Neurological disease treatment with zilucoplan

Abstract

To provide methods of treating myasthenia gravis.SOLUTION: Methods of treating myasthenia gravis includes administering zilucoplan (RA101495).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to the treatment of neurological disorders by inhibiting complement activity. [Background technology]

[0002] The vertebrate immune response is composed of adaptive and innate immune components. The adaptive immune response is selective for certain pathogens and is slow to respond, whereas the innate immune response components recognize a broad range of pathogens and respond rapidly to infection. One such component of the innate immune response is the complement system.

[0003] The complement system includes approximately 20 circulating complement component proteins that are primarily synthesized by the liver. This particular component of the immune response was first named "complement" due to the observation that they complemented the antibody response in the destruction of bacteria. These proteins remain in an inactive form prior to activation in response to infection. Activation occurs by a pathway of proteolytic cleavage that is initiated by pathogen recognition and leads to pathogen destruction. Three such pathways are known in the complement system, termed the classical pathway, the lectin pathway, and the alternative pathway. The classical pathway is activated when IgG or IgM molecules bind to the surface of a pathogen. The lectin pathway is initiated by mannan-binding lectin proteins recognizing sugar residues on the bacterial cell wall. The alternative pathway maintains a low level of activity in the absence of any specific stimulus. Although all three pathways differ with respect to the initiating event, all three pathways converge on the cleavage of complement component C3, which is cleaved into two products called C3a and C3b. Of these, C3b binds covalently to pathogen surfaces, whereas C3a acts as a diffusible signal to promote inflammation and recruit circulating immune cells. Surface-attached C3b forms complexes with other components to initiate a cascade of reactions between subsequent components of the complement system. The requirement for surface attachment ensures that complement activity remains localized, minimizing destruction of non-target cells.

[0004] C3b attached to pathogens promotes pathogen destruction in two ways. In one pathway, C3b is directly recognized by phagocytes, leading to phagocytosis of the pathogen. In the second pathway, C3b attached to pathogens initiates the formation of the membrane attack complex (MAC). In the first step, C3b combines with other complement components to form the C5 convertase complex. Depending on the initial complement activation pathway, the components of this complex may differ. The C5 convertase formed as a result of the classical complement pathway contains C4b and C2a in addition to C3b. When formed by the alternative pathway, the C5 convertase contains two subunits of C3b as well as a Bb component.

[0005] Complement component C5 is cleaved into C5a and C5b by either of the C5 convertase complexes. C5a, like C3a, diffuses into the circulation, promoting inflammation and acting as a chemoattractant for inflammatory cells. C5b remains attached to the cell surface where it interacts with C6, C7, C8, and C9 to cause the formation of the MAC, a hydrophilic pore that spans the membrane and facilitates the free flow of fluid into and out of the cell, thereby destroying it.

[0006] A key component of overall immune activity is the ability of the immune system to distinguish between self and non-self cells. Pathological conditions arise when the immune system is unable to make this distinction. In the case of the complement system, vertebrate cells express proteins that protect them from the action of the complement cascade. This ensures that the complement system is limited to targeting pathogenic cells. Many complement-related disorders and diseases are associated with the abnormal destruction of self cells by the complement cascade. Some complement-related disorders and diseases include neurological diseases and disorders such as myasthenia gravis.

[0007] Myasthenia gravis is a rare complement-mediated autoimmune disease characterized by the production of autoantibodies that target proteins important for the normal transmission of electrical signals from nerves to muscles. The prevalence of MG in the United States is estimated at approximately 60,000 cases. In approximately 15% of patients with MG, symptoms are limited to the eye muscles. The remaining patients have MG that affects multiple muscle groups throughout the body, typically referred to as generalized MG (gMG). Patients with gMG characteristically present with muscle weakness that becomes more severe with repeated use and resolves with rest. Weakness may be localized to a specific muscle, but often progresses to more diffuse weakness. Generalized myasthenia gravis symptoms can become life-threatening if weakness involves the diaphragm and intercostal muscles within the chest wall responsible for breathing. The most dangerous complication of gMG, known as myasthenic crisis, requires hospitalization, intubation, and mechanical ventilation. Approximately 15%-20% of patients with gMG will experience a myasthenic crisis within 2 years of diagnosis. Summary of the Invention [Problem to be solved by the invention]

[0008] There remains a need for compositions and methods for treating complement-related diseases and disorders, including those that affect the nervous system, such as myasthenia gravis. The present disclosure meets this need by providing related compositions and methods. [Means for solving the problem]

[0009] In some embodiments, the disclosure provides a method of treating complement-related indications and / or autoimmune indications and / or neurological disorders disclosed herein, such as myasthenia gravis (MG), comprising administering to a subject a compound or a composition comprising a compound that modulates complement activity. Such a compound can be an inhibitor that blocks complement activation (a complement inhibitor), such as a C5 inhibitor, such as a C5 inhibitor polypeptide described herein. The compound can be zilcoplan or an active metabolite or variant thereof as disclosed herein, and the indication or disorder can be MG, as further defined herein below. As used herein, MG can include systemic MG (gMG) or can be systemic MG. Compound (e.g., zilcoplan) administration can include subcutaneous (SC) administration. Compound (e.g., zilcoplan) can be administered at a dosage of about 0.1 mg / kg (mg compound / kg subject body weight) to about 0.6 mg / kg. Compound administration can include self-administration. Compound administration can include use of a pre-filled syringe. The syringe may include a 29 gauge needle. The compound administration may include self-administration using a self-administration device. The self-administration device may include a pre-filled syringe. The pre-filled syringe may include glass. Optionally, the pre-filled syringe is a glass syringe. The pre-filled syringe may include a maximum fill volume of at least 1 ml. The self-administration device may include a solution of the compound. The solution may be an aqueous solution. The solution may be preservative-free. The self-administration device may include a solution volume of about 0.15 ml to about 0.81 ml. The subject may be screened prior to administration of the compound (e.g., Zilcoplan). The screening may include assessment of a Quantitative Myasthenia Gravis (QMG) score. The subject QMG score may be 12 or greater. The subject may be prohibited from receiving MG therapy for at least 10 hours prior to assessment of the QMG score. The MG therapy may be an acetylcholinesterase inhibitor therapy. Screening may require 4 or more QMG test items to achieve a score of 2 or greater. Subjects may be between 18 and 85 years old. Screening may include selecting subjects who have previously been diagnosed with gMG.The gMG diagnosis may be made according to Myasthenia Gravis Foundation of America (MGFA) criteria. Screening may include assessment of acetylcholine receptor (AChR) autoantibody levels. Screening may include confirmation that there is no change in the corticosteroid dosage received by the subject for at least 30 days prior to screening. Screening may include confirmation that there is no change in the subject's immunosuppressive therapy for at least 30 days prior to screening. Screening may include serum pregnancy test and / or urine pregnancy test. Compound administration may include daily administration. The subject may concurrently receive standard of care gMG therapy. Standard of care gMG therapy may include one or more of pyridostigmine therapy, corticosteroid therapy, and immunosuppressant therapy. Subjects may be assessed or monitored for MG characteristic, which may include QMG score, Myasthenia Gravis-Activities of Daily Living (MG-ADL) score, MG-QOL15r score, and MG composite score (MG. The subject evaluation or monitoring may include one or more of the following: a change in MG characteristics during or after treatment of the subject with a compound described herein (e.g., Zilcoplan). The MG characteristics may include a decrease in QMG score. The treated subject's QMG score may decrease by at least 3 points. The treated subject's QMG score may decrease at or before 12 weeks of treatment. The treated subject's QMG score may be monitored over the course of treatment. The subject may receive cholinesterase inhibitor treatment over the course of treatment. The cholinesterase inhibitor treatment may be withheld for at least 10 hours prior to calculating the treated subject's QMG score. The change in MG characteristics may include a change in MG composite score of at least 3 points from a baseline MG composite score. The change in MG composite score from a baseline MG composite score may occur at or before 12 weeks of treatment. The change in MG characteristics may include a change in MG-ADL score of at least 2 points from a baseline MG-ADL score. The change in MG-ADL score from the baseline MG-ADL score may occur at or before 12 weeks of treatment. The compound may be in a solution, the solution comprising phosphate buffered saline (PBS). The solution may comprise about 4 mg / ml to about 200 mg / ml of the compound (e.g., Zilcoplan). The solution may comprise about 40 mg / ml of the compound (e.g., Zilcoplan). The subject's plasma level of the compound is measured at a maximum concentration (C) on the first day of treatment. max). At least 90% hemolysis inhibition may be achieved in the subject's serum, and optionally, hemolysis inhibition is measured by a sheep red blood cell (sRBC) hemolysis assay. The compound (e.g., zilcoplan) may be administered at a daily dose of about 0.1 mg / kg to about 0.3 mg / kg. Zilcoplan may be administered at a dosage of 0.3 mg / kg. The subject's QMG score and / or MG-ADL score may be decreased. The QMG score may be decreased by 3 points or more with 8 weeks of treatment. The MG-ADL score may be decreased by 2 points or more with 8 weeks of treatment. The risk of needing rescue therapy may be decreased. Administration may be performed at a stage of MG disease that occurs prior to the critical or critical stage of MG. Administration of the compound (e.g., zilcoplan) may result in a decrease in the subject's symptom expression. The decrease in the subject's symptom expression may exceed the decrease in the subject's symptom expression associated with eculizumab administration. Targeted neuromuscular junction (NMJ) membrane attack complex (MAC) pore formation may be inhibited. The safety factor at the NMJ may be improved. Zilcoplan may be administered in combination with a therapeutic agent. The therapeutic agent may include an immunosuppressant. The immunosuppressant may include a compound selected from one or more of azathioprine, cyclosporine, cyclosporine A, mycophenolate mofetil, methotrexate, tacrolimus, cyclophosphamide, and rituximab. The therapeutic agent may include an inhibitor of autoantibody-mediated tissue destruction. The inhibitor of autoantibody-mediated tissue destruction may include a fetal Fc receptor (FcRN) inhibitor. The administration of the FcRN inhibitor may include intravenous immunoglobulin (IVIG) therapy. Zilcoplan and the therapeutic agent may be administered in an overlapping regimen.

[0010] In some embodiments, the disclosure provides a kit that may include a syringe containing a compound (e.g., Zilcoplan) and instructions for use. The syringe may include an autoinjection device. The autoinjection device may include a BD ULTRASAFE PLUS™ self-administration device. The kit may include alcohol wipes. The kit may include a wound dressing. The kit may include a disposal container. The compound may be in a solution. The solution may be an aqueous solution. The solution may include phosphate buffered saline. The solution may include about 4 mg / ml to about 200 mg / ml of the compound (e.g., Zilcoplan). The solution may include about 40 mg / ml of the compound (e.g., Zilcoplan). The solution may include a preservative.

[0011] According to some embodiments, the present disclosure provides a method for evaluating treatment of complement-related indications and / or autoimmune indications and / or neurological disorders disclosed herein, such as MG. The method may include screening evaluation candidates for at least one evaluation inclusion criterion; selecting evaluation participants; administering a treatment for the indication or disorder (e.g., MG) to the evaluation participants; and calculating at least one efficacy endpoint, where, optionally, the treatment includes administration of a compound (e.g., Zilcoplan) or composition disclosed herein. At least one evaluation inclusion criterion may include an MG diagnosis. The MG diagnosis may include a gMG diagnosis. The MG diagnosis may be a gMG diagnosis. The gMG diagnosis may be made according to the MGFA criteria. At least one evaluation inclusion criterion may include a QMG score. Evaluation participant selection may require an evaluation candidate QMG score of 12 or greater. Evaluation candidates may have received at least one alternative MG treatment prior to screening. Evaluation candidate QMG score may be calculated at least 10 hours after receiving at least one alternative MG treatment. At least one alternative MG treatment may include acetylcholinesterase inhibitor administration. Evaluation participant selection may require a score of 2 or greater on four or more QMG test items. At least one evaluation inclusion criterion may include evaluation candidate age. Evaluation participant selection may require evaluation candidate age between 18 and 85 years. At least one evaluation inclusion criterion may include AChR autoantibody levels and / or anti-muscle specific kinase autoantibody levels. At least one evaluation inclusion criterion may include no change in corticosteroid dosage received by the evaluation candidate for at least 30 days prior to screening. At least one evaluation inclusion criterion may include no change in evaluation candidate immunosuppressive therapy for at least 30 days prior to screening. At least one evaluation inclusion criterion may include confirmation that the evaluation candidate is not pregnant. Screening may include a serum pregnancy test and / or a urine pregnancy test. The treatment for MG may be administered over an evaluation period. The evaluation period may be from about 1 day to about 12 weeks. The evaluation period may be about 12 weeks or longer. Evaluation participants will receive standard of care gMG therapy over the evaluation period.Standard of care gMG therapy may include one or more of pyridostigmine therapy, corticosteroid therapy, and immunosuppressant therapy. At least one efficacy endpoint may include a treated subject QMG score reduction. The treated subject QMG score reduction may be at least 3 points. Evaluation participants may receive cholinesterase inhibitor therapy during the evaluation period. Cholinesterase inhibitor therapy may be withheld for at least 10 hours prior to the calculation of the treated subject QMG score. At least one efficacy endpoint may include a change in baseline scores for one or more of MG-ADL score, MG-QOL15r score, and MG Composite score. At least one efficacy endpoint may include a change in baseline MG Composite score of at least 3 points. The change in baseline MG Composite score may occur at or prior to 12 weeks of treatment. At least one efficacy endpoint may include a change in baseline MG-ADL score of at least 2 points. The change in baseline MG-ADL score may occur at or prior to 12 weeks of treatment. Calculating at least one efficacy endpoint may include a set of calculations. The set of calculations may be performed in the following order: (1) calculating the assessment participant MG-QOL15r score; (2) calculating the assessment participant MG-ADL score; (3) calculating the assessment participant QMG score; and (4) calculating the assessment participant MG composite score. The set of calculations may be performed on one or more occasions after administration of the MG treatment. The one or more occasions after administration of the MG treatment may include 1 week, 2 weeks, 4 weeks, 8 weeks, and / or 12 weeks after administration of the MG treatment.

[0012] In some embodiments, the present disclosure provides an administration device prepared for the treatment of complement-related indications and / or neurological disorders disclosed herein, such as MG. The administration device may include an autoinjection device including a syringe and a needle. The administration device may include a predetermined volume of a pharmaceutical composition. The pharmaceutical composition may include a compound disclosed herein (e.g., Zilcoplan) at a concentration of 40 mg / mL in an aqueous solution. The predetermined volume may be adjusted to facilitate administration of the compound (e.g., Zilcoplan) to a subject at a dosage of 0.3 mg per kg of subject body weight. The administration device may include a BD ULTRASAFE PLUS™ self-administration device.

[0013] In some embodiments, the present disclosure provides a kit prepared for the treatment of MG. The kit may include a set of two or more administration devices described herein and instructions for using the kit. The kit may include alcohol wipes. The kit may include a wound dressing. The kit may include a disposal container. The kit administration device may include a pharmaceutical composition of the compound (e.g., Zilcoplan) that is preservative-free. The kit may be prepared for storage at room temperature.

[0014] The above and other objects, features, and advantages will be apparent from the following description of specific embodiments of the invention, as illustrated in the accompanying drawings. The drawings are not necessarily to scale; emphasis instead is placed upon illustrating the principles of various disclosed embodiments. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 is a schematic diagram showing the overlap between the classical and alternative complement pathways. [Diagram 2] FIG. 1 is a schematic showing myasthenia gravis treatment trial design. [Diagram 3] 1 is a graph showing quantitative myasthenia gravis (QMG) score change from baseline during 12 weeks of placebo vs. 0.3 mg / kg zilucoplan treatment. [Figure 4]1 is a graph showing Myasthenia Gravis-Activities of Daily Living (MG-ADL) score change from baseline during 12 weeks of placebo vs. 0.3 mg / kg zirucoplan treatment. [Diagram 5] 1 is a graph showing the change in QMG score from baseline during 12 weeks of placebo vs. 0.1 mg / kg zilucoplan treatment. [Figure 6] 1 is a graph showing MG-ADL score change from baseline during 12 weeks of placebo vs. 0.1 mg / kg zilucoplan treatment. [Figure 7] 1 is a graph showing the MG-ADL score change from baseline on placebo compared to the combined mean score change from 0.1 mg / kg and 0.3 mg / kg zilucoplan treatment doses over a 12-week period. [Figure 8] 1 is a graph showing point improvement in QMG score by percentage of patients treated with 0.3 mg / kg zilucoplan versus placebo. [Figure 9] 1 is a graph showing point improvement in MG-ADL score by percentage of patients treated with 0.3 mg / kg zilucoplan versus placebo. [Figure 10] FIG. 1 is a graph showing the percentage of patients achieving minimal symptom expression at specific periods of treatment based on MG-ADL analysis with eculizumab versus zilucoplan treatment. [Figure 11] 1 is a graph showing the concentration of zilcoplan in samples obtained from patients over the course of zilcoplan or placebo treatment. [Figure 12] 1 is a graph showing percent hemolysis values ​​obtained from hemolysis assay analysis of samples obtained from patients during the course of zilucoplan or placebo treatment. [Figure 13] 1 is a graph showing hemolysis values ​​plotted against zilucoplan concentration values, with both sets of values ​​relating to samples from placebo or zilucoplan treated patients. [Figure 14]Graph showing change in QMG score from pretreatment baseline values ​​over the course of 12 weeks placebo treatment or 24 weeks zilucoplan treatment (0.1 mg / kg or 0.3 mg / kg doses). Change in QMG score is also shown for subjects receiving 12-24 weeks of zilucoplan treatment (0.3 mg / kg) after switching from placebo treatment, where the 12-week placebo treatment score is used as the baseline for determining change in score. [Figure 15] Graph showing change in MG-ADL score from pre-treatment baseline values ​​over the course of 12 weeks of placebo treatment or 24 weeks of zilucoplan treatment (0.1 mg / kg or 0.3 mg / kg doses). Change in MG-ADL score is also shown for subjects receiving 12-24 weeks of zilucoplan treatment (0.3 mg / kg) after switching from placebo treatment, where the 12-week placebo treatment score is used as the baseline for determining change in score. [Figure 16] 1 is a graph showing the change in MG Composite score from pre-treatment baseline values ​​over the course of 12 weeks of placebo treatment or 24 weeks of Zilcoplan treatment (0.1 mg / kg or 0.3 mg / kg doses). Change in MG Composite score is also shown for subjects who received 12-24 weeks of Zilcoplan treatment (0.3 mg / kg) after switching from placebo treatment, where the 12-week placebo treatment score is used as the baseline for determining the change in score. [Figure 17] Graph showing change in MG-QOL15r score from pre-treatment baseline value over the course of 12 weeks placebo treatment or 24 weeks zilucoplan treatment (0.1 mg / kg or 0.3 mg / kg dose). Change in MG-QOL15r score is also shown for subjects receiving 12-24 weeks of zilucoplan treatment (0.3 mg / kg) after switching from placebo treatment, where the 12-week placebo treatment score is used as the baseline for determining the change in score. [Figure 18]FIG. 1 is a graph showing the percentage of each compound tested that migrates from the upper to the lower chamber in an in vitro permeability assay using a basement membrane model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present disclosure relates to treating neurological disorders by inhibiting complement activity. Complement activity protects the body from foreign pathogens, but increased or uncontrolled activity can lead to self-cell destruction. Myasthenia gravis is a neurological disorder characterized by autoantibody-mediated nervous system destruction. Included herein are methods of treating myasthenia gravis by administering complement inhibitors. Also included are methods of testing new treatments for MG. These and other embodiments of the present disclosure are described in detail below.

[0017] I. Compounds and Compositions In some embodiments, the disclosure provides compounds and compositions comprising said compounds that function to regulate complement activity. Such compounds and compositions may include inhibitors that block complement activation. As used herein, "complement activity" includes activation of the complement cascade, formation of cleavage products from complement components such as C3 or C5, assembly of downstream complexes following a cleavage event, or any process or event that accompanies or results from cleavage of a complement component, e.g., C3 or C5. Complement inhibitors may include C5 inhibitors that block complement activation at the level of complement component C5. C5 inhibitors may bind to C5 and prevent its cleavage by C5 convertase into cleavage products C5a and C5b. As used herein, "complement component C5" or "C5" is defined as the complex that is cleaved by C5 convertase into at least cleavage products C5a and C5b. As referred to herein, a "C5 inhibitor" includes any compound or composition that inhibits the processing or cleavage of the pre-cleaved complement component C5 complex or the cleavage products of complement component C5.

[0018] It is understood that inhibition of C5 cleavage suppresses the assembly and activity of the cytolytic membrane attack complex (MAC) on glycosylphosphatidylinositol (GPI)-linked protein-deficient erythrocytes. In some cases, the C5 inhibitors provided herein also bind C5b, suppressing C6 binding and subsequent assembly of the C5b-9MAC.

[0019] C5 inhibitor compounds may include, but are not limited to, any of those presented in Table 1. The information supporting the listed references and the listed clinical trial numbers are incorporated herein by reference in their entirety.

[0020] [Table 1-1]

[0021] [Table 1-2]

[0022] Peptide Compounds In some embodiments, the C5 inhibitors of the present disclosure are polypeptides. According to the present disclosure, any amino acid-based molecule (natural or non-natural) may be referred to as a "polypeptide", which term encompasses "peptides", "peptidomimetics", and "proteins". "Peptides" are conventionally considered to range in size from about 4 to about 50 amino acids. Polypeptides larger than about 50 amino acids are commonly referred to as "proteins".

[0023] C5 inhibitor polypeptides can be linear or cyclic. Cyclic polypeptides include any polypeptide that has one or more cyclic features, such as loops and / or internal links, as part of its structure. In some embodiments, a cyclic polypeptide is formed when a molecule acts as a bridging moiety to link two or more regions of a polypeptide. As used herein, the term "bridging moiety" refers to one or more components of a bridge formed between two adjacent or non-adjacent amino acids, non-natural amino acids, or non-amino acids in a polypeptide. A bridging moiety can be of any size or composition. In some embodiments, a bridging moiety can include one or more chemical bonds between two adjacent or non-adjacent amino acids, non-natural amino acids, non-amino acid residues, or combinations thereof. In some embodiments, such chemical bonds can be between one or more functional groups on adjacent or non-adjacent amino acids, non-natural amino acids, non-amino acid residues, or combinations thereof. A bridging moiety can include one or more of an amide bond (lactam), a disulfide bond, a thioether bond, an aromatic ring, a triazole ring, and a hydrocarbon chain. In some embodiments, the bridging moiety comprises an amide bond between an amine functionality and a carboxylate functionality present in an amino acid, non-natural amino acid, or non-amino acid residue side chain, respectively, in some embodiments, the amine or carboxylate functionality is part of the non-amino acid residue or non-natural amino acid residue.

[0024] The C5 inhibitor polypeptides may be cyclized by the carboxy terminus, the amino terminus, or any other convenient point of attachment, such as the sulfur of a cysteine ​​(e.g., by forming a disulfide bond between two cysteine ​​residues in the sequence) or any side chain of an amino acid residue. Additional bonds forming a cyclic loop may include, but are not limited to, maleimide bonds, amide bonds, ester bonds, ether bonds, thiol ether bonds, hydrazone bonds, or acetamide bonds.

[0025] In some embodiments, peptides can be synthesized on a solid support (e.g., Rink amide resin) by solid phase peptide synthesis (SPPS). SPPS methods are known in the art and can be performed with orthogonal protecting groups. In some embodiments, peptides of the present disclosure can be synthesized by SPPS with Fmoc and / or Boc chemistry. The synthesized peptides can be cleaved from the solid support using standard techniques.

[0026] The peptides can be purified by chromatography (e.g., size-exclusion chromatography (SEC) and / or high performance liquid chromatography (HPLC)). HPLC can include reverse-phase HPLC (RP-HPLC). The peptides can be lyophilized after purification. The purified peptides can be obtained as pure peptides or as peptide salts. Residual salts constituting the peptide salts can include, but are not limited to, trifluoroacetic acid (TFA), acetate, and / or hydrochloride salts. In some embodiments, the peptides of the present disclosure are obtained as peptide salts. The peptide salts can be peptide salts with TFA. Residual salts can be removed from the purified peptides by known methods (e.g., by using a desalting column).

[0027] In some embodiments, the cyclic C5 inhibitor polypeptide of the present disclosure is formed using a lactam moiety. Such cyclic polypeptides can be formed, for example, by synthesis on solid support Wang resin using standard Fmoc chemistry. In some cases, Fmoc-ASP(allyl)-OH and Fmoc-LYS(alloc)-OH are incorporated into the polypeptide to serve as precursor monomers for lactam bridge formation.

[0028] The C5 inhibitor polypeptide of the present disclosure can be a peptidomimetic. A "peptidomimetic" or "polypeptide mimetic" is a polypeptide whose molecule contains structural elements not found in natural polypeptides (i.e., polypeptides composed only of the 20 proteinogenic amino acids). In some embodiments, peptidomimetics are capable of repeating or mimicking the biological action of natural peptides. Peptidomimetics can differ from natural polypeptides in many ways, for example, by changes in backbone structure or by the presence of non-naturally occurring amino acids. In some cases, peptidomimetics may include amino acids with side chains not found in the 20 known proteinogenic amino acids; non-polypeptide bridging moieties used to effect cyclization between terminal or internal portions of the molecule; replacement of amide bond hydrogen moieties with methyl groups (N-methylation) or other alkyl groups; replacement of peptide bonds with chemical groups or bonds that are resistant to chemical or enzymatic treatment; N- and C-terminal modifications; and / or conjugation with non-peptidic extensions, such as polyethylene glycol, lipids, carbohydrates, nucleosides, nucleotides, nucleoside bases, various small molecules, or phosphate or sulfate groups.

[0029] As used herein, the term "amino acid" includes residues of natural amino acids as well as non-natural amino acids. The 20 naturally occurring proteinogenic amino acids are identified and referred to herein by either their one-letter or three-letter code as follows: aspartic acid (Asp: D), isoleucine (Ile: I), threonine (Thr: T), leucine (Leu: L), serine (Ser: S), tyrosine (Tyr: Y), glutamic acid (Glu: E), phenylalanine (Phe: F), proline (Pro: P), histidine (His: H), glycine (Gly: G), lysine (Lys: K), alanine (Ala: A), arginine (Arg: R), cysteine ​​(Cys: C), tryptophan (Trp: W), valine (Val: V), glutamine (Gln: Q), methionine (Met: M), and asparagine (Asn: N). Naturally occurring amino acids exist in their levorotatory (L) stereoisomeric form. The amino acids referred to herein are L-stereoisomers unless otherwise specified. The term "amino acid" also includes amino acids having conventional amino protecting groups (e.g., acetyl or benzyloxycarbonyl), as well as natural and unnatural amino acids protected at the carboxy terminus (e.g., as (C1-C6) alkyl, phenyl, or benzyl esters, or amides; or as α-methylbenzyl amides). Other suitable amino and carboxy protecting groups are known to those of skill in the art (see, for example, Greene, TW; Wutz, PGM, Protecting Groups In Organic Synthesis; 2nd Edition, 1991, New York, John Wiley & sons, Inc., the contents of each of which are incorporated herein by reference in their entirety, and documents cited therein). The polypeptides and / or polypeptide compositions of the present disclosure may also include modified amino acids.

[0030] "Unnatural" amino acids have side chains or other features not present in the twenty naturally occurring amino acids listed above, and include, but are not limited to, N-methyl amino acids, N-alkyl amino acids, alpha, alpha substituted amino acids, beta-amino acids, alpha-hydroxy amino acids, D-amino acids, and other unnatural amino acids known in the art (see, for example, Josephson et al., (2005), J. Am. Chem. Soc., vol. 12, no. 12). 7:11727-11735; Forster, AC et al. (2003), Proc. Natl. Acad. Sci. USA 100:6353-6357; Subtelny et al. (2008), J. Am. Chem. Soc. 130:6131-6136; Hartman, MCT et al. (2007), PLoS ONE 2:e972; and Hartman et al. (2006), Proc. Natl. Acad. Sci. USA 103:4356-4361). Additional unnatural amino acids useful for optimizing the polypeptides and / or polypeptide compositions of the disclosure include 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1-amino-2,3-hydro-1H-indene-1-carboxylic acid, homolysine, homoarginine, homoserine, 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 5-aminopentanoic acid, 5-aminohexanoic acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, desmosine, 2,3-Diaminopropionic acid, N-ethylglycine, N-ethylasparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylpentylglycine, naphthylalanine, ornithine, pentylglycine, thioproline, norvaline, tert-butylglycine, phenylglycine, azatryptophan, 5-azatryptophan, 7-azatryptophan, 4-fluorophenylalanine, penicillamine, sarcosine, homocysteine, 1-aminocyclopropanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclohexanecarboxylic acid, 4-aminotetrahydro-2H-pyran-4-carboxylic acid, (S)-2-amino-3-(1H-tetrazol-5-yl) Propanoic acid, cyclopentylglycine, cyclohexylglycine, cyclopropylglycine, η-ω-methyl-arginine, 4-chlorophenylalanine, 3-chlorotyrosine, 3-fluorotyrosine, 5-fluorotryptophan, 5-chlorotryptophan, citrulline, 4-chloro-homophenylalanine, homophenylalanine, 4-aminomethyl-phenylalanine, 3-aminomethyl-phenylalanine, octylglycine, norleucine, tranexamic acid, 2-aminopentanoic acid, 2-aminohexanoic acid, 2-aminoheptanoic acid, 2-aminooctanoic acid, 2-aminononanoic acid, 2-aminodecanoic acid, 2-aminoundecanoic acid, 2-aminododecanoic acid, aminovaleric acid, and 2-(2-aminoethoxy)acetic acid, pipecolic acid, 2-carboxyazetidine, hexafluoroleucine, 3-fluorovaline, 2-amino-4,4-Difluoro-3-methylbutanoic acid, 3-fluoro-isoleucine, 4-fluoroisoleucine, 5-fluoroisoleucine, 4-methyl-phenylglycine, 4-ethyl-phenylglycine, 4-isopropyl-phenylglycine, (S)-2-amino-5-azidopentanoic acid (also referred to herein as "X02"), (S)-2-aminohept-6-enoic acid (also referred to herein as "X30"), (S)-2-aminopent-4-ynoic acid (also referred to herein as "X31"), (S)-2-aminopent-4-enoic acid (also referred to herein as "X12"), (S)-2-amino-5-(3-methylguanidino)pentanoic acid, (S)-2-amino-3-(4-(aminomethyl)phenyl)propanoic acid, (S)-2-amino-3-(3-(aminomethyl)phenyl)propanoic acid, (S)-2-amino-4-(2-aminobenzo[d]oxazol-5-yl)butanoic acid, (S)-leucinol, (S)-valinol, (S)-tert-butyl ether ... -Leucinol, (R)-3-methylbutan-2-amine, (S)-2-methyl-1-phenylpropan-1-amine, and (S)-N,2-dimethyl-1-(pyridin-2-yl)propan-1-amine, (S)-2-amino-3-(oxazol-2-yl)propanoic acid, (S)-2-amino-3-(oxazol-5-yl)propanoic acid, (S)-2-amino-3-(1,3,4-oxadiazol-2-yl)propanoic acid, (S)-2-amino-3-(1,2,4 -oxadiazol-3-yl)propanoic acid, (S)-2-amino-3-(5-fluoro-1H-indazol-3-yl)propanoic acid, and (S)-2-amino-3-(1H-indazol-3-yl)propanoic acid, (S)-2-amino-3-(oxazol-2-yl)butanoic acid, (S)-2-amino-3-(oxazol-5-yl)butanoic acid, (S)-2-amino-3-(1,3,4-oxadiazol-2-yl)butanoic acid, (S)-2-amino-3-(1,2,4-oxadiazol-3-yl)butanoic acid, (S)-2-amino-3-(5-fluoro-1H-indazol-3-yl)butanoic acid, and (S)-2-amino-3-(1H-indazol-3-yl)butanoic acid, 2-(2'MeOphenyl)-2-aminoacetic acid, tetrahydro-3-isoquinolinecarboxylic acid, and stereoisomers thereof, including but not limited to D and L isomers.

[0031] Additional unnatural amino acids useful in optimizing the polypeptides or polypeptide compositions of the present disclosure include, but are not limited to, fluorinated amino acids in which one or more carbon-bonded hydrogen atoms are replaced with fluorine. The number of fluorine atoms included can range from 1 to all (inclusive) of the hydrogen atoms. Examples of such amino acids include, but are not limited to, 3-fluoroproline, 3,3-difluoroproline, 4-fluoroproline, 4,4-difluoroproline, 3,4-difluroproline, 3,3,4,4-tetrafluoroproline, 4-fluorotryptophan, 5-flurotryptophan, 6-fluorotryptophan, 7-fluorotryptophan, and stereoisomers thereof.

[0032] Additional unnatural amino acids useful in optimizing the polypeptides of the present disclosure include, but are not limited to, those disubstituted at the α-carbon. These include amino acids in which the two substituents on the α-carbon are the same, such as α-aminoisobutyric acid and 2-amino-2-ethylbutanoic acid, and those in which the substituents are different, such as α-methylphenylglycine and α-methylproline. Additionally, the substituents on the α-carbon may form a ring together, such as 1-aminocyclopentanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclohexanecarboxylic acid, 3-aminotetrahydrofuran-3-carboxylic acid, 3-aminotetrahydropyran-3-carboxylic acid, 4-aminotetrahydropyran-4-carboxylic acid, 3-aminopyrrolidine-3-carboxylic acid, 3-aminopiperidine-3-carboxylic acid, 4-aminopiperidine-4-carboxylix acid, and stereoisomers thereof.

[0033] Additional unnatural amino acids useful in optimizing a polypeptide or polypeptide composition of the disclosure include, but are not limited to, analogs of tryptophan in which the indole ring system is replaced by another 9- or 10-membered bicyclic ring system having 0, 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S. Each ring system may be saturated, partially unsaturated, or fully unsaturated. The ring system may be substituted at any substitutable atom with 0, 1, 2, 3, or 4 substituents. Each substituent may be independently selected from H, F, Cl, Br, CN, COOR, CONRR', oxo, OR, NRR'. Each R and R' may be independently selected from H, C1-C20 alkyl, or C1-C20 alkyl-O-C1-20 alkyl.

[0034] In some embodiments, analogs of tryptophan (also referred to herein as "tryptophan analogs") may be useful in optimizing the polypeptides or polypeptide compositions of the present disclosure. Tryptophan analogs may include, but are not limited to, 5-fluorotryptophan [(5-F)W], 5-methyl-O-tryptophan [(5-MeO)W], 1-methyltryptophan [(1-Me-W) or (1-Me)W], D-tryptophan (D-Trp), azatryptophan (including, but not limited to, 4-azatryptophan, 7-azatryptophan, and 5-azatryptophan), 5-chlorotryptophan, 4-fluorotryptophan, 6-fluorotryptophan, 7-fluorotryptophan, and stereoisomers thereof. Unless indicated to the contrary, the term "azatryptophan" and its abbreviation "azaTrp" herein refer to 7-azatryptophan.

[0035] Modified amino acid residues useful for optimizing the polypeptides and / or polypeptide compositions of the present disclosure include, but are not limited to, those that are chemically blocked (reversibly or irreversibly); those that are chemically modified at their N-terminal amino group or at their side chain groups; those that are chemically modified in the amide backbone, such as N-methylated, D (unnatural amino acid) and L (natural amino acid) stereoisomers; or residues where a side chain functional group has been chemically modified to another functional group. In some embodiments, modified amino acids include, but are not limited to, methionine sulfoxide; methionine sulfone; aspartic acid-(beta-methyl ester), a modified amino acid of aspartic acid; N-ethylglycine, a modified amino acid of glycine; alanine carboxamide; and / or a modified amino acid of alanine. Unnatural amino acids can be purchased from Sigma-Aldrich (St. Louis, MO), Bachem (Torrance, CA), or other suppliers. Unnatural amino acids can further include any of those listed in Table 2 of US Patent Application Publication No. 2011 / 0172126, the contents of which are incorporated by reference herein in their entirety.

[0036] The present disclosure contemplates variants and derivatives of the polypeptides presented herein. These include substitutional, insertional, deletional, and covalent variants and derivatives. As used herein, the term "derivative" is used synonymously with the term "variant" and refers to a molecule that has been modified or changed in any way relative to a reference or starting molecule.

[0037] Polypeptides of the disclosure may include any of the following components, features, or moieties, the abbreviations of which used herein include: "Ac" and "NH2" indicate acetyl and amidated termini, respectively; "Nvl" stands for norvaline; "Phg" stands for phenylglycine; "Tbg" stands for tert-butylglycine; "Chg" stands for cyclohexylglycine; "(N-Me)X" stands for the N-methylated form of an amino acid designated by the one-letter or three-letter amino acid code in place of the variable "X" written as N-methyl-X [e.g., (N-Me)D or (N-Me)Asp represent the N-methylated form of aspartic acid, i.e., N-methyl-aspartic acid; "azaTrp" represents azatryptophan; "(4-F)Phe" represents 4-fluorophenylalanine; "Tyr(OMe)" represents O-methyltyrosine and "Aib" represents aminoisobutyric acid; "(homo)F" or "(homo)Phe" represents homophenylalanine; "(2-OMe)Phg" refers to 2-O-methylphenylglycine; "(5-F)W" refers to 5-fluorotryptophan; "DX" represents the amino acid sequence given. refers to the D-stereoisomer of the amino acid "X" in the formula (e.g., (D-Chg) stands for D-cyclohexylglycine); "(5-MeO)W" refers to 5-methyl-O-tryptophan; "HomoC" refers to homocysteine; "(1-Me-W)" or "(1-Me)W" refers to 1-methyltryptophan; "Nle" refers to norleucine; "Tiq" refers to a tetrahydroisoquinoline residue; "Asp(T)" refers to (S)-2-amino-3-(1H-tetrazol-5-yl)propanoic acid; "(3-Cl-Phe)" refers to 3-chlorophenylalanine. "[(N-Me-4-F)Phe]" or "(N-Me-4-F)Phe" refers to N-methyl-4-fluorophenylalanine; "(m-Cl-homo)Phe" refers to meta-chlorohomophenylalanine; "(des-amino)C" refers to 3-thiopropionic acid; "(alpha-methyl)D" refers to alpha-methyl L-aspartic acid; "2Nal" refers to 2-naphthylalanine; "(3-aminomethyl)Phe" refers to 3-aminomethyl-L-phenyalanine; "Cle" refers to cycloleucine;"Ac-pyran" refers to 4-amino-tetrahydro-pyran-4-carboxylic acid; "(Lys-C16)" refers to N-ε-palmitoyl lysine; "(Lys-C12)" refers to N-ε-lauryl lysine; "(Lys-C10)" refers to N-ε-caprylysine; "(Lys-C8)" refers to N-ε-caprylic lysine; "[xylyl(y,z)]" refers to a xylyl bridge moiety between two thiol-containing amino acids, where x can be m, p, or o to indicate the use of meta-, para-, or ortho-dibromoxylene (respectively) to generate the bridge moiety, and the numerical identifiers y and z position the amino acid positions within the polypeptide of the amino acids participating in the cyclization; "[cyclo(y "[cyclo-olefinyl(y,z)]" refers to the formation of a bond between two amino acid residues, where the numerical identifiers y and z position the positions of the residues participating in the bond; "[cyclo-thioalkyl(y,z)]" refers to the formation of a thioether bond between two amino acid residues, where the numerical identifiers y and z position the positions of the residues participating in the bond; "[cyclo-triazolyl(y,z)]" refers to the formation of a triazole ring between two amino acid residues, where the numerical identifiers y and z position the positions of the residues participating in the bond. "B20" refers to N-ε-(PEG2-γ-glutamic acid-N-α-octadecanedioic acid) lysine [also known as (1S,28S)-1-amino-7,16,25,30-tetraoxo-9,12,18,21-tetraoxa-6,15,24,29-tetraazahexatetracontane-1,28,46-tricarboxylic acid];

[0038] B20

[0039] [ka]

[0040] "B28" refers to N-ε-(PEG24-γ-glutamic acid-N-α-hexadecanoyl)lysine. B28

[0041] [ka]

[0042] "K14" refers to N-ε-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl-L-lysine. All other symbols refer to the standard one-letter amino acid codes.

[0043] Some C5 inhibitor polypeptides include from about 5 amino acids to about 10 amino acids, from about 6 amino acids to about 12 amino acids, from about 7 amino acids to about 14 amino acids, from about 8 amino acids to about 16 amino acids, from about 10 amino acids to about 18 amino acids, from about 12 amino acids to about 24 amino acids, or from about 15 amino acids to about 30 amino acids. In some cases, the C5 inhibitor polypeptide includes at least 10 amino acids. In some cases, the C5 inhibitor polypeptide includes at least 30 amino acids. The C5 inhibitor polypeptide can include 14, 15, or 16 amino acids (e.g., 15 amino acids).

[0044] Some C5 inhibitors of the present disclosure include a C-terminal lipid moiety. Such lipid moieties can include fatty acyl groups (e.g., saturated or unsaturated fatty acyl groups). In some cases, the fatty acyl group can be a palmitoyl group.

[0045] C5 inhibitors having fatty acyl groups may include one or more molecular linkers linking the fatty acid to the peptide. Such molecular linkers may include amino acid residues. In some cases, L-gamma glutamic acid residues may be used as molecular linkers. In some cases, the molecular linker may include one or more polyethylene glycol (PEG) linkers. The PEG linkers of the present disclosure may include about 1 to about 5, about 2 to about 10, about 4 to about 20, about 6 to about 24, about 8 to about 32, or at least 32 PEG units.

[0046] The C5 inhibitors disclosed herein can have a molecular weight of about 200 g / mol to about 600 g / mol, about 500 g / mol to about 2000 g / mol, about 1000 g / mol to about 5000 g / mol, about 3000 g / mol to about 4000 g / mol, about 2500 g / mol to about 7500 g / mol, about 5000 g / mol to about 10000 g / mol, or at least 10000 g / mol.

[0047] In some embodiments, the C5 inhibitor polypeptide of the present disclosure comprises Zilcoplan. The core amino acid sequence of Zilcoplan ([cyclo(1,6)]Ac-KVERFD-(N-Me)D-Tbg-Y-azaTrp-EYP-Chg-K; SEQ ID NO: 1) comprises 15 amino acids (all L-amino acids) including four unnatural amino acids [N-methyl-aspartic acid or "(N-Me)D", tert-butylglycine or "Tbg", 7-azatryptophan or "azaTrp", and cyclohexylglycine or "Chg"]; a lactam bridge between K1 and D6 of the polypeptide sequence; and a C-terminal lysine residue with a modified side chain forming the N-ε-(PEG24-γ-glutamic acid-N-α-hexadecanoyl)lysine residue (also referred to herein as "B28"). The C-terminal lysine side chain modification contains a polyethylene glycol (PEG) spacer (PEG24) attached to an L-gamma glutamic acid residue derivatized with a palmitoyl group.

[0048] The free acid form of Zilcoplan is C 172 H 278 N 24 O 55 It has a molecular formula of 3,562.23 Daltons (Da), and an exact mass of 3,559.97 amu (see CAS number 1841136-73-9). The tetrasodium form of Zircoplan is C 172 H 278 N 24 O 55 Na 4 The chemical structure of Zilcoplan in its sodium salt form is shown in Structure I:

[0049] [ka]

[0050] Although the four sodium ions in the structure are shown associated with the designated carboxylates, they may be associated with any of the acidic groups in the molecule. Zilcoplan drug substance is typically provided as the sodium salt form and is lyophilized. The free base form of zilcoplan or any pharma- ceutically acceptable salt of zilcoplan is encompassed by the term "zilcoplan."

[0051] In some embodiments, the C5 inhibitors of the present disclosure include variants of zircoplan. In this specification, reference to zircoplan includes its active metabolites or variants, i.e., active metabolites or variants with C5 inhibitory activity. In some zircoplan variants, the C-terminal lysine side chain moiety may be altered. In some cases, the PEG24 spacer (having 24 PEG subunits) of the C-terminal lysine side chain moiety may contain fewer or additional PEG subunits. In other cases, the palmitoyl group of the C-terminal lysine side chain moiety may be replaced by another saturated or unsaturated fatty acid. In further cases, the L-gamma glutamic acid linker (between the PEG and acyl group) of the C-terminal lysine side chain moiety may be replaced by an alternative amino acid or non-amino acid linker.

[0052] In some embodiments, the C5 inhibitor may include an active metabolite or variant of zilcoplan. The metabolite may include ω-hydroxylation of the palmitoyl tail. Such variants may be synthesized or formed by hydroxylation of the zilcoplan precursor.

[0053] In some embodiments, zircoplan variants may include modifications to the core polypeptide sequence of zircoplan that may be used in combination with one or more of the cyclic or C-terminal lysine side chain moieties features of zircoplan. Such variants may have at least 50%, at least 55%, at least 65%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to the core polypeptide sequence of (SEQ ID NO:1).

[0054] In some cases, zircoplan variants can be cyclized by forming lactam bridges between amino acids other than those used in zircoplan. In some embodiments, C5 inhibitors of the present disclosure may include any of those listed in Table 1 of U.S. Patent Application Publication No. 2017 / 0137468, the contents of which are incorporated by reference in their entirety herein.

[0055] The C5 inhibitors of the present disclosure can be developed or modified to achieve specific binding properties. Inhibitor binding can be evaluated by determining the association rate and / or dissociation rate with a specific target. In some cases, the compound shows strong and rapid association with the target, combined with a slow dissociation rate. In some embodiments, the C5 inhibitors of the present disclosure show strong and rapid association with C5. Such inhibitors can further show a slow dissociation rate with C5.

[0056] The C5 protein-binding C5 inhibitors disclosed herein bind to the C5 complement protein at about 0.001 nM to about 0.01 nM, about 0.005 nM to about 0.05 nM, about 0.01 nM to about 0.1 nM, about 0.05 nM to about 0.5 nM, about 0.1 nM to about 1.0 nM, about 0.5 nM to about 5.0 nM, about 2 nM to about 10 nM, about an equilibrium dissociation constant (KD ) can be used to bind the

[0057] In some embodiments, the C5 inhibitors of the present disclosure block the formation or generation of C5a from C5. In some cases, the formation or generation of C5a is blocked following activation of the alternative pathway of complement activation. In some cases, the C5 inhibitors of the present disclosure block the formation of the membrane attack complex (MAC). Such inhibition of MAC formation is due to the C5 inhibitor binding to the C5b subunit. C5 inhibitors that bind to the C5b subunit can prevent C6 binding, resulting in blocking of MAC formation. In some embodiments, this inhibition of MAC formation occurs following activation of the classical pathway, the alternative pathway, or the lectin pathway.

[0058] The C5 inhibitor of the present disclosure can be synthesized using chemical processes.In some cases, such synthesis eliminates the risks associated with the manufacture of biological products in mammalian cell systems.In some cases, chemical synthesis can be simpler and more cost-effective than biological manufacturing processes.

[0059] In some embodiments, the C5 inhibitor (e.g., zilucoplan and / or its active metabolites or variants) composition may be a pharmaceutical composition comprising at least one pharma- ceutically acceptable excipient. In some embodiments, the pharma-ceutically acceptable excipient may comprise at least one of a salt and a buffering agent. The salt may be sodium chloride. The buffering agent may be sodium phosphate. The sodium chloride may be present at a concentration of about 0.1 mM to about 1000 mM. In some cases, the sodium chloride may be present at a concentration of about 25 mM to about 100 mM. The sodium phosphate may be present at a concentration of about 0.1 mM to about 1000 mM. In some cases, the sodium phosphate is present at a concentration of about 10 mM to about 100 mM.

[0060] In some embodiments, the C5 inhibitor (e.g., zilucoplan and / or its active metabolites or variants) composition may contain from about 0.01 mg / mL to about 4000 mg / mL of the C5 inhibitor. In some cases, the C5 inhibitor is present at a concentration of from about 1 mg / mL to about 400 mg / mL.

[0061] Polypeptide-based C5 inhibitors (e.g., Zilcoplan and / or its active metabolites or variants) may be used to treat indications that benefit from rapid and / or increased inhibitor tissue distribution. The tissue may include muscle and / or neuromuscular junction (NMJ). Polypeptide inhibitors (e.g., Zilcoplan) may provide superior penetration into muscle and / or NMJ compared to antibodies based on their smaller size and / or favorable charge profile. Such penetration may result in faster release from overly active complement. Furthermore, polypeptide inhibitor (e.g., Zilcoplan) penetration may stabilize and / or improve NMJ membrane potential by preventing MAC pore formation. Thus, the safety factor at the NMJ may be improved. The term "safety factor" refers to the excess transmitter level released after a nerve impulse that ensures neuromuscular transmission efficacy under physiological stress. The excess is an amount beyond that required to trigger a muscle fiber action potential, which contributes to membrane potential recovery.

[0062] Isotope Variants The compounds of the present disclosure may contain one or more atoms that are isotopes. As used herein, the term "isotope" refers to a chemical element that has one or more additional neutrons. In some embodiments, the compounds of the present disclosure may be deuterated. As used herein, the term "deuterated" refers to a substance in which one or more hydrogen atoms have been replaced with a deuterium isotope. A deuterium isotope is an isotope of hydrogen. A hydrogen nucleus contains one proton, whereas a deuterium nucleus contains both a proton and a neutron. The compounds and compositions of the present disclosure may be deuterated to alter physical properties such as stability, or to allow for use in diagnostic and experimental applications.

[0063] II. Method In some embodiments, the disclosure provides methods related to using and evaluating compounds and compositions for the therapeutic treatment of neurological disorders such as MG. Some methods include modulating complement activity using the compounds and / or compositions described herein.

[0064] Treatment indications In some embodiments, the disclosure provides methods of treating a therapeutic indication using the compounds and compositions described herein. A "therapeutic indication" herein refers to any disease, disorder, condition, or symptom that can be alleviated, cured, ameliorated, reversed, stabilized, or otherwise addressed by one or more forms of therapeutic intervention (e.g., administration of a therapeutic agent or a specific treatment method).

[0065] The therapeutic indication may include a complement-related indication. As used herein, the term "complement-related indication" refers to any disease, disorder, condition, or symptom associated with the complement system, e.g., the cleavage or processing of a complement component, such as C5. In some embodiments, the methods of the disclosure include treating a complement-related indication with the compounds and compositions provided herein.

[0066] In some embodiments, the disclosed methods include treating complement-related indications by inhibiting complement activity in a subject using the compounds and compositions provided herein. In some cases, the percentage of complement activity inhibited in a subject can be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%. In some cases, this level of inhibition and / or maximum inhibition of complement activity can be achieved from about 1 hour to about 3 hours after administration, from about 2 hours to about 4 hours after administration, from about 3 hours to about 10 hours after administration, from about 5 hours to about 20 hours after administration, or from about 12 hours to about 24 hours after administration. The inhibition of complement activity may last for a period of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks. In some cases, this level of inhibition may be achieved by daily administration. Such daily administration may include administration for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 4 months, at least 6 months, at least 1 year, or at least 5 years. In some cases, a subject may be administered a compound or composition of the present disclosure for the lifetime of such subject.

[0067] In some embodiments, the present disclosure provides a method of treating a complement-related indication by inhibiting C5 activity in a subject. "C5-dependent complement activity" or "C5 activity" herein refers to activation of the complement cascade by cleavage of C5, assembly of downstream cleavage products of C5, or any other process or event associated with or resulting from cleavage of C5. In some cases, the percentage of C5 activity inhibited in a subject can be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%.

[0068] C5 inhibitors can be used to treat one or more complement-related indications with little or no adverse effects resulting from the treatment. In some cases, no adverse cardiovascular, respiratory, and / or central nervous system (CNS) effects occur. In some cases, no changes in heart rate and / or arterial pressure occur. In some cases, no changes in respiratory rate, tidal volume, and / or minute ventilation occur.

[0069] "Lowering" or "reducing" in the context of a disease marker or symptom means a significant, often statistically significant, decrease in such levels, which can be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, preferably to levels recognized as within the normal range for individuals without such disorder.

[0070] "Increase" or "elevate" in the context of a disease marker or symptom means a significant, often statistically significant, increase in such level, which can be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, to a level recognized as within the normal range for individuals without such disorder.

[0071] Therapeutic or prophylactic effects are evident when there is a marked, often statistically significant, improvement in one or more parameters of the disease state, or by failure to aggravate or develop symptoms that would otherwise be expected. As an example, at least a 10% favorable change in a measurable parameter of the disease, and at least 20%, 30%, 40%, 50% or more, may indicate effective treatment. The efficacy of a given compound or composition may also be determined using an experimental animal model of a given disease, as known in the art. When using an experimental animal model, the efficacy of the treatment is demonstrated when a statistically significant modulation of a marker or symptom is observed.

[0072] The compounds of the present disclosure can be administered in combination with additional therapeutic agents. Such combinations can be in the same composition, or the additional therapeutic agents can be administered as part of a separate composition, or by other methods described herein.

[0073] In some embodiments, the present disclosure provides a method of inhibiting C5 activity in a tissue by contacting the tissue with a tissue-permeable C5 inhibitor. As used herein, the term "tissue permeability" refers to a property characterized by tissue permeability. An agent with increased tissue penetration may exhibit better distribution in tissues compared to an agent with low or no tissue penetration. Tissue penetration may be assessed by the ability to cross a basement membrane. As used herein, the term "basement membrane" refers to the extracellular matrix (ECM) protein layer that separates endothelial cells from the underlying tissue. Tissue penetration assessment may be performed in vivo or in vitro and may include the use of a basement membrane model. Such a model may include measuring the diffusion of a compound through an artificial basement membrane. Such a model may include the use of upper and lower reservoirs separated by an artificial basement membrane. The artificial basement membrane may include any of the ECM gel membranes described in Arends, F et al., 2016, IntechOpen, Digital Object Identifier: 10.5772 / 62519, the contents of which are incorporated herein by reference in their entirety. ECM gel membranes can be prepared to contain matrix components that mimic those found in the basal lamina of neuromuscular junctions. In some models, the compound being tested is introduced into the upper reservoir and compound diffusion is detected in the lower reservoir.

[0074] Tissue penetration assessments may include visual assessments, for example, by using fluorescent labels to visualize the movement of analytes across the basement membrane. Some assessments may include biochemical analysis of samples obtained from the permeabilized side of the basement membrane.

[0075] In some embodiments, compound permeability can be measured using quantitative whole body analysis (QWBA). QWBA is a form of analysis that uses radiography to assess the distribution of a radiolabeled analyte. In some embodiments, a radiolabeled compound is administered to a subject and the tissue distribution of the compound is analyzed over time.

[0076] The tissue-penetrating C5 inhibitor may be a polypeptide. The tissue-penetrating C5 inhibitor may include zilucoplan. Contacting the tissue with the tissue-penetrating C5 inhibitor may include administering the tissue-penetrating C5 inhibitor to the tissue as part of a formulation. Such a formulation may be administered by subcutaneous injection. The tissue-penetrating C5 inhibitor may be capable of penetrating the basement membrane. The basement membrane permeability of the polypeptide tissue-penetrating C5 inhibitor may be greater than that of larger proteins such as antibodies. Such an advantage may be due to the limiting large size of the proteins and antibodies. Zilucoplan basement membrane permeability may be about 3-fold to about 5-fold that of eculizumab, providing an advantage over eculizumab for inhibiting C5 activity in tissues and treating related complement-related indications. In some embodiments, zilucoplan permeability increases distribution in one or more of the lung, heart, muscle, small intestine, large intestine, spleen, liver, bone, stomach, lymph nodes, fat, brain, pancreas, testes, and thymus compared to eculizumab.

[0077] Polypeptide-based C5 inhibitors (e.g., Zilcoplan and / or its active metabolites or variants) can be used to treat complement-related indications (e.g., myasthenia gravis) that benefit from rapid and / or increased inhibitor tissue distribution. The tissues can include muscle and / or neuromuscular junctions (NMJs). Polypeptide inhibitors (e.g., Zilcoplan) can provide superior penetration into muscle and / or NMJs compared to antibodies based on their smaller size and / or favorable charge profile. Such penetration can result in faster release from overly active complement. Furthermore, polypeptide inhibitor (e.g., Zilcoplan) penetration can stabilize and / or improve NMJ membrane potential by preventing MAC pore formation. Thus, the safety factor at the NMJ can be improved. The term "safety factor" refers to the excess transmitter levels released after a nerve impulse that ensures neuromuscular transmission efficacy under physiological stress. The excess is an amount beyond that required to trigger a muscle fiber action potential, contributing to membrane potential recovery.

[0078] In some embodiments, the present disclosure provides a method of treating a subject's complement-related indication by administering zircoplan in combination with other therapeutic agents. Cyclosporine A is a known immunosuppressant, an inhibitor of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3, and is a potential comedication in PNH and other complement-related indications. In some embodiments, cyclosporine A and zircoplan can be administered in combination to a subject with a complement-related indication (e.g., myasthenia gravis). Cyclosporine A and zircoplan can be administered in an overlapping dosing regimen. Other immunosuppressants that can be administered in combination with zircoplan or in an overlapping dosing regimen can include, but are not limited to, azathioprine, cyclosporine, mycophenolate mofetil, methotrexate, tacrolimus, cyclophosphamide, and rituximab.

[0079] In some embodiments, the present disclosure provides a method of treating a complement-related indication in a subject by administering zilucoplan in combination with fetal Fc receptor (FcRN) inhibitor therapy. FcRN inhibitor therapy can be used to treat autoimmune diseases, including autoantibody-mediated tissue destruction. FcRN inhibitor therapy can include intravenous immunoglobulin (IVIG) therapy, which reduces the half-life of IgG antibodies by overwhelming the Fc recycling mechanism with high doses of immunoglobulin. Some FcRN inhibitor therapy can include administration of DX-2504 or a functionally equivalent variant thereof, such as DX-2507 (Nixon, AE et al., 2015, Front Immunol. 6:176), which includes modifications that reduce aggregation and improve manufacturability. DX-2504 is an inhibitor of FcRN recycling. By inhibiting FcRN, DX-2504 inhibits Fc-mediated recycling, thereby decreasing the half-life of IgG antibodies. Administration of DX-2504 can also be used in models of IVIG therapy. In some embodiments, zilucoplan can be administered to treat complement-related indications (e.g., myasthenia gravis) in an overlapping dosing regimen with FcRN inhibitor therapy. FcRN inhibitor therapy can include DX-2504 (or DX-2507) administration and / or IVIG therapy.

[0080] Neurological Indications In some embodiments, the compounds and compositions disclosed herein may be used to treat complement-related indications that are neurological indications. As used herein, "neurological indications" refers to any disease, disorder, condition, or symptom associated with the nervous system. In some embodiments, complement-related neurological indications include myasthenia gravis.

[0081] Autoimmune Indications In some embodiments, the compounds and compositions disclosed herein may be used to treat complement-related indications that are autoimmune indications. As used herein, the term "autoimmune indication" refers to any disease, disorder, condition, or symptom associated with self-destructive immune activity. The ability of the immune system to distinguish between self and non-self cells is a critical feature of the system. Pathologies occur when the immune system is unable to make this distinction. The immune system can be divided into the innate and adaptive systems, which refer to non-specific immediate defense mechanisms and more complex antigen-specific systems, respectively. The complement system is part of the innate immune system, which recognizes and eliminates pathogens. Additionally, complement proteins can regulate adaptive immunity, connecting innate and adaptive responses. Autoimmune diseases may involve specific tissues or organs of the body.

[0082] In the case of the complement system, vertebrate cells express inhibitory proteins that protect them from the effects of the complement cascade, ensuring that the complement system is targeted to foreign pathogens. Many complement-related indications are associated with the abnormal destruction of self-cells by the complement cascade.

[0083] In some embodiments, the complement-associated autoimmune indication comprises myasthenia gravis. myasthenia gravis In some embodiments, the compounds and compositions disclosed herein may be used to treat complement-related indications, including myasthenia gravis. Myasthenia gravis (MG) is a rare complement-mediated autoimmune disease characterized by the production of autoantibodies that target proteins, such as acetylcholine receptor (AChR) proteins, that are important for the normal transmission of chemical or neurotransmitter signals from nerves to muscles. The presence of AChR autoantibodies in patient samples may be used as an indicator of the disease. As used herein, the term "MG" encompasses all forms of MG. Approximately 15% of patients have symptoms limited to the ocular muscles, but the majority of patients experience generalized myasthenia gravis. As used herein, the term "generalized myasthenia gravis" or "gMG" refers to MG that affects multiple muscle groups throughout the body. The prognosis for MG is generally benign, but 10%-15% of patients have refractory MG. As used herein, the term "refractory MG" or "rMG" refers to MG where disease control cannot be achieved with current therapies or results in severe side effects of immunosuppressive therapy. This severe form of MG affects approximately 9,000 individuals in the United States.

[0084] Patients with MG characteristically present with muscle weakness that becomes more severe with repetitive use and resolves with rest. Weakness may be localized to specific muscles, such as those responsible for eye movement, but often progresses to more diffuse weakness. MG can even become life-threatening when the weakness involves the diaphragm and other chest wall muscles responsible for breathing. This is the most feared complication of MG, known as myasthenic crisis or MG crisis, and requires hospitalization, intubation, and mechanical ventilation. Approximately 15% to 20% of patients with gMG experience a myasthenic crisis within 2 years of diagnosis.

[0085] The most common target of autoantibodies in MG is the acetylcholine receptor, or AChR, located at the neuromuscular junction, where motor neurons transmit signals to skeletal muscle fibers. Current therapies for gMG focus on either increasing AChR signaling or nonspecifically suppressing the autoimmune response. The first-line therapy for symptomatic gMG is treatment with acetylcholinesterase inhibitors, such as pyridostigmine, which is the only approved therapy for MG. Although sometimes sufficient to control mild ocular symptoms, pyridostigmine monotherapy is usually insufficient to treat the systemic weakness, and dosing of this therapy may be limited by cholinergic side effects. Thus, in patients who remain symptomatic despite pyridostigmine therapy, corticosteroids with or without systemic immunosuppressants are indicated (Sanders DB et al., 2016, Neurology 87(4):419-25). Immunosuppressants used in gMG include azathioprine, cyclosporine, mycophenolate mofetil, methotrexate, tacrolimus, cyclophosphamide, and rituximab. To date, efficacy data for these agents are sparse, and neither steroid therapy nor immunosuppressive therapy has been approved for the treatment of gMG at all. Furthermore, all of these agents are associated with well-documented long-term toxicity. Surgical removal of the thymus may be recommended for patients with nonthymomatous gMG and moderate to severe symptoms in an attempt to reduce the production of AChR autoantibodies (Wolfe GI et al. 2016 N Engl J Med 375(6):511-22). Intravenous (IV) immunoglobulin and plasma exchange (PLEX) is usually limited to short-term use in patients with myasthenic crisis or life-threatening signs such as respiratory failure or dysphagia (Sanders et al., 2016).

[0086] There is considerable evidence supporting the role of the terminal complement cascade in the pathogenesis of AChR autoantibody-positive gMG. Results from animal models of experimental autoimmune MG demonstrated that autoantibody immune complex formation at the neuromuscular junction triggers activation of the classical complement pathway, leading to local activation of C3 and deposition of the membrane attack complex (MAC) at the neuromuscular junction, resulting in impaired signaling and ultimately muscle weakness (Kusner LL et al., 2012, Ann NY Acad Sci 1274(1):127-32).

[0087] Furthermore, inhibition of C5 has been established as a target for the treatment of refractory gMG based on clinical trials using the C5-blocking antibody, eculizumab, which has been approved for use in MG and two other complement-driven rare diseases, paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). In a phase 2 randomized, double-blind, placebo-controlled study, eculizumab was tested in 14 AChR autoantibody-positive patients with refractory gMG who had a quantitative myasthenia gravis (QMG) score of 12 or greater and had previously failed at least two immunosuppressant therapies (ISTs) (Howard, JF, 2013, Myasthenia Gravis Foundation of America Clinical Overview of MG, the contents of which are incorporated herein by reference in their entirety). Patients were randomized in a 1:1 ratio to receive eculizumab or placebo. Patients receiving eculizumab received 600 mg per week for 4 weeks followed by 900 mg by IV infusion every other week for a total of 16 weeks of treatment. After a 5-week washout period, patients were crossed over to the opposite arm of the study. Patients receiving placebo for the first 16 weeks of the study were treated with eculizumab and vice versa. The primary endpoints were safety and efficacy as measured by the percentage of patients who achieved a 3-point or greater reduction in QMG score. The effect of C5 inhibition by eculizumab on QMG score occurred rapidly (within 1 week of treatment initiation) and favored eculizumab compared to placebo across all study visits (p=0.0144). After the first 16-week treatment period, 6 of 7 patients receiving eculizumab achieved a 3-point or greater improvement in QMG score compared to 4 of 7 patients in the placebo arm. Four of the patients who responded to eculizumab achieved an 8-point reduction in QMG score, compared with only one in the placebo arm.

[0088] The QMG is a standardized, validated, quantitative strength scoring system developed specifically for MG and previously used in clinical trials. The scoring system assesses 13 items related to ocular, bulbar, and limb function (Barnet, C et al., 2015, J Neuromuscul Dis, vol. 2:301-11). Each item is scored from 0 to 3. The maximum total score is 39. Higher scores represent more severe impairment. Recent data suggest that an improvement in QMG score of 2-3 points may be considered clinically meaningful depending on disease severity [Barohn RJ et al. 1998 Ann NY Acad Sci 841:769-772; Katzberg HD et al. 2014 Muscle Nerve 49(5):661-665].

[0089] A phase 3 trial (NCT01997229) has also been completed that enrolled 125 AChR autoantibody-positive patients with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or greater who had previously failed two ISTs or had failed one IST and required chronic plasma exchange or IV immunoglobulin therapy. The MG-ADL is a brief 8-item survey designed to assess MG symptom severity. Each item is scored from 0 to 3. The maximum total score is 24. Higher scores are associated with more severe symptoms of MG. The MG-ADL has been shown to correlate with other validated MG outcome measures (e.g., MG-QOL15r), and a 2-point improvement in the MG-ADL score is considered clinically meaningful (Wolfe GI et al., 1999, Neurology 52(7):1487-9; Muppidi S et al., 2011, Muscle Nerve 44(5):727-31). The MG-QOL15r is a 15-item survey designed to assess the quality of life of patients with MG based on patient report. Each item is scored from 0 to 2. The maximum total score is 30. Higher scores indicate a more severe impact of the disease on aspects of the patient's life [Burns, TM et al., 2010, Muscle Nerve 41(2):219-26; Burns TM et al., 2016, Muscle Nerve 54(6):1015-22].

[0090] Patients were randomized 1:1 to receive either placebo or eculizumab for a 26-week treatment period, followed by an extension study. Patients receiving eculizumab were treated with 900 mg per week for 4 weeks, followed by 1200 mg every other week by IV infusion. Eculizumab treatment was not associated with a statistically significant benefit versus placebo in this study in the change from baseline of the primary endpoint in MG-ADL (p=0.0698). However, statistically significant results were observed in 18 of 22 prespecified analyses, including the change from baseline of the secondary endpoint in QMG score (p=0.0129). Taken together, the results of these two clinical trials establish that inhibition of the terminal complement cascade by blocking cleavage of C5 is a clinically validated target for the treatment of gMG. Despite failure to meet the primary endpoint in a phase 3 trial, eculizumab was approved in 2017 based on the totality of data in the United States, European Union, and Japan for the treatment of adult MG patients with AChR autoantibodies.

[0091] Binding of anti-AChR autoantibodies to muscle endplates results in activation of the classical complement cascade and deposition of MAC on postsynaptic muscle fibers, leading to localized damage of the muscle membrane and reduced responsiveness of the muscle to stimulation by neuronal cells. Inhibition of terminal complement activity can be used to block complement-mediated damage resulting from MG (e.g., gMG and / or rMG). In some embodiments, C5 inhibitors disclosed herein can be used to treat MG. Such inhibitors can include zilucoplan. Inhibition of C5 cleavage can prevent downstream assembly and activity of MAC, for example, at the post-junctional membranes of the patient's neuromuscular junction, reducing or preventing neuromuscular problems associated with MG (e.g., gMG and / or rMG). Unlike eculizumab, zilucoplan binds to the C5b portion of C5 and inhibits cleavage into C5a and C5b subunits. Zilucoplan also binds free C5b, preventing binding to C6 and subsequent MAC assembly. Thus, zircoplan inhibits MAC assembly by two distinct mechanisms (see Figure 1). Furthermore, zircoplan specifically binds C5 and displays a strong and rapid association with C5 coupled with a slow dissociation rate.

[0092] screening Subjects to be treated with zilucoplan may be screened prior to administration of zilucoplan. As used herein, the term "screen" refers to a test or evaluation performed for the purpose of selection or filtration. Subjects may be screened to select individuals in need of treatment. In some embodiments, subjects are screened to select individuals most likely to respond favorably to treatment. In some embodiments, screening is performed to exclude individuals with higher risks associated with treatment. Screening may include calculating a QMG score. As previously mentioned, QMG is a standardized, validated, quantitative intensity scoring system developed specifically for MG and previously used in clinical trials. Higher scores represent more severe impairment. Recent data suggests that an improvement in QMG score of 2-3 points may be considered clinically meaningful depending on disease severity [Barohn RJ et al., 1998, Ann NY Acad Sci 841:769-772; Katzberg HD et al., 2014, Muscle Nerve 49(5):661-665, the contents of which are incorporated herein by reference in their entirety]. In some embodiments, subjects are screened to select subjects having a QMG score of 12 or greater. In some embodiments, subjects selected have a QMG score that achieves a score of 2 or greater on 4 or more QMG test items.

[0093] Subjects who receive MG therapy prior to or during screening may remain on such therapy during the screening process or may be asked to withhold one or more therapies prior to or during the screening process. In some embodiments, a period between previous MG therapy and screening assessment is required. The period may be required to obtain reliable results from certain screening assessments. In some embodiments, subjects whose QMG score is being calculated may be removed from MG therapy for at least 10 hours prior to QMG score calculation. Subjects whose QMG score is being calculated may be removed from acetylcholinesterase inhibitor therapy (e.g., pyridostigmine therapy) for at least 10 hours prior to QMG score calculation.

[0094] Screening may include selecting subjects based on age, in some embodiments, screening may be performed to select subjects between the ages of 18 and 85 years.

[0095] Screening may include selecting subjects who have previously been diagnosed with gMG. gMG diagnosis may be made according to the Myasthenia Gravis Foundation of America (MGFA) criteria; Class II-IVa (see Howard, JF, 2009, Myasthenia Gravis A Manual for the Health Care Provider, Myasthenia Gravis Foundation of America, Inc.).

[0096] Screening may include assessing biomarker levels. In some embodiments, the biomarkers include acetylcholine receptor (AChR) autoantibody levels. AChR autoantibodies may bind to AChR and stimulate complement activation, resulting in disease. Thus, AChR autoantibody levels may be a good indicator of complement-mediated disease. In some embodiments, the biomarkers include autoantibodies against muscle-specific tyrosine kinase (MuSK). Subjects with anti-MuSK antibodies are part of a distinct MG subset that is associated with poorly predictable treatment outcomes (Lavrnic, D. et al., 2005, J Neurol Neurosurg Psychiatry 76:1099-102). Screening may include excluding subjects with anti-MuSK antibodies from treatment and / or evaluation.

[0097] Screening may include examination of the subject's previous and current treatments. In some embodiments, subjects are screened based on recent changes in treatment. In some embodiments, subjects are screened to ensure there are no changes in corticosteroid dosage or immunosuppressive therapy prior to screening. Screening may exclude subjects from treatment if the subject's corticosteroid treatment dosage or immunosuppressive therapy regimen changes within the 30 days prior to screening.

[0098] Subjects may be screened for pregnancy status. In some embodiments, pregnant subjects may be excluded from treatment. Pregnancy status screening may be performed by serum pregnancy testing. In some embodiments, pregnancy screening may include a urine pregnancy test.

[0099] In some embodiments, screening can be performed to identify subjects with stages of MG that occur before reaching a critical or critical stage. Such screening can be performed to identify subjects prior to developing MG or early in the disease course who may benefit from aggressive or preventative treatment.

[0100] Zilcoplan treatment Zilcoplan dose-dependently inhibits C5a formation upon activation of the classical pathway and inhibits C5b formation upon activation of both the classical and alternative complement pathways (as measured by deposition of C5b-9 or MAC on complement-activating surfaces) (U.S. Pat. No. 9,937,222).

[0101] In some embodiments, the methods of the disclosure include methods of treating MG by administering zilcoplan to a subject. MG treatment can include gMG. Zilcoplan administration can be subcutaneous (SC). Zilcoplan can be administered at doses ranging from about 0.01 mg / kg (mg zilcoplan / kg subject body weight) to about 1.0 mg / kg, about 0.02 mg / kg to about 2.0 mg / kg, about 0.05 mg / kg to about 3.0 mg / kg, about 0.10 mg / kg to about 4.0 mg / kg, about 0.15 mg / kg to about 4.5 mg / kg, about 0.20 mg / kg to about 5.0 mg / kg, about 0.30 mg / kg to about 7.5 mg / kg, about 0.40 mg / kg to about 10 mg / kg, about 0.50 mg / kg to about 12.5 mg / kg, about 0.1 mg / kg to about 0.6 mg / kg, about 1.0 mg / kg to about 15 mg / kg, or about 2.0 mg / kg to about 2.5 mg / kg. g / kg, about 2.0 mg / kg to about 20 mg / kg, about 5.0 mg / kg to about 25 mg / kg, about 10 mg / kg to about 45 mg / kg, about 20 mg / kg to about 55 mg / kg, about 30 mg / kg to about 65 mg / kg, about 40 mg / kg to about 75 mg / kg, about 50 mg / kg to about 150 mg / kg, about 100 mg / kg to about 250 mg / kg, about 200 mg / kg to about 350 mg / kg, about 300 mg / kg to about 450 mg / kg, about 400 mg / kg to about 550 mg / kg, or about 500 mg / kg to about 1000 mg / kg.

[0102] In some embodiments, zilucoplan may be administered at a dosage of about 0.10 mg / kg to about 0.42 mg / kg. The disclosed methods may include administering zilucoplan in a daily dose of about 0.1 mg / kg to about 0.3 mg / kg. In some embodiments, zilucoplan is administered in a daily dose of 0.3 mg / kg. Subject QMG score and / or MG-ADL score may be decreased as a result of administration. QMG score may be decreased by 3 points or more with 8 weeks of treatment. MG-ADL score may be decreased by 2 points or more with 8 weeks of treatment. Risk of needing rescue therapy (IVIG or plasma exchange) may be decreased.

[0103] Zilcoplan administration may be by self-administration. Zilcoplan administration may include the use of a pre-filled syringe. Self-administration may include the use of a self-administration device. The self-administration device may include or incorporate a pre-filled syringe.

[0104] Zilcoplan may be provided in a dissolved state. The zilcoplan solution may comprise an aqueous solution. The zilcoplan solution may comprise phosphate buffered saline (PBS). The zilcoplan solution may be preservative-free. Zilcoplan may be provided in a range of concentrations from about 0.01 mg / mL to about 1 mg / mL, from about 0.05 mg / mL to about 2 mg / mL, from about 1 mg / mL to about 5 mg / mL, from about 2 mg / mL to about 10 mg / mL, from about 4 mg / mL to about 16 mg / mL, from about 5 mg / mL to about 20 mg / mL, from about 8 mg / mL to about 24 mg / mL, from about 10 mg / mL to about 30 mg / mL, from about 12 mg / mL to about 32 mg / mL, from about 14 mg / mL to about 34 mg / mL, from about 16 mg / mL to about 36 mg / mL, from about 18 mg / mL to about 38 mg / mL, from about 20 mg / mL to about 40 mg / mL, from about 22 mg / mL to about 42 mg / mL, It may be present in the solution at a concentration of about 24 mg / mL to about 44 mg / mL, about 26 mg / mL to about 46 mg / mL, about 28 mg / mL to about 48 mg / mL, about 30 mg / mL to about 50 mg / mL, about 35 mg / mL to about 55 mg / mL, about 40 mg / mL to about 60 mg / mL, about 45 mg / mL to about 75 mg / mL, about 50 mg / mL to about 100 mg / mL, about 60 mg / mL to about 200 mg / mL, about 70 mg / mL to about 300 mg / mL, about 80 mg / mL to about 400 mg / mL, about 90 mg / mL to about 500 mg / mL, or about 100 mg / mL to about 1000 mg / mL.

[0105] In some embodiments, the self-administration device contains a Zilcoplan solution. The self-administration device may be about 0.010 mL to about 0.500 mL, about 0.050 mL to about 0.600 mL, about 0.100 mL to about 0.700 mL, about 0.150 mL to about 0.810 mL, about 0.200 mL to about 0.900 mL, about 0.250 mL to about 1.00 mL, about 0.300 mL to about 3.00 mL, about 0.350 mL to about 3.50 mL, about 0.400 mL to about 4.00 mL, about 0.450 mL to about 4.50 mL, about 0.500 mL to about 5.00 mL, about 0.550 mL to about 10.0 mL, about 0.600 mL to about 25.0 mL, about 0.6 The Zilcoplan solution may contain a volume of 50 mL to about 50.0 mL, about 0.700 mL to about 60.0 mL, about 0.750 mL to about 75.0 mL, about 0.800 mL to about 80.0 mL, about 0.850 mL to about 85.0 mL, about 0.900 mL to about 90.0 mL, about 0.950 mL to about 95.0 mL, about 1.00 mL to about 100 mL, about 2.00 mL to about 200 mL, about 5.00 mL to about 500 mL, about 10.0 mL to about 750 mL, about 25.0 mL to about 800 mL, about 50.0 mL to about 900 mL, or about 100 mL to about 1000 mL.

[0106] Zilcoplan treatment may be continuous or in one or more doses. In some embodiments, treatment is hourly, daily, every other day, weekly, biweekly, monthly, or a combination thereof. Zilcoplan treatment may include daily administration. Subject zilcoplan plasma levels are measured at a maximum concentration (C max ). Serum hemolysis can be inhibited by zilcoplan treatment. In some embodiments, at least 90% hemolysis inhibition is achieved in the subject's serum by zilcoplan treatment. During administration, the subject can receive standard of care therapy for gMG. Standard of care therapy for MG can include, but is not limited to, plasma exchange, intravenous immunoglobin (IVIG) therapy, biologics (e.g., rituximab or eculizumab), pyridostigmine therapy, corticosteroid therapy, and / or immunosuppressant therapy. In some embodiments, the subject receives cholinesterase inhibitor therapy during the course of zilcoplan treatment.

[0107] Zilcoplan treatment of MG may be performed with a variety of subjects of different demographic backgrounds and stages of the disease. Treatment may be performed with subjects with refractory (resistant or unresponsive to other standard therapies) MG as well as with subjects with non-refractory MG. Refractory subjects may include subjects who are resistant or unresponsive to previous therapy with eculizumab.

[0108] In some embodiments, subjects with stages of MG that occur prior to reaching a critical or critical stage are treated with zilucoplan. Such treatment may be administered to treat subjects prior to developing MG or early in the disease course to provide the benefit of aggressive or preventative treatment.

[0109] In some embodiments, the present invention provides zilucoplan for use in a method for treating MG comprising administering 0.1 to 0.3 mg / kg zilucoplan subcutaneously or intravenously to a subject. In some embodiments, the present invention provides zilucoplan for use in a method for treating MG comprising administering 0.1 mg / kg or 0.3 mg / kg zilucoplan subcutaneously or intravenously to a subject. In some embodiments, the present invention provides zilucoplan for use in a method for treating MG comprising administering 0.1 mg / kg or 0.3 mg / kg zilucoplan subcutaneously to a subject. In some embodiments, the present invention provides zilucoplan for use in a method for treating MG comprising administering 0.3 mg / kg zilucoplan subcutaneously to a subject. In some embodiments, the MG is gMG. In some embodiments, the subject is AChR autoantibody positive.

[0110] evaluation A subject receiving zilucoplan treatment for MG may be evaluated for effectiveness during or after treatment. As used herein, the term "treated subject" refers to an individual who has received at least one treatment. A zilucoplan treated subject evaluation may include evaluation of one or more metrics of effectiveness. In some embodiments, an evaluation may require that the subject treatment be withheld for a period of time prior to the evaluation. Some evaluations may require that the subject maintain consistent treatment before, during, and / or after the evaluation. The treatment that is withheld or maintained may be zilucoplan treatment. In some embodiments, the treatment that is withheld or maintained includes other treatments for MG or non-MG conditions.

[0111] Evaluations may be performed to calculate primary efficacy endpoints. As used herein, the term "primary endpoint" refers to an outcome that answers the most important question asked by a particular study. The term "secondary endpoint" refers to an outcome that answers other related questions below the primary question. Primary efficacy endpoints are outcomes that examine whether a treatment is effective, while secondary efficacy endpoints examine one or more peripheral questions (e.g., quality of life impact, side effect severity, etc.).

[0112] An evaluation may be performed to assess a subject's MG characteristics. As used herein, the term "MG characteristics" refers to a physical or mental attribute or set of attributes associated with the presence or severity of MG in a subject. MG characteristics may include scores obtained using various disease assessment methods. MG characteristics may include, but are not limited to, QMG score, MG-ADL score, MG-QOL15r score, and MG composite score. In some embodiments, a subject may be monitored for MG characteristics over time. Such monitoring may be performed during the course of MG disease. Monitoring may be performed during the course of disease treatment. In some embodiments, subject evaluation or monitoring is performed to assess changes in MG characteristics during or after treatment of the subject with zilucoplan.

[0113] In some embodiments, zilucoplan-treated subjects are evaluated or monitored for QMG score. As mentioned above, QMG is a standardized, validated, quantitative intensity scoring system developed specifically for MG and previously used in clinical trials. The scoring system assesses 13 items related to ocular, medulla, and limb function (Barnet, C et al., 2015, J Neuromuscul Dis, vol. 2: 301-11). Each item is scored from 0 to 3. The maximum total score is 39. Higher scores represent more severe impairment. Recent data suggests that an improvement in QMG score of 2-3 points may be considered clinically meaningful depending on disease severity [Barohn RJ et al., 1998, Ann NY Acad Sci 841:769-772; Katzberg HD et al., 2014, Muscle Nerve 49(5):661-665, the contents of which are incorporated herein by reference in their entirety]. Subjects being assessed for QMG score may be removed from MG therapy for at least 10 hours prior to QMG score assessment. MG therapy may include acetylcholinesterase inhibitor therapy (e.g., pyridostigmine treatment) for at least 10 hours prior to QMG score assessment.

[0114] In some embodiments, the change in QMG score may be the primary efficacy endpoint. The treated subject's QMG score may be reduced. The QMG score may be reduced by at least 3 points. The QMG score may be reduced at or before 12 weeks of zilucoplan treatment. The treated subject's QMG score may be monitored over the course of zilucoplan treatment.

[0115] In some embodiments, zilucoplan treated subject evaluation may include testing and / or monitoring for one or more of MG-ADL score, MG-QOL15r score, and MG composite score. Such scores may be assessed as secondary efficacy endpoints. As previously explained, the MG-ADL is a brief 8-item survey designed to assess MG symptom severity. Each item is scored from 0 to 3. The maximum overall score is 24. Higher scores are associated with more severe symptoms of MG. The MG-ADL has been shown to correlate with other validated MG outcome measures (e.g., MG-QOL15r), and a 2-point improvement in the MG-ADL score is considered clinically meaningful [Wolf et al. Wolfe GI et al., 1999, Neurology 52(7):1487-9; Muppidi S et al., 2011, Muscle Nerve 44(5):727-31, the contents of which are incorporated herein by reference in their entireties. The MG-QOL15r is a 15-item survey designed to assess quality of life in patients with MG based on patient report, as previously described. Each item is scored from 0 to 2. The maximum total score is 30. Higher scores indicate a more severe impact of the disease on aspects of the patient's life [Burns, TM et al., 2010, Muscle Nerve 41(2):219-26; Burns TM et al., 2016, Muscle Nerve 54(6):1015-22, the contents of which are incorporated herein by reference in their entirety]. The MG Composite is a 10-item scale that has been used to measure the clinical status of patients with MG in both practice settings and clinical trials to assess treatment response (Burns, TM et al., 2008, Muscle Nerve 38:1553-62). Ten items are assessed relating to ocular, bulbar, respiratory, neck, and limb function. Items are weighted and scored from 0 to 9. The maximum total score is 50. Higher scores on the MG composite indicate more severe disability due to the disease. A 3-point change in this instrument is considered clinically meaningful (Burns, TM et al., 2010, Neurology 74(18):1434-40; Sadjadi, DB et al., 2012, Neurology 2016;87(4):419-425, the contents of which are incorporated herein by reference in their entireties).

[0116] Testing or monitoring of MG-ADL, MG-QOL15r, and / or MG Composite scores can be used to identify changes from baseline scores. As used herein, the term "baseline score" refers to a score obtained before initial treatment. A baseline score can be a score obtained during a switch from one treatment to another. A switch can be from a placebo to an active pharmaceutical compound. In some embodiments, zilucoplan treatment can be evaluated for a reduction in MG-ADL score of at least 2 points. The reduction can occur at or prior to 12 weeks of zilucoplan treatment. In some embodiments, zilucoplan treatment can be evaluated for a reduction in MG Composite score of at least 3 points. The reduction can occur at or prior to 12 weeks of zilucoplan treatment.

[0117] In some embodiments, zilucoplan treatment leads to a reduction in the subject's symptoms. The reduction in the subject's symptoms may exceed the reduction in the subject's symptoms associated with eculizumab administration. Evaluation method In some embodiments, the present disclosure provides a method for evaluating a treatment for MG. Such a method may include screening evaluation candidates for at least one evaluation inclusion criterion. As used herein, the term "evaluation candidate" refers to any individual who is being considered for participation in an evaluation (e.g., a clinical trial). "Evaluation inclusion criterion" refers to a metric or factor used to select individuals to include in the evaluation. Evaluation candidates selected to participate in the evaluation are referred to herein as "evaluation participants." In some embodiments, a method for evaluating a treatment for MG may include screening evaluation candidates for at least one evaluation inclusion criterion; selecting evaluation participants; administering a treatment for MG to the evaluation participants; and calculating at least one efficacy endpoint.

[0118] In some embodiments, the evaluation inclusion criteria include a MG diagnosis. The MG diagnosis may include a gMG diagnosis. The diagnosis of gMG may be made according to the MGFA criteria. In some embodiments, the evaluation inclusion criteria include a QMG score. Evaluation participant selection may require an evaluation candidate QMG score of 12 or greater. A portion of the evaluation candidates may have received at least one alternative MG treatment (i.e., an alternative to the treatment for MG being tested, such as standard of care) prior to screening. In some embodiments, such candidates may be assessed for a QMG score at least 10 hours after their most recent alternative MG treatment. Alternative MG treatments may include standard of care MG treatments, including, but not limited to, cholinesterase inhibitor treatment, acetylcholinesterase inhibitor treatment, pyridostigmine treatment, corticosteroid treatment, and immunosuppressant treatment. Evaluation participant selection may require a score of 2 or greater on four or more QMG test items.

[0119] In some embodiments, the assessment participation criteria include the age of the assessment candidate, hi some embodiments, the assessment candidate must be between 18 and 85 years old. Evaluation entry criteria may include candidate biomarker levels. In some embodiments, biomarkers include acetylcholine receptor (AChR) autoantibody levels. AChR autoantibodies can bind to AChR and stimulate complement activation, resulting in disease. Therefore, AChR autoantibody levels can be a good indicator of susceptibility to complement-mediated disease.

[0120] Evaluation inclusion criteria may include the candidate's previous and current alternative MG treatment status. In some embodiments, evaluation participants are selected based on the consistency of current or previous alternative MG treatments. In some embodiments, candidates with no recent changes in corticosteroid dosage or immunosuppressive therapy are selected. Candidates with corticosteroid treatment dosage or immunosuppressive therapy regimen changes within the past 30 days may be excluded from evaluation participation.

[0121] Evaluation inclusion criteria may include pregnancy status. In some embodiments, pregnant subjects may be excluded from evaluation participation. Pregnancy status screening may be performed by serum pregnancy testing. In some embodiments, pregnancy screening may include a urine pregnancy test.

[0122] Methods for evaluating a treatment for MG can include administering a treatment for MG to an evaluation participant over an evaluation period. As used herein, the term "evaluation period" refers to the time frame during which a particular test is conducted. The treatment can be administered over an evaluation period of about 1 day to about 24 weeks. Some evaluation periods are about 12 weeks or longer. Evaluation participants can continue to receive standard of care gMG therapy over the evaluation period. Such therapy can include, but is not limited to, cholinesterase inhibitor therapy, acetylcholinesterase inhibitor therapy, pyridostigmine therapy, corticosteroid therapy, and / or immunosuppressant therapy.

[0123] Efficacy endpoints may include specific scores or changes in scores associated with the assessment of individuals with MG. Such assessments may include, but are not limited to, QMG score, MG-ADL score, MG-QOL15r score, and MG composite score. In some embodiments, efficacy endpoints include QMG score reduction. Efficacy endpoints may include at least a 3 point reduction in QMG score. For assessment participants receiving alternative MG treatments (e.g., acetylcholinesterase inhibitor treatments) during the assessment period, one or more of these treatments may be withheld for at least 10 hours prior to QMG score assessment. In some embodiments, efficacy endpoints include one or more reductions in MG-ADL score, MG-QOL15r score, and MG composite score relative to baseline score. Efficacy endpoints may include a 2 point reduction in MG-ADL score relative to baseline score. The reduction in MG-ADL score may occur at or prior to 12 weeks of MG treatment.

[0124] In some embodiments, calculating the efficacy endpoints includes a set of calculations. The set of calculations may be performed in a particular order. In some embodiments, the set of calculations is performed in the following order: (1) calculating the assessment participant's MG-QOL15r score; (2) calculating the assessment participant's MG-ADL score; (3) calculating the assessment participant's QMG score; and (4) calculating the assessment participant's MG composite score.

[0125] Calculations of efficacy endpoints may be performed on one or more occasions after administration of a treatment for MG. Such calculations may be performed at specific times and / or days, or may be performed repeatedly (e.g., hourly, daily, weekly, monthly, or combinations thereof). In some embodiments, calculations are performed 1 week, 2 weeks, 4 weeks, 8 weeks, and / or 12 weeks after initiating administration of a treatment for MG.

[0126] formulation In some embodiments, the compounds or compositions of the present disclosure, e.g., pharmaceutical compositions, are formulated in an aqueous solution. In some cases, the aqueous solution further comprises one or more salts and / or one or more buffering agents. The salts may include sodium chloride, which may be included at a concentration of about 0.05 mM to about 50 mM, about 1 mM to about 100 mM, about 20 mM to about 200 mM, or about 50 mM to about 500 mM. The further solution may include at least 500 mM sodium chloride. In some cases, the aqueous solution includes sodium phosphate. The sodium phosphate may be included in the aqueous solution at a concentration of about 0.005 mM to about 5 mM, about 0.01 mM to about 10 mM, about 0.1 mM to about 50 mM, about 1 mM to about 100 mM, about 5 mM to about 150 mM, or about 10 mM to about 250 mM. In some cases, a sodium phosphate concentration of at least 250 mM is used.

[0127] The compositions of the present disclosure may comprise a C5 inhibitor at a concentration of about 0.001 mg / mL to about 0.2 mg / mL, about 0.01 mg / mL to about 2 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 5 mg / mL, about 1 mg / mL to about 20 mg / mL, about 15 mg / mL to about 40 mg / mL, about 25 mg / mL to about 75 mg / mL, about 50 mg / mL to about 200 mg / mL, or about 100 mg / mL to about 400 mg / mL. In some cases, the compositions comprise a C5 inhibitor at a concentration of at least 400 mg / mL.

[0128] The compositions of the present disclosure may include a concentration of C5 inhibitor that is approximately, about, or exactly any of the following values: 0.001 mg / mL, 0.2 mg / mL, 0.01 mg / mL, 2 mg / mL, 0.1 mg / mL, 10 mg / mL, 0.5 mg / mL, 5 mg / mL, 1 mg / mL, 20 mg / mL, 15 mg / mL, 40 mg / mL, 25 mg / mL, 75 mg / mL, 50 mg / mL, 200 mg / mL, 100 mg / mL, or 400 mg / mL. In some cases, the compositions include a C5 inhibitor at a concentration of at least 40 mg / mL.

[0129] In some embodiments, the compositions of the present disclosure include an aqueous composition comprising at least water and a C5 inhibitor (e.g., a cyclic C5 inhibitor polypeptide). The aqueous C5 inhibitor composition may further comprise one or more salts and / or one or more buffering agents. In some cases, the aqueous composition comprises water, a cyclic C5 inhibitor polypeptide, a salt, and a buffering agent.

[0130] Aqueous C5 inhibitor formulations can have a pH level of about 2.0 to about 3.0, about 2.5 to about 3.5, about 3.0 to about 4.0, about 3.5 to about 4.5, about 4.0 to about 5.0, about 4.5 to about 5.5, about 5.0 to about 6.0, about 5.5 to about 6.5, about 6.0 to about 7.0, about 6.5 to about 7.5, about 7.0 to about 8.0, about 7.5 to about 8.5, about 8.0 to about 9.0, about 8.5 to about 9.5, or about 9.0 to about 10.0.

[0131] In some cases, the compounds and compositions of the present disclosure are prepared in accordance with Good Manufacturing Practice (GMP) and / or current GMP (cGMP). Guidelines used to implement GMP and / or cGMP can be obtained from one or more of the U.S. Food and Drug Administration (FDA), the World Health Organization (WHO), and the International Council on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH).

[0132] Dosage and Administration For the treatment of human subjects, C5 inhibitors (e.g., zilucoplan and / or its active metabolites or variants) can be formulated as pharmaceutical compositions. Depending on the subject to be treated, the mode of administration, and the type of treatment desired (e.g., prevention, prophylaxis, or therapy), C5 inhibitors can be formulated in a manner consistent with these parameters. Compilations of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0133] The C5 inhibitor (e.g., zilucoplan and / or its active metabolites or variants) may be provided in a therapeutically effective amount. In some cases, a therapeutically effective amount of a C5 inhibitor may be achieved by administration of one or more C5 inhibitors in a dosage of about 0.1 mg to about 1 mg, about 0.5 mg to about 5 mg, about 1 mg to about 20 mg, about 5 mg to about 50 mg, about 10 mg to about 100 mg, about 20 mg to about 200 mg, or at least 200 mg.

[0134] In some embodiments, a subject may be administered a therapeutic amount of a C5 inhibitor (e.g., zilucoplan and / or an active metabolite or variant thereof) based on the body weight of such subject. In some cases, the C5 inhibitor may be administered at a dose of about 0.001 mg / kg to about 1.0 mg / kg, about 0.01 mg / kg to about 2.0 mg / kg, about 0.05 mg / kg to about 5.0 mg / kg, about 0.03 mg / kg to about 3.0 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 2.0 mg / kg, about 0.2 mg / kg to about 3.0 mg / kg, about 0.4 mg / kg to about 4.0 mg / kg, about 1.0 mg / kg to about 5.0 mg / kg, about 2 ... g / kg to about 4.0 mg / kg, about 1.5 mg / kg to about 7.5 mg / kg, about 5.0 mg / kg to about 15 mg / kg, about 7.5 mg / kg to about 12.5 mg / kg, about 10 mg / kg to about 20 mg / kg, about 15 mg / kg to about 30 mg / kg, about 20 mg / kg to about 40 mg / kg, about 30 mg / kg to about 60 mg / kg, about 40 mg / kg to about 80 mg / kg, about 50 mg / kg to about 100 mg / kg, or at least 100 mg / kg. Such ranges may include ranges suitable for administration to human subjects. Dose levels may be highly dependent on the nature of the condition; drug efficacy; patient condition; practitioner judgment; and frequency and mode of administration. In some embodiments, zilucoplan and / or its active metabolites or variants may be administered at a dosage of about 0.01 mg / kg to about 10 mg / kg. In some cases, zilucoplan and / or its active metabolite or variant may be administered at a dosage of about 0.1 mg / kg to about 3 mg / kg.

[0135] In some cases, the C5 inhibitor (e.g., zilucoplan and / or its active metabolite or variant) is provided at a concentration adjusted to achieve a desired level of the C5 inhibitor in a sample, biological system, or subject (e.g., plasma level in a subject). In some cases, the desired concentration of the C5 inhibitor in a sample, biological system, or subject may include a concentration of about 0.001 μM to about 0.01 μM, about 0.005 μM to about 0.05 μM, about 0.02 μM to about 0.2 μM, about 0.03 μM to about 0.3 μM, about 0.05 μM to about 0.5 μM, about 0.01 μM to about 2.0 μM, about 0.1 μM to about 50 μM, about 0.1 μM to about 10 μM, about 0.1 μM to about 5 μM, about 0.2 μM to about 20 μM, about 5 μM to about 100 μM, or about 15 μM to about 200 μM. In some cases, the desired concentration of the C5 inhibitor in the subject's plasma may be about 0.1 μg / mL to about 1000 μg / mL. The desired concentration of the C5 inhibitor in the subject plasma is about 0.01 μg / mL to about 2 μg / mL, about 0.02 μg / mL to about 4 μg / mL, about 0.05 μg / mL to about 5 μg / mL, about 0.1 μg / mL to about 1.0 μg / mL, about 0.2 μg / mL to about 2.0 μg / mL, about 0.5 μg / mL to about 5 μg / mL, about 1 μg / mL to about 5 μg / mL, about 2 ... In other embodiments, the C5 inhibitor has a maximum serum concentration (C5 concentration) of at least 0.1 μg / mL, at least 0.5 μg / mL, at least 1 μg / mL, at least 5 μg / mL, at least 10 μg / mL, at least 50 μg / mL, at least 100 μg / mL, or at least 1000 μg / mL. max ) is administered at a dosage sufficient to achieve

[0136] In some embodiments, the C5 inhibitor (e.g., zilucoplan and / or its active metabolites or variants) is administered daily at a dose sufficient to deliver about 0.1 mg / day to about 60 mg / kg of the subject's body weight per day. In some cases, the C5 inhibitor achieved with each dose is max is from about 0.1 μg / mL to about 1000 μg / mL. In such cases, the area under the curve (AUC) during administration can be from about 200 μg·hr / mL to about 10,000 μg·hr / mL.

[0137] According to some methods of the disclosure, a C5 inhibitor (e.g., zilucoplan and / or its active metabolites or variants) is provided at a concentration required to achieve a desired effect. In some cases, the compounds and compositions of the disclosure are provided in an amount required to reduce a given reaction or process by half. The concentration required to achieve such a reduction is referred to herein as the median inhibitory concentration, or "IC 50 Alternatively, the compounds and compositions of the disclosure may be provided in an amount required to increase a given reaction, activity, or process by half. The concentration required for such an increase is referred to herein as the half maximal effective concentration, or "EC 50 "It is called "

[0138] The C5 inhibitor (e.g., zilucoplan and / or its active metabolites or variants) may be present in an amount that totals 0.1-95% by weight of the total weight of the composition. In some cases, the C5 inhibitor is provided by intravenous (IV) administration. In some cases, the C5 inhibitor is provided by subcutaneous (SC) administration.

[0139] SC administration of C5 inhibitors (e.g., zilucoplan and / or its active metabolites or variants) may, in some cases, provide advantages over IV administration. SC administration may include self-administration by using an administration device, such as a self-administration device. As used herein, the term "self-administration" refers to any form of therapeutic delivery performed in whole or in part by the recipient of the therapeutic treatment. Self-administration devices may include self-injection devices. Self-administration therapy may be advantageous in that patients can provide themselves with therapy at home, avoiding the need to travel to a provider or medical facility. Furthermore, SC therapy allows patients to avoid long-term complications associated with IV administration, such as infection, loss of venous access, local thrombosis, and hematoma. In some embodiments, self-administration using an auto-injection device may increase patient compliance, patient satisfaction, quality of life, and reduce treatment costs and / or drug requirements.

[0140] In some cases, daily SC administration provides for steady state C5 inhibitor concentrations to be reached within 1-3 administrations, 2-3 administrations, 3-5 administrations, or 5-10 administrations. In some cases, daily SC doses of about 0.1 mg / kg to about 0.3 mg / kg can achieve sustained C5 inhibitor levels of 2.5 μg / mL or greater and / or greater than 90% inhibition of complement activity.

[0141] C5 inhibitors (e.g., zilucoplan and / or its active metabolites or variants) can exhibit slow absorption kinetics (time to peak concentration greater than 4-8 hours) and high bioavailability (about 75% to about 100%) following SC administration.

[0142] In some embodiments, the dose and / or administration is altered to reduce the half-life (t 1 / 2 ) is adjusted. In some cases, t 1 / 2is at least 1 hour, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 16 hours, at least 20 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 60 hours, at least 72 hours, at least 96 hours, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, or at least 16 weeks.

[0143] In some embodiments, C5 inhibitors (e.g., zilucoplan and / or its active metabolites or variants) have a long terminal t 1 / 2 A long terminal phase t 1 / 2 This may be due to extensive target binding and / or additional plasma protein binding. In some cases, C5 inhibitors have been shown to have a t of >24 hours in both plasma and whole blood. 1 / 2 Values ​​are shown in Table 1. In some cases, C5 inhibitors do not lose functional activity after 16 hours of incubation in human whole blood at 37°C.

[0144] In some embodiments, the dose and / or administration is altered to adjust the steady-state volume of distribution of the C5 inhibitor. In some cases, the steady-state volume of distribution of the C5 inhibitor is about 0.1 mL / kg to about 1 mL / kg, about 0.5 mL / kg to about 5 mL / kg, about 1 mL / kg to about 10 mL / kg, about 5 mL / kg to about 20 mL / kg, about 15 mL / kg to about 30 mL / kg, about 10 mL / kg to about 200 mL / kg, about 20 mL / kg to about 60 mL / kg, about 30 mL / kg to about 70 mL / kg, about 50 mL / kg to about 200 mL / kg, about 100 mL / kg to about 500 mL / kg, or at least 500 mL / kg. In some cases, the dose and / or administration of the C5 inhibitor is adjusted to ensure that the steady-state volume of distribution is at least 50% of the total blood volume. In some embodiments, the C5 inhibitor distribution may be limited to the plasma compartment.

[0145] In some embodiments, a C5 inhibitor (e.g., zilucoplan and / or an active metabolite or variant thereof) exhibits a total clearance rate of about 0.001 mL / hr / kg to about 0.01 mL / hr / kg, about 0.005 mL / hr / kg to about 0.05 mL / hr / kg, about 0.01 mL / hr / kg to about 0.1 mL / hr / kg, about 0.05 mL / hr / kg to about 0.5 mL / hr / kg, about 0.1 mL / hr / kg to about 1 mL / hr / kg, about 0.5 mL / hr / kg to about 5 mL / hr / kg, about 0.04 mL / hr / kg to about 4 mL / hr / kg, about 1 mL / hr / kg to about 10 mL / hr / kg, about 5 mL / hr / kg to about 20 mL / hr / kg, about 15 mL / hr / kg to about 30 mL / hr / kg, or at least 30 mL / hr / kg.

[0146] The time period during which the maximum concentration of C5 inhibitor is maintained in the subject (e.g., in the subject's serum) (T maxThe T value can be adjusted by modifying the dose and / or administration (e.g., subcutaneous administration). In some cases, the C5 inhibitor has a T of about 1 minute to about 10 minutes, about 5 minutes to about 20 minutes, about 15 minutes to about 45 minutes, about 30 minutes to about 60 minutes, about 45 minutes to about 90 minutes, about 1 hour to about 48 hours, about 2 hours to about 10 hours, about 5 hours to about 20 hours, about 10 hours to about 60 hours, about 1 day to about 4 days, about 2 days to about 10 days, or at least 10 days. max It has a value.

[0147] In some embodiments, C5 inhibitors (e.g., zilucoplan and / or its active metabolites or variants) can be administered without off-target effects. In some cases, C5 inhibitors do not inhibit hERG (human ether-a-go-go related gene) even at concentrations of 300 μM or less. SC injections of C5 inhibitors with dose escalations up to 10 mg / kg can be well tolerated and do not result in any adverse cardiovascular (e.g., high risk of ventricular repolarization prolongation) and / or respiratory effects.

[0148] C5 inhibitor dosages may be determined using a no-observed-adverse-effect level (NOAEL) observed in another species. Such species may include, but are not limited to, monkeys, rats, rabbits, and mice. In some cases, a human equivalent dose (HED) may be determined by allometric scaling from the NOAEL observed in the other species. In some cases, the HED results in therapeutic margins of about 2-fold to about 5-fold, about 4-fold to about 12-fold, about 5-fold to about 15-fold, about 10-fold to about 30-fold, or at least 30-fold. In some cases, the therapeutic margins are determined by the exposure in primates and the estimated C5 inhibitor dose in humans. max The level is determined by using

[0149] In some embodiments, the C5 inhibitors of the present disclosure allow for a rapid drug holiday in cases of infection where prolonged inhibition of the complement system would prove detrimental. The administration of C5 inhibitors according to the present disclosure may be adjusted to reduce potential clinical risks to the subject. Infection with Neisseria meningitidis is a known risk of C5 inhibitors, including eculizumab. In some cases, the risk of infection with Neisseria meningitides is minimized by instituting one or more preventative steps. Such steps may include the exclusion of subjects who may already be colonized with these bacteria. In some cases, the preventative steps may include the co-administration of one or more antibiotics. In some cases, ciprofloxacin may be co-administered. In some cases, ciprofloxacin may be co-administered orally at a dosage of about 100 mg to about 1000 mg (e.g., 500 mg).

[0150] In some embodiments, the C5 inhibitor (e.g., zilucoplan and / or its active metabolites or variants) is administered hourly, every 2 hours, every 4 hours, every 6 hours, every 12 hours, every 18 hours, every 24 hours, every 36 hours, every 72 hours, every 84 hours, every 96 hours, every 5 days, every 7 days, every 10 days, every 14 days, every week, every 2 weeks, every 3 weeks, every 4 weeks, every month, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every year, or at least every year. In some cases, the C5 inhibitor is administered once a day or as two, three, or more subdoses at appropriate intervals throughout the day.

[0151] In some embodiments, the C5 inhibitor is administered in multiple daily doses. In some cases, the C5 inhibitor is administered daily for 7 consecutive days. In some cases, the C5 inhibitor is administered daily for 7-100 consecutive days. In some cases, the C5 inhibitor is administered daily for at least 100 consecutive days. In some cases, the C5 inhibitor is administered daily indefinitely.

[0152] The disclosed methods may include administering a C5 inhibitor (e.g., zilucoplan and / or its active metabolites or variants) in a daily dose of about 0.1 mg / kg to about 0.3 mg / kg. In some embodiments, the C5 inhibitor (e.g., zilucoplan and / or its active metabolites or variants) is administered in a daily dose of 0.3 mg / kg. The subject's QMG score and / or MG-ADL score may be decreased as a result of administration. The QMG score may be decreased by 3 points or more with 8 weeks of treatment. The MG-ADL score may be decreased by 2 points or more with 8 weeks of treatment. The risk of needing rescue therapy (IVIG or plasma exchange) may be decreased.

[0153] The C5 inhibitor delivered intravenously can be delivered over a period of time, such as over a period of 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 25 minutes, by infusion. Administration can be repeated periodically, such as hourly, daily, weekly, biweekly (i.e., every two weeks), for one month, two months, three months, four months, or more than four months. After an initial treatment regimen, treatment can be administered less frequently. For example, after three months of biweekly administration, administration can be repeated once a month for six months or a year or more. C5 inhibitor administration can reduce, decrease, increase, or alter binding or any physiologically deleterious process (e.g., in cells, tissues, blood, urine, or other parts of a patient) by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, or more.

[0154] Prior to administration of the full amount of C5 inhibitor and / or C5 inhibitor composition, the patient can be administered a lower dose, such as 5% of the full amount, and monitored for adverse effects, such as allergic or infusion reactions, or for elevated lipid levels or blood pressure. In another example, the patient can be monitored for undesired immunostimulatory effects, such as increased levels of cytokines (e.g., TNF-alpha, IL-1, IL-6, or IL-10).

[0155] Genetic predisposition plays a role in the development of some diseases or disorders. Thus, patients who need C5 inhibitors can be identified by family history analysis or screening for, for example, one or more genetic markers or variants. A medical provider (e.g., a doctor or nurse) or a relative can analyze family history information before prescribing or administering the therapeutic composition of the present disclosure.

[0156] III. Kits and Apparatus In some embodiments, the present disclosure provides kits and devices. Such kits and devices may include any of the compounds or compositions described herein. In a non-limiting example, Zilcoplan may be included.

[0157] The device of the present disclosure may include an administration device. As used herein, the term "administration device" refers to any device that administers a substance to a recipient. An administration device may include a self-administration device. As used herein, the term "self-administration device" refers to any device that is used to administer a substance to a recipient, where the use of the device is performed in whole or in part by the recipient. A self-administration device may include a self-injection device. An "self-injection device" is a self-administration device that allows an individual to administer a substance subcutaneously to his or her own body. An self-injection device may include a pre-filled syringe. As used herein, the term "pre-filled syringe" refers to a syringe that is filled with a substance or cargo before access or use by an operator of the syringe. For example, a pre-filled syringe (also referred to herein as a "pre-filled syringe") may be filled with a therapeutic composition before packaging in a kit; before shipment of the syringe to a distributor, an administerer, or an operator; or before access by a subject who uses the syringe for self-administration. Due to the stability of cyclic peptides, cyclic peptide inhibitors (e.g., Zilcoplan) are particularly suitable for manufacturing, storing and distributing into pre-filled syringes.Furthermore, pre-filled syringes are particularly suitable for self-administration (i.e., administration by subjects without the assistance of medical professionals).Self-administration is a convenient way for subjects to obtain treatment without relying on medical professionals who may be far away or otherwise difficult to access.This makes the option of self-administration suitable for treatments that require frequent injections (e.g., daily injections).

[0158] The prefilled syringe may be of any material (e.g., glass, plastic, or metal). In some embodiments, the prefilled syringe is a glass syringe. The prefilled syringe may include a maximum fill volume (meaning the maximum amount of liquid that can be accommodated) of at least 0.1 ml, at least 0.2 ml, at least 0.3 ml, at least 0.4 ml, at least 0.5 ml, at least 0.75 ml, at least 1.0 ml, at least 1.5 ml, at least 2.0 ml, at least 5.0 ml, at least 10 ml, or more than 10 ml. The syringe may include a needle. The needle may be of any gauge. In some embodiments, the syringe includes a 29-gauge needle. The needle may be assembled with the syringe or may be attached before the syringe is used. The self-injection device may include the BD ULTRASAFE PLUS™ self-administration device (Becton Dickinson (BD), Franklin Lakes, NJ).

[0159] The administration device may include an autoinjection device including a syringe and needle and a predetermined volume of the zilcoplan composition. The zilcoplan composition may be a pharmaceutical composition. The composition may include a zilcoplan concentration of about 1 mg / mL to about 200 mg / mL. In some embodiments, the zilcoplan concentration is about 40 mg / mL. The predetermined volume may be predetermined based on the subject's body weight. In some embodiments, the predetermined zilcoplan composition volume is adjusted to facilitate administration of zilcoplan to the subject at a dosage of about 0.1 mg / kg to about 0.6 mg / kg. The volume may be adjusted to facilitate a 0.3 mg / kg zilcoplan dose. The autoinjection device may include a BD ULTRASAFE PLUS™ self-administration device. In some embodiments, the administration device is prepared for storage at a particular temperature or temperature range. Some administration devices may be prepared for storage at room temperature. Some administration devices may be prepared for storage at about 2°C to about 8°C.

[0160] The prefilled syringe may include ULTRASAFE PLUS™ passive needle guard (Becton Dickenson, Franklin Lakes, NJ). Other prefilled syringes may include pen injectors. The pen injectors may be multi-dose pens. Some prefilled syringes may include a needle. In some embodiments, the needle gauge is about 20 to about 34. The needle gauge may be about 29 to about 31.

[0161] In some embodiments, the kits of the present disclosure include kits for carrying out the methods of treating MG described herein. Such kits may include one or more administration devices described herein and instructions for using the kit.

[0162] The kit components may be packaged in liquid (e.g., aqueous or organic) media or in dry (e.g., lyophilized) form. The kit may include containers that may include, but are not limited to, vials, test tubes, flasks, bottles, syringes, or bags. The kit containers may be used to subdivide, preserve, store, isolate, and / or protect the kit components. The kit components may be packaged together or separately. Some kits may include containers of sterile, pharma- ceutically acceptable buffers and / or other diluents (e.g., phosphate-buffered saline). In some embodiments, the kit includes containers of kit components in dry form along with another container of a solution for dissolving the dried components. In some embodiments, the kit includes a syringe for administering one or more of the kit components.

[0163] If the polypeptide is provided as a dry powder, it is contemplated that between 10 micrograms and 1000 milligrams of the polypeptide, or at least that amount, or at most that amount, will be provided in the kit.

[0164] The containers may include at least one vial, test tube, flask, bottle, syringe, and / or other receptacle into which the polypeptide formulation may be placed, and preferably suitably dispensed. The kits may also include containers for sterile, pharma- ceutically acceptable buffers and / or other diluents.

[0165] The kit may include instructions for utilizing the kit components as well as the use of any other reagents not included in the kit. The instructions may include executable variants. The kits may include one or more items for treating syringe wounds. Such items may include, but are not limited to, alcohol wipes and wound dressings (e.g., cotton balls, mesh pads, bandages, tape, gauze, etc.). The kits may further include a disposal container for disposal of used kit components. The disposal container may be designed for disposal of sharp objects such as needles and syringes. Some kits may include instructions for disposal of sharp objects.

[0166] In some embodiments, the kits of the present disclosure include zircoplan in powder form or in a dissolved state (e.g., as a pharmaceutical composition). The solution may be an aqueous solution. The solution may include PBS. The zircoplan solution may include about 4 mg / ml to about 200 mg / ml zircoplan. In some embodiments, the zircoplan solution includes about 40 mg / ml zircoplan. The zircoplan solution may include a preservative. In some embodiments, the zircoplan solution is preservative-free.

[0167] In some embodiments, the kits are prepared for storage at a particular temperature or range of temperatures. Some kits may be prepared for storage at room temperature. Some kits may be prepared for storage at about 2°C to about 8°C.

[0168] IV. Definition Bioavailability: As used herein, the term "bioavailability" refers to the systemic availability of a given amount of a compound (e.g., a C5 inhibitor) administered to a subject. Bioavailability is measured as the area under the curve (AUC) or maximum serum or plasma concentration (C) of the unchanged form of the compound following administration of the compound to a subject. max ) can be calculated. AUC is a determination of the area under the curve when the serum or plasma concentration of a compound is plotted on the ordinate (Y-axis) versus time on the abscissa (X-axis). In general, the AUC of a particular compound can be calculated using methods known to those of skill in the art and / or as described in GS Banker, Modern Pharmaceutics, Drugs and the Pharmaceutical Sciences, Vol. 72, Marcel Dekker, New York, Inc., 1996, the contents of which are incorporated herein by reference in their entirety.

[0169] Biological system: As used herein, the term "biological system" refers to a cell, a group of cells, a tissue, an organ, a group of organs, an organelle, a biological fluid, a biological signaling pathway (e.g., a receptor-activated signaling pathway, a charge-activated signaling pathway, a metabolic pathway, a cell signaling pathway, etc.), a group of proteins, a group of nucleic acids, or a group of molecules (including, but not limited to, biomolecules) that perform at least one biological function or role within a cell membrane, a subcellular compartment, a cell, a cell culture, a tissue, an organ, an organ system, an organism, a multicellular organism, a biological fluid, or any biological entity. In some embodiments, the biological system is a cell signaling pathway that includes intracellular and / or extracellular signaling biomolecules. In some embodiments, the biological system includes a proteolytic cascade (e.g., the complement cascade).

[0170] Buffering Agent: As used herein, the term "buffering agent" refers to a compound used in a solution to resist changes in pH. Such compounds may include, but are not limited to, acetic acid, adipic acid, sodium acetate, benzoic acid, citric acid, sodium benzoate, maleic acid, sodium phosphate, tartaric acid, lactic acid, potassium metaphosphate, glycine, sodium bicarbonate, potassium phosphate, sodium citrate, and sodium tartrate.

[0171] Clearance rate: As used herein, the term "clearance rate" refers to the rate at which a particular compound is removed from a biological system or fluid. Compound: As used herein, the term "compound" refers to an individual chemical entity. In some embodiments, a particular compound may exist in one or more isomeric or isotopic forms (including, but not limited to, stereoisomers, geometric isomers, and isotopes). In some embodiments, a compound is provided or utilized in only one such form. In some embodiments, a compound is provided or utilized as a mixture of two or more such forms (including, but not limited to, racemic mixtures of stereoisomers). One of ordinary skill in the art will recognize that some compounds exist in different forms and exhibit different properties and / or activities (including, but not limited to, biological activity). In such cases, it is within the ordinary skill of one of ordinary skill in the art to select or avoid a particular form of a compound for use in accordance with the present disclosure. For example, a compound containing an asymmetrically substituted carbon atom can be isolated in optically active or racemic form.

[0172] Circular or Cyclized: As used herein, the term "cyclic" refers to the presence of a continuous loop. A cyclic molecule need not be circular, it need only be joined to form an unbroken chain of subunits. A cyclic polypeptide may contain a "cyclic loop" formed when two amino acids are joined by a bridging moiety. A cyclic loop includes the amino acids along the polypeptide that lie between the bridged amino acids. A cyclic loop may contain 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acids.

[0173] Downstream event: As used herein, the term "downstream" or "downstream event" refers to any event that occurs after and / or as a result of another event. In some cases, a downstream event is an event that occurs after and as a result of C5 cleavage and / or complement activation. Such events may include, but are not limited to, the generation of C5 cleavage products, activation of MAC, hemolysis, and hemolysis-related diseases (e.g., PNH).

[0174] Equilibrium dissociation constant: As used herein, the term "equilibrium dissociation constant" or "K D " refers to a value that represents the tendency of two or more agents (e.g., two proteins) to reversibly separate. In some cases, K D indicates the concentration of the primary agent at which half of the total level of the secondary agent is associated with the primary agent.

[0175] Half-life: As used herein, the term "half-life" or "t 1 / 2 "Terminal half-life" or "terminal t" refers to the time it takes for a given process or compound concentration to reach half of its final value. 1 / 2 " refers to the time it takes for the plasma concentration of a factor to decrease by half after the factor's concentration has reached pseudoequilibrium.

[0176] Identity: As used herein, the term "identity" when referring to a polypeptide or nucleic acid refers to the relative relationship between sequences. The term is used to describe the degree of sequence similarity between polymer sequences and may include the percentage of matching monomeric components, with gap alignment (if present) being considered by a particular mathematical model or computer program (i.e., "algorithm"). The identity of related polypeptides can be readily calculated by known methods.Such methods include those previously described by others (Lesk, A. M., Computational Molecular Biology, Oxford University Press, New York, 1988; Smith, D. W., Biocomputing: Informatics and Genome Projects, Academic Press, New York, 1993; Griffin, A. M. et al., eds., Computer Analysis of Sequence Data, Part 1, Humana Press, New Jersey, 1994; von Heinje, G., Sequence Analysis in Molecular Biology, 1996; Examples of suitable primers include, but are not limited to, Gribskov, M. et al., eds., Sequence Analysis Primer, M. Stockton Press, New York, 1991; and Carillo et al., Applied Mathematics, Society for Industrial and Applied Mathematics, Applied Math, SIAM J, Vol. 48, p. 1073, 1988.

[0177] Inhibitor: As used herein, the term "inhibitor" refers to any agent that blocks or reduces the occurrence of a particular event; a cell signal; a chemical pathway; an enzymatic reaction; a cellular process; an interaction between two or more entities; a biological event; a disease; a disorder; or a pathological condition.

[0178] Loading dose: As used herein, an "initial loading dose" refers to an initial dose of a therapeutic agent, which may be different from one or more subsequent doses. A loading dose may be used to achieve an initial concentration or level of activity of a therapeutic agent before subsequent doses are administered.

[0179] Intravenous: As used herein, the term "intravenous" refers to the area within a blood vessel. Intravenous administration typically refers to the delivery of a compound into the blood by injection into a blood vessel (e.g., a vein). In vitro: As used herein, the term "in vitro" refers to events that take place in an artificial environment (e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc.) rather than in a living organism (e.g., an animal, plant, or microorganism).

[0180] In vivo: As used herein, the term "in vivo" refers to events that take place within an organism (e.g., an animal, plant, or microorganism, or its cells or tissues). Lactam bridge: As used herein, the term "lactam bridge" refers to an amide bond that forms a bridge between chemical groups in a molecule. In some cases, lactam bridges are formed between amino acids in a polypeptide.

[0181] Linker: As used herein, the term "linker" refers to a group of atoms (e.g., 10-1,000 atoms), molecule, or other compound used to link two or more entities. A linker may link such entities by covalent or non-covalent (e.g., ionic or hydrophobic) interactions. A linker may include a chain of two or more polyethylene glycol (PEG) units. In some cases, a linker may be cleavable.

[0182] Minute ventilation: As used herein, the term "minute ventilation" refers to the volume of air inspired or expired from a subject's lungs per minute. Non-proteinogenic: As used herein, the term "non-proteinogenic" refers to any non-naturally occurring protein, including those that have non-naturally occurring components, such as non-naturally occurring amino acids.

[0183] Patient: As used herein, "patient" refers to a subject who may be seeking or in need of treatment, who is requesting treatment, who is receiving treatment, who will receive treatment, or who is receiving the care of a trained specialist for a particular disease or condition.

[0184] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to a composition having at least one active ingredient (e.g., a C5 inhibitor) in a form and amount that renders the active ingredient therapeutically effective.

[0185] Pharmaceutically acceptable: The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0186] Pharmaceutically acceptable excipient: The phrase "pharmaceutical acceptable excipient" herein refers to any component other than the active agent (e.g., the active agent zilucoplan and / or its active metabolite or variant) that is present in a pharmaceutical composition and has substantially non-toxic and non-inflammatory properties in patients. In some embodiments, the pharmaceutical acceptable excipient is a vehicle capable of suspending or dissolving the active agent. Excipients may include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), softeners, emulsifiers, fillers (diluents), film-forming agents or coatings, flavorings, flavorings, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water of hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0187] Plasma Compartment: As used herein, the term "plasma compartment" refers to the intravascular space occupied by plasma. Salt: As used herein, the term "salt" refers to a chemical compound made up of a cation and a combined anion. Such compounds may include sodium chloride (NaCl) or other types of salts, including, but not limited to, acetates, chlorides, carbonates, cyanides, nitrites, nitrates, sulfates, and phosphates.

[0188] Sample: As used herein, the term "sample" refers to an aliquot or portion taken from a source and / or provided for analysis or processing. In some embodiments, a sample is derived from a biological source, such as tissue, cells, or components (e.g., bodily fluids, including but not limited to blood, mucus, lymph, synovial fluid, cerebrospinal fluid, saliva, amniotic fluid, amniotic cord blood, urine, vaginal fluid, and semen). In some embodiments, a sample can be or include a homogenate, lysate, or extract prepared from a whole organism or a subset of its tissues, cells, or components, or a part or portion thereof, including but not limited to, for example, plasma, serum, spinal fluid, lymph, external strips of skin, respiratory tract, intestinal tract, and genitourinary tract, tears, saliva, milk, blood cells, tumors, or organs. In some embodiments, a sample is or includes a medium, such as a nutrient broth or gel, that may contain cellular components, such as proteins. In some embodiments, a "primary" sample is an aliquot of a source. In some embodiments, the primary sample is subjected to one or more processing (eg, separation, purification, etc.) steps to prepare the sample for analysis or other use.

[0189] Subcutaneous: As used herein, the term "subcutaneous" refers to the space below the skin. Subcutaneous administration is the delivery of a compound below the skin. Subject: As used herein, the term "subject" refers to any organism to which a compound or method according to the present disclosure may be administered or applied, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Exemplary subjects include animals (e.g., mammals such as mice, rats, rabbits, porcine subjects, non-human primates, and humans). In some applications, the subject is a human.

[0190] Substantially: As used herein, the term "substantially" refers to a qualitative state that indicates a degree or extent that is entirely or nearly entirely of the characteristic or property in question. Those skilled in the art of biology will understand that biological and chemical phenomena rarely, if ever, proceed to completion and / or completeness, or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of completeness that is inherent in many biological and chemical phenomena.

[0191] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" refers to an amount of an agent (e.g., a C5 inhibitor) delivered that, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, is sufficient to treat, ameliorate the symptoms of, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition.

[0192] Tidal Volume: As used herein, the term "tidal volume" refers to the normal lung volume of air expelled during breathing (without special effort). T max In this specification, the term "T max " refers to the period of time during which the maximum concentration of a compound in a subject or fluid is maintained.

[0193] Treating: As used herein, the term "treating" refers to partially or completely alleviating, ameliorating, improving, relieving, delaying the onset of, inhibiting the progression of, reducing the severity of, and / or reducing the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. Treatment may be administered to subjects who do not show signs of the disease, disorder, and / or condition and / or to subjects who show only early signs of the disease, disorder, and / or condition, for the purpose of reducing the risk of developing a condition associated with the disease, disorder, and / or condition.

[0194] Therapeutic Dose: As used herein, a "therapeutic dose" refers to one or more doses of a therapeutic agent administered in the course of treating or alleviating a therapeutic indication. Therapeutic doses may be adjusted to maintain a desired concentration or activity level of the therapeutic agent in a bodily fluid or biological system.

[0195] Volume of distribution: As used herein, the term “volume of distribution” or “V dist " refers to the volume of fluid required to contain the entire amount of a compound in the body at the same concentration as in blood or plasma. The volume of distribution may reflect the extent to which a compound is present in extravascular tissues. A large volume of distribution reflects the tendency of a compound to bind to tissue components relative to plasma protein components. In a clinical situation, V dist can be used to determine a loading dose of a compound to achieve a steady state concentration of that compound.

[0196] V. Equivalence and Scope While various embodiments of the present invention have been shown and described in detail, it will be understood by those skilled in the art that various changes in form or detail can be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

[0197] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the invention described herein. The scope of the invention is not limited by the above description, but is as set forth in the appended claims.

[0198] In the claims, articles such as "a," "an," and "the" can mean one or more, unless otherwise indicated or clear from the context. A claim or description containing "or" between one or more members of a group is considered to be satisfied when one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process, unless otherwise indicated or clear from the context. The invention includes embodiments in which exactly one member of a group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which two or more or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0199] It is noted that the term "comprising" is intended to be open-ended, allowing but not requiring the inclusion of additional elements or steps. When the term "comprising" is used herein, the terms "consisting of" and "or including" are also included and disclosed.

[0200] Where ranges are given, the endpoints are included. Additionally, unless otherwise specified or apparent from the context and the understanding of one of ordinary skill in the art, it should be understood that values ​​expressed as ranges can include any specific value or subrange within the stated range in different embodiments of the invention, down to one tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0201] Furthermore, it should be understood that any particular embodiment of the present invention that is within the prior art may be specifically excluded from any one or more of the claims. Such embodiments are deemed to be known to those of skill in the art, and therefore may be excluded even if the exclusion is not expressly stated herein. Any particular embodiment of the composition of the present invention (e.g., any nucleic acid or protein encoded thereby; any method of manufacture; any method of use, etc.) may be excluded from any one or more of the claims for any reason, whether related to the existence of prior art or not.

[0202] All cited sources, e.g., references, publications, databases, database entries, and art cited therein, are incorporated by reference into this application, even if not expressly stated in the citation. In the event of a conflict between a statement in a cited source and this application, the statement in this application shall control.

[0203] Section and table headings are non-limiting. EXAMPLES

[0204] Example 1. Preparation of an aqueous solution of Zircoplan Polypeptides were synthesized using standard solid-phase Fmoc / tBu methods. Synthesis was performed using standard protocols with Rink amide resin on a Liberty automated microwave peptide synthesizer (CEM, Matthews, NC), although other automated synthesizers without microwave capabilities can be used. All amino acids were obtained from commercial sources. The coupling reagent used was 2-(6-chloro-1-H-benzotriazol-1-yl)-1,1,3,3,-tetramethylaminium hexafluorophosphate (HCTU) and the base was diisopropylethylamine (DIEA). Polypeptides were cleaved from the resin with 95% TFA, 2.5% TIS, and 2.5% water for 3 h and isolated by precipitation with ether. Crude polypeptides were purified by reversed-phase preparative HPLC using a C18 column with a gradient of 20% to 50% acetonitrile / water 0.1% TFA over 30 min. Fractions containing pure polypeptide were collected, lyophilized, and the total polypeptide was analyzed by LC-MS.

[0205] Zircoplan (SEQ ID NO: 1; CAS number: 1841136-73-9) was prepared as a cyclic peptide containing 15 amino acids (four of which are unnatural amino acids), an acetylated N-terminus, and a C-terminal carboxylic acid. The C-terminal lysine of the core peptide has a modified side chain to form an N-ε-(PEG24-γ-glutamic acid-N-α-hexadecanoyl) lysine residue. This modified side chain contains a polyethylene glycol spacer (PEG24) attached to an L-γ-glutamic acid residue derivatized with a palmitoyl group. Cyclization of Zircoplan is by a lactam bridge between the side chains of L-Lys1 and L-Asp6. All amino acids in Zircoplan are L-amino acids. Zircoplan has a molecular weight of 3562.23 g / mol and a C 172 H 278 N 24 O 55 It has the chemical formula:

[0206] Like eculizumab, zircoplan blocks the proteolytic cleavage of C5 into C5a and C5b. Unlike eculizumab, zircoplan can also bind C5b and block C6 binding, which prevents the subsequent assembly of the MAC.

[0207] Zilcoplan was prepared as an aqueous solution for injection containing 40 mg / mL zilcoplan in a sterile, preservative-free formulation of 50 mM sodium phosphate and 76 mM sodium chloride at pH 7.0. The resulting composition was used to prepare drug products in accordance with current Good Manufacturing Practice (cGMP), which contained a prefilled 1 ml glass syringe with a 29 gauge 1 / 2 inch (12.7 mm) staked needle placed in a BD ULTRASAFE PLUS™ (Becton Dickinson (BD), Franklin Lakes, NJ) self-administration device.

[0208] Example 2. Zilcoplan Administration and Storage Zilcoplan is administered by subcutaneous (SC) or intravenous (IV) injection, and the administered dose (dose volume) is adjusted based on subject weight in mg / kg. This is accomplished using a bracket with a set of fixed doses and a set of body weights. Overall, human dosing supports a broad body weight range of 43-109 kg. Subjects with higher body weights (>109 kg) are addressed on an individual basis in consultation with the medical monitor.

[0209] Store Zilcoplan at 2°C to 8°C [36°F to 46°F]. Once distributed to a subject, Zilcoplan is stored at controlled room temperature (20°C to 25°C [68°F to 77°F]) for a maximum of 30 days, protected from sources of excessive temperature fluctuations such as exposure to high temperatures or light. Storage of Zilcoplan outside of room temperature is preferably avoided. Zilcoplan may be stored under these conditions for a maximum of 30 days.

[0210] Example 3. Evaluation of Zilcoplan for the Treatment of Myasthenia Gravis A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate the safety, tolerability, and preliminary efficacy of zilucoplan in the treatment of subjects with gMG. A schematic of the study design is depicted in Figure 2. Subjects were randomized in a 1:1:1 ratio to receive daily SC doses of 0.1 mg / kg zilucoplan, 0.3 mg / kg zilucoplan, or matching placebo during the study. Randomization was stratified based on screening quantitative myasthenia gravis (QMG) score (≤17 vs. ≥18).

[0211] The main part of the study included a screening period of up to 4 weeks and a treatment period of 12 weeks. During the treatment period, subjects returned to the clinic weekly after the Day 1 visit for the first two visits (Days 8 and 15), followed by visits at Weeks 4 (Day 29), 8 (Day 57), and 12 (Day 84) to assess safety, tolerability, and preliminary efficacy. Additional assessments included quality of life questionnaires, biomarker samples, pharmacokinetics, pharmacodynamics, and optional pharmacogenomics. Safety assessments included physical examination, vital signs, electrocardiogram, laboratory tests, AEs, and immunogenicity.

[0212] Zilucoplan and matching placebo were supplied as sterile, preservative-free aqueous solutions prefilled into 1 mL glass syringes with 29 gauge, 12.7 mm (½ inch) staked needles that were placed into the self-administration device. Fill volumes were adjusted based on subject weight range to achieve the correct mg / kg dose range. Subjects were instructed to self-administer the SC dose daily.

[0213] Zilucoplan doses were determined by target dose and body weight and achieved using fixed dose combination tables by weight. These combination tables were categorized by body weight category so that each subject received at least the target minimum dose to avoid subtherapeutic dosing. At the 0.1 mg / kg dose, subjects received a minimum fixed dose of 0.1 mg / kg (range: 0.10-0.14 mg / kg). At the 0.3 mg / kg dose, subjects received a minimum dose of 0.3 mg / kg (range: 0.30-0.42 mg / kg). Table 2 summarizes dose presentations for the 0.1 and 0.3 mg / kg doses of Zilucoplan. Subjects presenting with higher body weight (>150 kg) were accommodated on an individual basis. Matching placebo was given in two presentations, 0.220 mL for the 0.1 mg / kg dose and 0.574 mL for the 0.3 mg / kg dose.

[0214] [Table 2]

[0215] screening Screening was performed to determine subject study eligibility. Screening included QMG score calculation. The optimal patient population for zilucoplan treatment was expected to have a QMG score of 12 or more calculated at screening and baseline (at least 10 hours off acetylcholinesterase inhibitor therapy, e.g., pyridostigmine), with a score of 2 or more on 4 or more test items. Other eligibility criteria assessed during screening included age between 18 and 85; gMG diagnosis at screening [according to Myasthenia Gravis Foundation of America (MGFA) criteria; class II-IVa]; positive serum for AChR autoantibodies; no change in corticosteroid dosage for at least 30 days prior to baseline or no change in corticosteroid dosage expected to occur during the 12-week treatment period; and no change in immunosuppressive therapy, including dosage, for at least 30 days prior to baseline or no change in immunosuppressive therapy, including dosage, expected to occur during the 12-week treatment period. Female subjects of childbearing potential were required to have a negative serum pregnancy test at screening and a negative urine pregnancy test within 24 hours prior to the first dose of investigational drug, and sexually active female subjects of childbearing potential (i.e., women who are not postmenopausal and have not had a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) and all male subjects (not sterilized by vasectomy) agreed to use effective contraception during the study.

[0216] During screening, evaluations were performed that included collection of disease history with gMG diagnosis according to MGFA criteria (class II-IVa); serology for AChR autoantibodies; QMG score calculation; height and weight measurements; assessment of vital signs [heart rate (HR), temperature, and sitting blood pressure]; 12-lead electrocardiogram; evaluation of previous Neisseria meningitidis vaccination; collection of blood samples for clinical testing [hematological, chemistry, coagulation, adenosine deaminase (ADA) testing, and pharmacogenomic analyses]; collection of urine samples for urinalysis; and a serum pregnancy test for women of childbearing potential.

[0217] Subjects were excluded from the study if they met any of the following criteria: (1) thymectomy within 6 months prior to baseline or planned thymectomy during the 12-week treatment period; (2) abnormal thyroid function as determined by local standards; (3) known seropositivity for muscle-specific kinase (MuSK) or lipoprotein receptor-related peptide 4 (LRP4); (4) minimally symptomatic state of myasthenia gravis based on clinical assessment. (5) 60 mL / min / 1.73 m based on the Modification of Diet in Renal Disease (MDRD) formula at screening; 2 Calculated glomerular filtration rate of less than:

[0218]

number

[0219] (6) elevated liver function tests (LFTs) defined as total bilirubin or transaminases [aspartate aminotransferase (AST) / alanine aminotransferase (ALT)] greater than twice the upper limit of normal (× ULN); (7) history of meningococcal disease; (8) current or recent systemic infection within 2 weeks prior to baseline or infection requiring IV antibiotics within 4 weeks prior to baseline; (9) pregnant, planning to become pregnant, or breastfeeding female subjects; (10) recent surgery requiring general anesthesia within 2 weeks prior to screening or surgery scheduled during screening or the 12-week treatment period; (11) treatment with an experimental drug or another complement inhibitor within 30 days or 5 half-lives of the experimental drug (whichever is longer) prior to baseline; (12) (13) ongoing treatment with IV immunoglobulin G (IVIG) or plasma exchange (PLEX) or treatment within 4 weeks prior to baseline; (14) active neoplasm (other than benign thymoma) requiring surgery, chemotherapy, or radiation within the previous 12 months (subjects with a history of malignancy who have undergone curative resection or who have otherwise not required treatment and have had no detectable recurrence for at least 12 months prior to screening are permitted); (15) fixed muscle weakness based on clinical judgment ("burnout" MG); (16) history of significant medical or psychiatric disorder making the subject unsuitable to participate in the study; and (17) participation in another concurrent clinical trial involving an experimental therapeutic intervention (participation in observational and / or registry studies is permitted).

[0220] Duration of treatment Randomized subjects received 0.1 mg / kg zircoplan, 0.3 mg / kg zircoplan, or matching placebo subcutaneously at visit day 1. After in-clinic education and training, all subjects self-injected blinded study drug at SC doses daily for the following 12 weeks according to their randomized treatment assignment. Injection equipment was provided for use during the study. Subjects were expected to continue receiving stable doses of gMG standard of care (SOC) therapy, including pyridostigmine, corticosteroids, or immunosuppressants, throughout the study. Dosing on study visit days was withheld until QMG scoring and blood sampling [for pharmacokinetic (PK) and pharmacodynamic (PD) analyses] were completed. On days when rescue therapy was administered concomitantly, study drug dosing was withheld until after rescue therapy administration and PK / PD sampling. Rescue therapy included titration of gMG therapy due to deterioration of subject clinical condition. During salvage therapy, subjects received immunoglobulin (IVIG) or plasma exchange treatment.

[0221] During the main part of the study, the total duration of study participation for all subjects was up to approximately 16 weeks, including a screening period of up to 4 weeks and a treatment period of 12 weeks. An extension part of the study was made available for continued Zilcoplan administration.

[0222] Subjects received treatment with 0.1 mg / kg zircoplan, 0.3 mg / kg zircoplan, or matching placebo according to randomization from days 1 to 84 during the treatment period of the main part of the study. Subjects who completed the day 84 visit (including those randomized to the placebo arm) had the option to continue treatment with zircoplan in the extension part of the study.

[0223] End-of-study and final study procedures included: weight measurement; review and documentation of concomitant medications; symptom-based physical examination; assessment of vital signs (e.g., heart rate, temperature, and sitting blood pressure); 12-lead electrocardiogram; collection of blood samples for clinical testing (hematology, chemistry, coagulation, ADA testing, pharmacokinetic, pharmacodynamic, and biomarker analyses); collection of urine for urinalysis; urine pregnancy test in women of childbearing potential; QMG score calculation; and calculation of MG-ADL, MG-QOL15r, and MG Composite (MGC).

[0224] Sample analysis During the main portion of the study, blood samples for PK and PD analyses were collected from all subjects at the time points depicted in Table 3. Extension blood sample collections for PK and PD analyses were designed to be identical under the salvage therapy scenario. Additionally, blood drawn at Week 36 of the extension portion was planned to follow the "Day 1" schedule described for the main portion blood draws.

[0225] [Table 3]

[0226] On all other study visits, a single PK and PD sample was collected prior to administration of study drug. Plasma concentrations of zilcoplan and its metabolites were measured in all blood samples. Blood samples for safety analyses were collected at the following time points on Day 1: (i) pre-dose (within 1 hour prior to administration of the first dose of study drug) and (ii) 6 hours (± 90 minutes) post-dose. At all other study visits, samples for safety analyses were collected prior to administration of study drug. An additional blood sample for study was drawn 6 hours (± 90 minutes) post-dose on Day 84 from subjects intending to participate in the extension portion of the study. Blood sample analytes evaluated included those listed in Table 4.

[0227] [Table 4]

[0228] MG pathophysiology biomarker analysis [e.g., complement fixation, complement function, complement pathway proteins, autoantibody characterization (titer and immunoglobulin class), and inflammatory markers] could be used to provide further insight into the clinical efficacy and safety of zilucoplan in subjects with gMG. Assessment of complement protein levels and complement activity could be used to assess response to zilucoplan and understand subject characteristics associated with variability in drug response. Inflammatory marker testing could be used to assess correlation with complement function and clinical response to zilucoplan. The list of analytes could be developed by review of the literature, ongoing clinical trials, and ongoing exploratory work and finalized after completion of studies.

[0229] The primary efficacy outcome was the change in QMG score from baseline to week 12 (day 84). The QMG score is a standardized, validated, quantitative intensity scoring system developed specifically for MG and previously used in clinical trials. Higher scores represent more severe disability. Recent data suggest that an improvement in QMG score of 2-3 points may be considered clinically meaningful depending on disease severity [Barohn, RJ, et al., Ann NY 1998, Journal of Clinical Oncology, 1998, 111:111–112]. Acad Sci 841:769-72; Katzberg, HD et al., 2014, Muscle Nerve 49(5):661-5. QMG calculations were performed at each study visit and at screening to assess subject eligibility. QMG calculations were performed at approximately the same time of day (preferably in the morning) at each visit throughout the study. If subjects were receiving a cholinesterase inhibitor (e.g., pyridostigmine), the medication was withheld for at least 10 hours prior to QMG testing. The 0.3 mg / kg and 0.1 mg / kg dose groups were compared to the placebo dose group to assess linear trends based on all three treatment groups.

[0230] Secondary efficacy outcomes included change from baseline in MG-ADL, MG-QOL15r, and MG composite at week 12. Each active treatment was compared to a placebo group. Among subjects with a 3-point or greater decrease in QMG score at week 12 and subjects requiring rescue therapy over the 12-week treatment period, the proportion of subjects meeting each outcome in the active treatment group was compared to the placebo group.

[0231] The specific order of efficacy outcome analyses was arranged to reduce subject fatigue and increase the reliability of the results. MG-QOL15r analyses were performed first, followed by MG-ADL analyses, QMG score calculations, and MG composite. The same assessors were used throughout the study to reduce assessment variability.

[0232] result Study results were obtained from a broad, demographically balanced population of participants. Pre-study baseline characteristics of study participants are presented in Table 5. In the table, "SD" refers to "standard deviation" and "SOC" refers to "standard of care."

[0233] [Table 5]

[0234] The population included subjects with baseline disease characteristics indicative of refractory as well as non-refractory disease states. Baseline disease characteristics, including MGFA classification and efficacy outcome measures, were also balanced among study participants. In the study, 15 subjects received placebo, 15 subjects received low-dose zilucoplan (0.1 mg / kg), and 14 subjects received high-dose zilucoplan (3 mg / kg). Significance tests were predefined with a one-sided alpha of 0.1.

[0235] Baseline demographic characteristics were similar between groups with respect to mean age (48.4-54.6 years), racial representation (78.6%-86.7% Caucasian), mean weight (85.27-110.9 kg), and mean BMI (30.856-36.000). There was an imbalance between groups with respect to gender, with 71.4%, 46.7%, and 26.7% male in the 0.3 mg / kg zilucoplan, 0.1 mg / kg zilucoplan, and placebo groups, respectively. However, gender is not known to play a significant role in treatment response in gMG.

[0236] Medical history, including disease duration, previous MG crisis, previous thymectomy, and previous treatment with pyridostigmine, corticosteroid therapy, immunosuppressants, or salvage therapy with IVIG or PLEX, was balanced between treatment groups. More than 90% of subjects in each group had received an acetylcholinesterase inhibitor; more than 85% had received corticosteroids; 64.3-80% had received immunosuppressive therapy; 53.3-71.4% had received IVIG; and 46.7-60.0% had received plasma exchange.

[0237] MG disease severity as measured by MGFA classification was similar between treatment groups, with all subjects in the 0.1 mg / kg zilucoplan and placebo groups in MGFA class II (mild disease severity) and III (moderate disease severity), whereas the 0.3 mg / kg zilucoplan group also contained four subjects in MGFA class IV (severe disease).

[0238] MG-specific baseline characteristics were well balanced across primary (QMG) and primary secondary (MG-ADL) outcome scores, with mean baseline QMG scores of 19.1, 18.7, and 18.7; and mean MG-ADL scores of 7.6, 6.9, and 8.8 in the 0.3 mg / kg zilucoplan, 0.1 mg / kg zilucoplan, and placebo groups, respectively. MG-QOL15r was approximately 3 points higher in the 0.1 mg / kg zilucoplan group than in the 0.3 mg / kg zilucoplan group, with mean MG-QOL15r scores of 16.5, 19.1, and 15.9 in the 0.3 mg / kg zilucoplan, 0.1 mg / kg zilucoplan, and placebo groups, respectively. The MGC was more than 4 points higher in the placebo group than in the other two groups, with mean MGC scores of 14.6, 14.5, and 18.7 in the 0.3 mg / kg zilucoplan, 0.1 mg / kg zilucoplan, and placebo groups, respectively.

[0239] Clinical efficacy outcomes are given in Table 6. In the table, P values ​​are one-sided based on an analysis of covariance (ANCOVA) model with baseline values ​​as covariates and last observation carried forward (LOCF) for subjects who received salvage therapy. "LS" refers to "least squares," "CFB" refers to change from baseline, and "se" refers to "standard error."

[0240] [Table 6]

[0241] The 0.3 mg / kg treatment group demonstrated a clinically meaningful and statistically significant improvement in QMG score (≥3 points) versus baseline at week 12 (Figure 3), with a mean difference versus placebo of -2.8. A clinically meaningful and statistically significant improvement in MG-ADL score (≥2 points) versus baseline was also observed in this treatment group at week 12 (Figure 4), with a mean difference versus placebo of -2.3. Clinically meaningful and statistically significant improvements were also observed in the lower dose treatment group, representing only slightly lower changes from baseline than those observed in the higher dose subjects. In the lower dose treatment (0.1 mg / kg), a clinically meaningful and statistically significant improvement in QMG score was observed at week 12 with a mean difference versus placebo of -2.3 points (Figure 5). A clinically meaningful and statistically significant change in MG-ADL score at week 12 was also observed in this group (-2.2 mean difference versus placebo; Figure 6). The change in MG-ADL from baseline for placebo versus the mean change for the pooled low and high dose zilucoplan treatment groups (n=29) is shown in Figure 7 and indicates a statistically significant advantage of zilucoplan treatment versus placebo (-2.2 mean difference versus placebo; p=0.047, two-sided). When comparing treatment responders in the high dose group versus placebo at week 12 versus placebo responders, the highest levels of improvement in QMG score and MG-ADL were all in the zilucoplan treatment group, with more patients overall improving at each cutoff level with zilucoplan compared to placebo.

[0242] Zilcoplan reduced the need for rescue therapy, with only 1 subject (7%) in the low-dose treatment group and 0 subjects in the high-dose treatment group requiring rescue therapy (compared to 3 subjects (20%) in the placebo group). No significant endpoint differences were observed between treatment groups based on prior therapy covariates (immunosuppressive therapy, IVIG, or PLEX), all with P values ​​greater than 0.20.

[0243] Responder analyses were performed for the QMG and MG-ADL endpoints. A clinically meaningful response on the QMG total score was defined as an improvement of ≥3 points, consistent with the upper end of the established minimal clinically important difference (MCID) for the QMG (Barohn et al., 1998; Katzberg et al., 2014). The proportion of responders at week 12 using a cutoff of ≥3 points on the QMG was higher in subjects receiving 0.3 mg / kg zilucoplan (n=10 / 14) and 0.1 mg / kg zilucoplan (n=10 / 15) compared with the placebo (n=8 / 15) group (Figure 8). Additional preplanned analyses showed a benefit for the zilucoplan-treated group at all QMG cutoffs, including no subjects worsening in the 0.3 mg / kg zilucoplan group compared with 3 and 2 subjects worsening in the 0.1 mg / kg zilucoplan and placebo groups, respectively. None of these differences were statistically significant, with the exception of the 0.1 mg / kg zilucoplan group vs. placebo at the 7-point and 11-point improvement cutoffs (Table 7), and no correction for multiple testing was performed. Overall, the data are consistent with the primary analysis, generally indicating greater clinical responses in the zilucoplan treatment arm than in the placebo group.

[0244] [Table 7]

[0245] The commonly accepted MCID for MG-ADL total score is an improvement of ≥2 points (Wolfe et al., 1999; Muppidi et al., 2011). Analyses also included higher cutoffs up to a difference of at least 11 points. The proportion of responders at week 12 using a cutoff of ≥2 points on the MG-ADL was higher in subjects receiving zilucoplan at 0.3 mg / kg (n=10 / 14, 71.4%) and 0.1 mg / kg (n=10 / 15) than in the placebo (n=8 / 15) groups (Figure 9 and Table 8).

[0246] [Table 8]

[0247] A minimal symptom expression (MSE) endpoint was calculated to determine how many subjects were free of or virtually free of MG symptoms with zilucoplan therapy (based on achieving an MG-ADL total score of 0 or 1). In this study, 35.7% (5 / 14) of subjects in the 0.3 mg / kg zilucoplan group achieved an MG-ADL of 0 or 1 compared to 26.7% (4 / 15) in the 0.1 mg / kg zilucoplan group and 13.3% (2 / 15) in the placebo group (placebo-corrected rates shown in Figure 10). Furthermore, the percentage of achievement in the high-dose treatment group was higher than that observed with 26 weeks of eculizumab treatment (based on eculizumab study results presented in Vissing, J. et al., 2018, American Association of Neuromuscular and Electrodiagnostic Medicine Abstracts (AANEM Abstract) 193). This analysis clearly demonstrated the magnitude of improvement in subjective perception of disease burden that could be achieved with zilucoplan in a short period of time. The dose response, with a higher proportion of patients achieving MSE in the 0.3 mg / kg zilucoplan group, was also evident in this analysis.

[0248] Few samples were taken to assess pharmacokinetic and pharmacodynamic data. Steady-state zircoplan plasma concentrations were achieved within the first 2 weeks of treatment, and no further accumulation was observed (Figure 11). Zircoplan trough levels at steady state (after 2 weeks) in the 0.3 mg / kg zircoplan dose group ranged from 7,168 ng / mL to 13,710 ng / mL, whereas they ranged from 2,364 ng / mL to 7,290 ng / mL in the 0.1 mg / kg zircoplan dose group. The 0.3 mg / kg zircoplan dose consistently achieved complete terminal complement pathway inhibition as measured by a sheep red blood cell (sRBC) hemolysis assay (>95% inhibition at trough). The 0.1 mg / kg zircoplan dose, in contrast, did not consistently achieve complete hemolysis inhibition (Figure 12). Pharmacokinetic and pharmacodynamic results correlated closely in patients with gMG (Figure 13), demonstrating complete inhibition of the terminal complement pathway with zilucoplan plasma concentrations above approximately 9,000 ng / ml.

[0249] Overall, both high- and low-dose zilucoplan treatment was effective, with minimal adverse effects, and the higher doses produced more robust clinical improvement. Example 4. Extension part At the end of the treatment period in the main part of the study described in the above examples, all subjects were given the option to receive zilcoplan in the extension part of the study, provided they met the extension selection criteria. Subjects assigned to the zilcoplan treatment arm during the main part of the study continued to receive the same dose of study drug during the extension part. Subjects assigned to the placebo arm during the main part of the study were randomized in a 1:1 ratio to receive 0.1 mg / kg zilcoplan or 0.3 mg / kg zilcoplan administered SC daily. Assessments and visits during the first 12 weeks of the extension part were identical to those in the main part of the study for all subjects, ensuring adequate monitoring of subjects moving from placebo to active treatment and maintaining blinding of treatment assignment.

[0250] Selection criteria for acceptance into the extension portion included: (1) seropositivity for AChR autoantibodies; (2) for female subjects of childbearing potential, a negative serum pregnancy test at screening and a negative urine pregnancy test within 24 hours prior to the first dose of investigational drug; (3) for sexually active female subjects of childbearing potential (i.e., women who are not postmenopausal and have not had a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) and for all male subjects (not sterilized by vasectomy), agreement to use effective contraception during the study; (4) use of any medicines not authorized by the exclusion criteria for the main portion of the study or changed dosing of any other concomitant medications, except when medically indicated; (5) and no new medical conditions since enrollment in the main portion of the study.

[0251] During the extension portion of the study, biopsy sections from subjects who underwent thymectomy, lymphadenectomy, or other surgical resections were sent for exploratory immunohistochemical and biomarker analysis. Forty-one patients completed the 12-week extension portion of the study (total treatment period of 24 weeks). Sustained responses were observed in each of the following: (1) QMG, 8.7 points decrease from baseline, p<0.0001 (Figure 14); (2) MG-ADL, 4.5 points decrease from baseline, p<0.0001 (Figure 15); (3) MG Composite, 10.2 points decrease from baseline, p<0.0001 (Figure 16); and MG-QOL15r, 7.5 points decrease from baseline, p=0.0006 (Figure 17).

[0252] Placebo subjects who crossed over to active treatment after 12 weeks also experienced rapid, clinically meaningful, and statistically significant improvements in each endpoint: (1) QMG, 3.1 point decrease from pretreatment levels (levels associated with 12 weeks of placebo treatment), p=0.01 (Figure 14); (2) MG-ADL, 3.6 point decrease from pretreatment levels, p=0.0004 (Figure 15); (3) MG Composite, 5.5 point decrease from pretreatment levels, p=0.004 (Figure 16); and MG-QOL15r, 4.0 point decrease from pretreatment levels, p=0.04 (Figure 17).

[0253] Example 5. Pharmacogenomic analysis Pharmacogenomic analyses will be performed on blood samples obtained at screening. Genomic testing (e.g., deoxyribonucleic acid (DNA) sequence, DNA copy number analysis, and ribonucleic acid expression profiling) will be performed, including exploring whether specific genomic features correlate with response or resistance to the investigational drug.

[0254] Example 6. Urine test Urinalysis will be performed on samples collected during screening and during all study and rescue care visits to assess pH, specific gravity, protein (qualitative), glucose (qualitative), ketones (qualitative), bilirubin (qualitative), urobilinogen, occult blood, hemoglobin, and cells. Microscopy will be performed to confirm measurements, if necessary.

[0255] Example 7. Phase III Study A single, global, randomized, double-blind, placebo-controlled, parallel-group, multicenter study (n=130) will be conducted to evaluate the efficacy of zilucoplan in subjects with gMG, testing daily subcutaneous 0.3 mg / kg zilucoplan treatment versus placebo for 12 weeks. After the 12-week double-blind, placebo-controlled period, all subjects will have the option to receive zilucoplan in an open-label extension. Subjects will be evaluated for change in MG-ADL (primary endpoint), QMG, MG composite, and MG-QOL15r during and after the main and extension treatments.

[0256] Patients with gMG will be enrolled in the study provided they meet the following key inclusion criteria: (1) MGFA clinical classification class II-IV; (2) positive serology for anti-AChR antibodies; (3) MG-ADL score ≥ 5; (4) QMG total score ≥ 12; (5) no change in corticosteroid dosage or immunosuppressive therapy for at least 4 weeks prior to randomization, or no change expected to occur during the 12-week treatment period; and have not received PLEX or IVIG for at least 4 weeks prior to dosing, and have not received rituximab for at least 12 months. Selection will be based on anti-AChR positive status, ensuring that patients who are predicted to not respond to complement inhibitor therapy due to lack of complement-fixing antibodies, such as anti-MUSK-antibody positive patients, are excluded; and ensuring that all patients participating in the study have a clinically and laboratory confirmed diagnosis of MG. The study population will not be limited to "treatment-resistant" patients, and will allow for enrollment of patients across the disease spectrum. There is no underlying mechanism by which terminal complement inhibition would be believed to be effective only in patients who have exhausted all other therapies.

[0257] Example 8. Zilcoplan inhibits autoantibody-induced complement activity at the neuromuscular junction (NMJ) Co-cultures of human myotubes and neuroblastoma cells were prepared and cultured with human serum as an in vitro NMJ model. Cells were cultured with or without 10 μM zircoplan and with anti-acetylcholine receptor (AChR) 637 antibody in either IgG1 or IgG4 format. IgG1 antibodies are known to promote complement-mediated C5b-9 deposition, whereas IgG4 antibodies do not. Subsequent deposition of C5b-9 was observed by immunofluorescence using anti-C5b-9 antibody (aE11, AbCam, Cambridge, UK). C5b-9 deposition was observed in cells cultured with anti-AChR 637 IgG1 without zircoplan. C5b-9 deposition was absent in cells cultured under the same conditions but with 10 μM zircoplan. Because complement-mediated destruction of the NMJ contributes to the pathogenesis of gMG, the present data illustrate the mechanistic basis for the favorable clinical responses observed in the human studies described above.

[0258] Example 9. Zilcoplan permeability Zilucoplan in vitro permeability was evaluated using a basement membrane model. In the model, the diffusion of zilucoplan across an extracellular matrix (ECM) gel membrane (prepared as described in Arends, F. et al., 2016, IntechOpen, Digital Object Identifier: 10.5772 / 62519) was evaluated and compared to the diffusion of eculizumab. In the model, compounds were introduced into an upper reservoir separated from a lower reservoir by an ECM gel membrane. The ECM gel membrane was prepared to contain matrix components mimicking those found in the basal lamina of neuromuscular junctions. Compound permeability across the membrane was evaluated by detection in the lower reservoir. More than 20% of zilucoplan introduced into the upper reservoir diffused into the lower reservoir after 12 hours, and more than 60% had diffused by 24 hours (see Figure 18). In contrast, less than 20% of eculizumab diffused into the lower reservoir after 24 hours. The results demonstrated superior permeability (approximately 4-fold higher) through the basement membrane of zilucoplan compared with eculizumab, suggesting preferential tissue penetration.

[0259] The increased permeability of zilcoplan was confirmed by quantitative whole body analysis (QWBA). For this study, zilcoplan was modified to the C-terminal lysine 14 C and administered to rats. Animals were imaged to measure the concentration of radiolabeled zilucoplan in multiple organs and tissues over time (24 hours). The area under the curve (AUC) for each organ or tissue analyzed was expressed as a percentage of the plasma AUC, giving the biodistribution values ​​presented in Table 9 below. Estimated eculizumab biodistribution values ​​based on monoclonal antibody biodistribution studies published in Shah, DK et al., 2013, mAbs, 5:297-305, are provided for comparison.

[0260] [Table 9]

[0261] These results support the use of zilucoplan to inhibit C5 activity in tissues where C5 inhibitor tissue penetration is required and eculizumab tissue penetration is insufficient. Example 10. Zilcoplan drug-drug interactions Zilcoplan in vivo drug-drug interaction studies were conducted in non-human primates with potential co-medications. First, the effect of cyclosporine A on the pharmacokinetics of zilcoplan and vice versa was investigated. Cyclosporine A is a known inhibitor of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3, and is a potential co-medication in PNH. No effect on zilcoplan exposure was observed after administration of cyclosporine A, and no effect on cyclosporine A exposure was observed after administration of zilcoplan. These results support the method of administering zilcoplan in combination with cyclosporine A to treat complement-related indications (e.g., myasthenia gravis) in subjects.

[0262] A second in vivo drug-drug interaction study was performed with zilucoplan and DX-2507, an inhibitor of fetal Fc receptor (FcRN) recycling, a functionally equivalent variant of DX-2504 with a cysteine ​​to alanine mutation to improve manufacturability (described in Nixon, AE et al., Front Immunol. 6:176, 2015). By inhibiting FcRN, DX-2504 inhibits Fc-mediated recycling, thereby decreasing the half-life of IgG antibodies. Administration of DX-2504 serves as a model for intravenous immunoglobulin (IVIG) therapy, which reduces the half-life of IgG antibodies by overwhelming the Fc recycling mechanism with high doses of immunoglobulin. Zilucoplan pharmacokinetics and pharmacodynamics were not altered by coadministration of anti-FcRN monoclonal antibody DX-2507 in cynomolgus monkeys. Furthermore, no changes in zilucoplan levels were observed in patients receiving co-therapeutic administration of IVIG. These results demonstrate no effect of FcRN inhibition on zilucoplan pharmacokinetics and support the method of treating complement-related indications (e.g., myasthenia gravis) in subjects by administering zilucoplan in combination with an FcRN inhibitor (DX-2504, DX-2507, or IVIG). (Additional Note) The technical ideas that can be understood from the above-described embodiment and modified examples will be described. [Item 1] A method of treating myasthenia gravis (MG) comprising administering zilucoplan to a subject. [Item 2] 2. The method of claim 1, wherein the MG is generalized MG (gMG). [Item 3] 3. The method of item 1 or 2, wherein administering zircoplan comprises subcutaneous (SC) administration. [Item 4] 4. The method according to any one of items 1 to 3, wherein zilcoplan is administered at a dosage of about 0.1 mg / kg (mg zilcoplan / kg subject body weight) to about 0.6 mg / kg. [Item 5] 5. The method of any one of items 1 to 4, wherein administration of zircoplan comprises self-administration. [Item 6] The method according to any one of items 1 to 5, wherein administration of zilcoplan comprises use of a prefilled syringe. [Item 7] 7. The method of claim 6, wherein the syringe comprises a 29 gauge needle. [Item 8] The method of any one of items 1 to 7, wherein administration of zilcoplan comprises self-administration using a self-administration device. [Item 9] 9. The method of claim 8, wherein the self-administration device comprises a pre-filled syringe according to claim 6 or 7. [Item 10] 10. The method of claim 9, wherein the prefilled syringe is a glass syringe. [Item 11] 11. The method of claim 9 or 10, wherein the prefilled syringe comprises a maximum filling volume of at least 1 ml. [Item 12] 12. The method of any one of items 8 to 11, wherein the self-administration device contains a Zilcoplan solution. [Item 13] 13. The method according to item 12, wherein the Zilcoplan solution is an aqueous solution. [Item 14] 14. The method according to claim 12 or 13, wherein the Zilcoplan solution is preservative-free. [Item 15] 15. The method of any one of items 12 to 14, wherein the self-administration device contains a volume of Zilcoplan solution of about 0.15 ml to about 0.81 ml. [Item 16] 16. The method of any one of items 1 to 15, wherein the subject is screened prior to administration of zilucoplan. [Item 17] 17. The method of claim 16, wherein the screening comprises calculating a quantitative myasthenia gravis (QMG) score. [Item 18] 18. The method of item 17, wherein the subject's QMG score is 12 or greater. [Item 19] 19. The method of claim 18, wherein the subject does not receive MG therapy for at least 10 hours prior to the QMG score calculation. [Item 20] 20. The method according to item 18 or 19, wherein the subject is not receiving acetylcholinesterase inhibitor therapy for at least 10 hours prior to the QMG score assessment. [Item 21] 21. The method according to any one of items 18 to 20, wherein 4 or more QMG test items achieve a score of 2 or more. [Item 22] 22. The method according to any one of items 1 to 21, wherein the subject is 18 to 85 years old. [Item 23] 23. The method of any one of items 16 to 22, wherein screening comprises selecting a subject previously diagnosed with gMG. [Item 24] 24. The method of item 23, wherein the gMG diagnosis is made according to the Myasthenia Gravis Foundation of America (MGFA) criteria. [Item 25] 25. The method of any one of items 16 to 24, wherein the screening comprises assessment of acetylcholine receptor (AChR) autoantibody levels. [Item 26] 26. The method of any one of items 16-25, wherein screening comprises confirming that there is no change in the corticosteroid dosage received by the subject for at least 30 days prior to screening. [Item 27] 27. The method of any one of items 16 to 26, wherein screening comprises confirming that there is no change in the subject's immunosuppressive therapy for at least 30 days prior to screening. [Item 28] 28. The method according to any one of items 16 to 27, wherein screening comprises a serum pregnancy test and / or a urine pregnancy test. [Item 29] 29. The method of any one of items 1 to 28, wherein administration of zilcoplan comprises daily administration. [Item 30] 30. The method of any one of items 1 to 29, wherein the subject is concurrently receiving standard of care gMG therapy. [Item 31] 31. The method of claim 30, wherein the standard of care gMG therapy comprises one or more of pyridostigmine therapy, corticosteroid therapy, and immunosuppressant therapy. [Item 32] 32. The method of any one of items 1 to 31, wherein the subject is assessed or monitored for MG features, and the MG features comprise one or more of the QMG score, Myasthenia Gravis-Activities of Daily Living (MG-ADL) score, MG-QOL15r score, and MG composite score. [Item 33] 33. The method of claim 32, wherein subject evaluation or monitoring comprises assessing changes in said MG characteristics during or after subject zilucoplan treatment. [Item 34] The method of item 33, wherein the treated subject's QMG score is reduced. [Item 35] 35. The method of item 34, wherein the treated subject's QMG score is reduced by at least 3 points. [Item 36] 36. The method according to item 34 or 35, wherein the treated subject's QMG score is reduced at or before 12 weeks of treatment. [Item 37] 37. The method according to any one of items 34 to 36, wherein the subject's QMG score is monitored during the course of Zilcoplan treatment. [Item 38] 38. The method according to any one of items 34 to 37, wherein the subject is undergoing cholinesterase inhibitor treatment during Zilcoplan treatment. [Item 39] 39. The method of item 38, wherein cholinesterase inhibitor treatment is withheld for at least 10 hours prior to calculation of the subject's QMG score. [Item 40] 40. The method of claim 39, wherein the change in the MG characteristic comprises a change in MG composite score of at least 3 points from a baseline MG composite score. [Item 41] 41. The method of item 40, wherein said change in MG composite score from baseline MG composite score occurs at or prior to 12 weeks of Zilcoplan treatment. [Item 42] 40. The method of claim 39, wherein the change in the MG characteristic comprises a change in MG-ADL score of at least 2 points from a baseline MG-ADL score. [Item 43] 43. The method of item 42, wherein said change in MG-ADL score from baseline MG-ADL score occurs at or prior to 12 weeks of Zilcoplan treatment. [Item 44] 44. The method of any one of items 1 to 43, wherein the zircoplan is in a solution, and the solution comprises phosphate buffered saline (PBS). [Item 45] 45. The method according to any one of claims 1 to 44, wherein the zircoplan is in a solution, the solution comprising from about 4 mg / ml to about 200 mg / ml zircoplan. [Item 46] 46. ​​The method of claim 45, wherein the solution contains about 40 mg / ml zircoplan. [Item 47] Subject zirconia plasma levels were measured at maximum concentration (C max 47. The method according to any one of items 1 to 46, wherein [Item 48] 48. The method of any one of items 1-47, wherein at least 90% hemolysis inhibition is achieved in the subject serum, and optionally, the hemolysis inhibition is measured by a sheep red blood cell (sRBC) hemolysis assay. [Item 49] A syringe containing Zilcoplan; and User manual Kit including: [Item 50] 50. The kit according to item 49, wherein the syringe constitutes an autoinjection device. [Item 51] 51. The kit of item 49 or 50, wherein the self-injection device comprises a BD ULTRASAFE PLUS™ self-administration device. [Item 52] 52. The kit of any one of items 49 to 51, comprising an alcohol wipe. [Item 53] 53. The kit according to any one of items 49 to 52, comprising a wound dressing. [Item 54] 54. The kit according to any one of items 49 to 53, comprising a disposal container. [Item 55] 55. The kit according to any one of items 49 to 54, wherein the zircoplan is in solution. [Item 56] 56. The kit according to item 55, wherein the solution is an aqueous solution. [Item 57] 57. The kit of item 56, wherein the solution comprises phosphate buffered saline. [Item 58] 58. The kit according to any one of items 55 to 57, wherein the solution contains about 4 mg / ml to about 200 mg / ml of Zilcoplan. [Item 59] Item 59. The kit of item 58, wherein the solution contains about 40 mg / ml Zilcoplan. [Item 60] 60. The kit according to any one of items 55 to 59, wherein the solution comprises a preservative. [Item 61] 1. A method for evaluating a treatment for MG, comprising: Screening evaluation candidates for at least one evaluation inclusion criterion; Selecting evaluation participants; administering to said evaluation participant said treatment for MG; and At least one efficacy endpoint will be calculated; and optionally wherein said treatment of MG is according to any one of items 1 to 48 and 95 to 112. [Item 62] 62. The method of claim 61, wherein the at least one evaluation inclusion criterion includes an MG diagnosis. [Item 63] Item 63. The method of item 62, wherein the MG diagnosis is a gMG diagnosis. [Item 64] Item 64. The method of item 63, wherein the gMG diagnosis is made according to MGFA criteria. [Item 65] 65. The method according to any one of items 61 to 64, wherein the at least one evaluation participation criterion comprises a QMG score. [Item 66] 66. The method of item 65, wherein evaluation participant selection requires an evaluation candidate QMG score of 12 or greater. [Item 67] 67. The method of claim 65 or 66, wherein the evaluation candidate has received at least one alternative MG treatment prior to screening. [Item 68] 68. The method of claim 67, wherein the candidate QMG score is calculated at least 10 hours after receiving said at least one alternative QMG treatment. [Item 69] 69. The method of claim 68, wherein the at least one alternative MG treatment comprises administration of an acetylcholinesterase inhibitor. [Item 70] 70. The method of any one of items 65 to 69, wherein evaluation participant selection requires a score of 2 or greater on four or more QMG test items. [Item 71] 71. The method according to any one of items 61 to 70, wherein the at least one evaluation participation criterion includes evaluation candidate age. [Item 72] 72. The method according to item 71, wherein the selection of assessment participants requires assessment candidate ages between 18 and 85 years old. [Item 73] 73. The method according to any one of items 61 to 72, wherein the at least one evaluation inclusion criterion comprises AChR autoantibody levels and / or anti-muscle specific kinase autoantibody levels. [Item 74] 74. The method of any one of items 61 to 73, wherein the at least one evaluation inclusion criterion comprises no change in corticosteroid dosage received by the evaluation candidate for at least 30 days prior to screening. [Item 75] 75. The method of any one of items 61 to 74, wherein the at least one evaluation inclusion criterion includes no change in evaluation candidate immunosuppressive therapy for at least 30 days prior to screening. [Item 76] 76. The method of any one of items 61 to 75, wherein the at least one evaluation participation criterion includes confirmation that the evaluation candidate is not pregnant. [Item 77] 77. The method of item 76, wherein screening comprises a serum pregnancy test and / or a urine pregnancy test. [Item 78] 78. The method of any one of items 61-77, wherein the treatment for MG is administered over an evaluation period. [Item 79] Item 79. The method according to item 78, wherein the evaluation period is from about 1 day to about 12 weeks. [Item 80] 80. The method of claim 78, wherein the evaluation period is about 12 weeks or longer. [Item 81] 81. The method of any one of items 78 to 80, wherein the evaluation participants receive standard of care gMG therapy over the evaluation period. [Item 82] 82. The method of item 81, wherein the standard of care gMG therapy comprises one or more of pyridostigmine therapy, corticosteroid therapy, and immunosuppressant therapy. [Item 83] 83. The method according to any one of items 61 to 82, wherein the at least one efficacy evaluation item comprises a reduction in the treated subject's QMG score. [Item 84] 84. The method of item 83, wherein the treated subject's QMG score reduction is at least 3 points. [Item 85] 85. The method according to item 83 or 84, wherein the evaluation participant receives cholinesterase inhibitor treatment during the evaluation period. [Item 86] 86. The method of claim 85, wherein the cholinesterase inhibitor treatment is withheld for at least 10 hours prior to calculating the subject's QMG score. [Item 87] 87. The method of any one of items 61 to 86, wherein the at least one efficacy endpoint comprises a change in baseline score for one or more of MG-ADL score, MG-QOL15r score, and MG composite score. [Item 88] 88. The method of item 87, wherein the at least one efficacy endpoint comprises a change in baseline MG composite score of at least 3 points. [Item 89] 90. The method of item 88, wherein the change in baseline MG composite score occurs at or prior to 12 weeks of the treatment. [Item 90] 90. The method of any one of items 87 to 89, wherein the at least one efficacy endpoint comprises a change in baseline MG-ADL score of at least 2 points. [Item 91] 91. The method of item 90, wherein said change in baseline MG-ADL score occurs at or prior to 12 weeks of said treatment for MG. [Item 92] 92. The method of any one of items 61 to 91, wherein calculating the at least one efficacy evaluation item comprises a set of calculations, the set of calculations being performed in the following order: (1) calculating the evaluation participant's MG-QOL15r score; (2) calculating the evaluation participant's MG-ADL score; (3) calculating the evaluation participant's QMG score; and (4) calculating the evaluation participant's MG Composite score. [Item 93] 93. The method of item 92, wherein the set of calculations is performed on one or more occasions after administration of the treatment for MG. [Item 94] 94. The method of item 93, wherein the one or more times after administration of the treatment for MG include 1 week, 2 weeks, 4 weeks, 8 weeks, and / or 12 weeks after administration of the treatment for MG. [Item 95] 49. The method according to any one of items 1 to 48, wherein Zilcoplan is administered in a daily dose of about 0.1 mg / kg to about 0.3 mg / kg. [Item 96] 96. The method of claim 95, wherein zilcoplan is administered at a dosage of 0.3 mg / kg. [Item 97] 97. The method of any one of items 1 to 48, 95, and 96, wherein the subject's QMG score and / or MG-ADL score is decreased. [Item 98] 98. The method according to item 97, wherein the QMG score is reduced by 3 points or more after 8 weeks of treatment. [Item 99] 99. The method according to item 97 or 98, wherein the MG-ADL score is reduced by 2 or more points after 8 weeks of treatment. [Item 100] 99. The method according to any one of items 1 to 48 and 95 to 99, wherein the risk of needing salvage therapy is reduced. [Item 101] The method according to any one of items 1 to 48 and 95 to 100, wherein the administration is carried out at a stage of the MG disease that occurs prior to the critical or critical stage of MG. [Item 102] The method according to any one of items 1 to 48 and 95 to 101, wherein administration of zilucoplan results in a reduction in the manifestation of the target symptom. [Item 103] 103. The method of claim 102, wherein the reduction in the subject symptom expression exceeds a reduction in the subject symptom expression associated with administration of eculizumab. [Item 104] 104. The method of any one of items 1 to 48 and 95 to 103, wherein the target neuromuscular junction (NMJ) membrane attack complex (MAC) pore formation is inhibited. [Item 105] Item 105. The method of item 104, wherein the safety factor at the NMJ is improved. [Item 106] The method according to any one of items 1 to 48 and 95 to 105, wherein Zilcoplan is administered in combination with a therapeutic agent. [Item 107] 107. The method of claim 106, wherein the therapeutic agent comprises an immunosuppressant. [Item 108] 108. The method of claim 107, wherein the immunosuppressant comprises a compound selected from one or more of azathioprine, cyclosporine, cyclosporine A, mycophenolate mofetil, methotrexate, tacrolimus, cyclophosphamide, and rituximab. [Item 109] 109. The method according to any one of items 106 to 108, wherein the therapeutic agent comprises an inhibitor of autoantibody-mediated tissue destruction. [Item 110] 110. The method of claim 109, wherein the inhibitor of autoantibody-mediated tissue destruction comprises a fetal Fc receptor (FcRN) inhibitor. [Item 111] The method of item 110, wherein administration of the FcRN inhibitor comprises intravenous immunoglobulin (IVIG) therapy. [Item 112] 112. The method of any one of items 106 to 111, wherein Zilcoplan and the therapeutic agent are administered in an overlapping regimen. [Item 113] 1. An administration device adapted for the treatment of MG, comprising: An autoinjection device, including a syringe and a needle; and A volume of pharmaceutical composition wherein the pharmaceutical composition comprises zilcoplan at a concentration of 40 mg / mL in an aqueous solution, and the predetermined volume is adjusted to facilitate administration of zilcoplan to a subject at a dosage of 0.3 mg per kg of the subject's body weight. [Item 114] The administration device of item 113, wherein the self-injection device comprises a BD ULTRASAFE PLUS (trademark) self-administration device. [Item 115] A kit prepared for the treatment of MG, comprising: A set of administration devices comprising two or more administration devices according to items 113 or 114; and Instructions for use of said kit Kit including: [Item 116] Item 116. The kit of item 115, comprising an alcohol wipe. [Item 117] 117. The kit according to item 115 or 116, comprising a wound dressing. [Item 118] 118. The kit according to any one of items 115 to 117, comprising a disposal container. [Item 119] 119. The kit according to any one of items 115 to 118, wherein the pharmaceutical composition is preservative-free. [Item 120] 120. The kit according to any one of items 115 to 119, wherein the kit is prepared for storage at room temperature. [Sequence table] JPEG2025011136000015.jpg235159 JPEG2025011136000016.jpg105170

Claims

[Claim 1] 1. A method of treating myasthenia gravis (MG) comprising administering zilucoplan to a subject.

Images