fc region contains Met-429 substitutions -Leu and Asn-435-Ser at residues corresponding to methionine 428 and asparagine 434, each represented according to EU numbering. 17. Use of an antibody according to claim 15 or 16, wherein said antibody is ravulizumab. 18. A method of treating a human patient with myasthenia gravis (MG), the method comprising administering to the patient an effective amount of an antibody or antigen binding fragment thereof comprising the heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively , and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 4, 5 and 6, respectively, wherein said antibody or antigen binding fragment thereof is administered in an administration cycle comprising (a) once on day 1 of loading dose (i) 2400 mg in a patient weighing >40 to <60 kg, (ii) 2700 mg in a patient weighing >60 to <100 kg, or (iii) 3000 mg in a patient weighing >100 kg; and (b) on day 15 and every 8 weeks thereafter at a maintenance dose of (i) 3000 mg in a patient weighing >40 to <60 kg, (ii) 3300 mg in a patient weighing >60 to <100 kg, or (iii) 3600 mg in a patient weighing >100 kg. 19. The method according to claim 18, wherein said antibody or antigen-binding fragment thereof contains a human variant constant Fc region that binds to the neonatal human Fc receptor (FcRn), wherein CH3 of the human variant constant Fc region contains substitutions Met-429- Leu and Asn-435-Ser at residues corresponding to methionine 428 and asparagine 434, each represented according to EU numbering. 20. The method according to any one of claims 18 and 19, wherein said 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. 21. The method according to any one of claims 18 to 20, wherein said antibody or antigen binding fragment thereof further comprises a heavy chain constant region of SEQ ID NO: 13. 22. The method according to any one of claims 18 to 21, wherein said antibody or antigen binding fragment thereof comprises a heavy chain polypeptide containing the amino acid sequence of SEQ ID NO: 14, and a light chain polypeptide containing the amino acid sequence of SEQ ID NO: 11. - 70 046524 23. The method according to any one of claims 18-22, wherein said antibody or antigen-binding fragment thereof binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) that is in the range of 0.1 hM<KD <1 nM. 24. The method according to any one of claims 18-23, wherein said antibody or antigen-binding fragment thereof binds to human C5 at pH 6.0 and 25°C with a KD> 10 nM. 25. The method according to any one of claims 18 to 24, wherein said treatment maintains a residual concentration of the antibody or antigen-binding fragment thereof in the blood serum at a level of 100 μg/ml or more during the administration cycle, preferably said treatment maintains a residual concentration of the antibody or antigen-binding fragment thereof in serum at a level of 200 mcg/ml or more during the administration cycle. 26. The method according to any one of claims 18 to 25, wherein said treatment maintains the concentration of free antibodies at a level of from 0.309 to 0.5 μg/ml or less. 27. The method according to any one of claims 18-26, wherein said antibody or antigen-binding fragment thereof is administered at a dose of 3000, 3300 or 3600 mg once every 8 weeks after a cycle of administration for up to two years. 28. The method according to any one of claims 18-27, wherein said antibody or antigen-binding fragment thereof is included in a composition for intravenous administration. 29. The method according to any one of claims 18 to 28, wherein said patient has not previously received treatment with a complement inhibitor. 30. Method according to any one of claims 18 to 29, wherein said administration cycle is a total of 26 weeks of treatment. 31. The method according to any one of claims 18 to 30, wherein said treatment results in inhibition of the terminal complement complex. 32. The method according to any one of claims 18 to 31, wherein said treatment results in the patient experiencing a clinically significant improvement (decrease) in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale after 26 weeks of treatment, preferably clinically indicated The significant improvement experienced by the patient is a decrease in the patient's MGADL score of at least 3 points after 26 weeks of treatment. 33. The method according to any one of claims 18 to 32, wherein said treatment results in a clinically significant improvement (decrease) in the quantitative myasthenia gravis (QMG) scale after 26 weeks of treatment, and preferably the specified clinically significant improvement experienced by the patient is a decrease in the patient's QMG score by at least 5 points after 26 weeks of treatment. 34. The method according to any one of claims 18 to 33, wherein said treatment results in a clinically significant improvement (decrease) in the Myasthenia Gravis Composite Score (MGC) after 26 weeks of treatment, and/or wherein said treatment results in a clinically significant improvement (decrease in severity) of quality of life, as measured by the Myasthenia Gravis Quality of Life Scale (MG-QOL15r), after 26 weeks of treatment, and/or wherein the treatment results in a clinically significant improvement (decrease) in neuronal fatigue, as measured by the Nervous Fatigue Scale. fatigue QOL, after 26 weeks of treatment, and/or wherein said treatment results in a clinically significant improvement in health status, as measured by the European Quality of Life Questionnaire (EQ-5D-5L) health status scale, after 26 weeks of treatment, and /or wherein said treatment results in a clinically significant improvement (decrease) in the Myasthenia Foundation of America (MGFA) Post-Intervention Score after 26 weeks of treatment. 35. The method according to any one of claims 18 to 34, wherein said myasthenia gravis is generalized myasthenia gravis (gMG). 36. The method of claim 35, wherein said gMG patient is positive for anti-AChR antibodies. 37. The method according to any one of claims 18 to 36, wherein said antibody is ravulizumab.