Complement inhibitor dosing regimens

Abstract

Complement is a weapon of the innate immune system that plays an important role in defending the body against infectious pathogens. Although compositions that inhibit complement are known, there remains a need for compositions that can acutely inhibit complement. Methods for inhibiting complement and compositions that include PEGylated compstatin analogs are described.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 275,274, filed November 3, 2021, the entire contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Complement is a weapon of the innate immune system that plays a key role in defending the body against infectious pathogens. The complement system is composed of more than 30 serum and cellular proteins that participate in three major pathways, known as the classical, alternative, and lectin pathways. Although compositions that inhibit complement are known, there remains a need for compositions that can acutely inhibit complement. Summary of the Invention

[0003] In one aspect, the disclosure features a method of inhibiting complement in a subject. In some embodiments, the method of inhibiting complement in a subject includes intravenously administering to a subject in need thereof about 100 mg to about 2500 mg of a PEGylated compstatin analog comprising about 40 kD PEG. In some embodiments, complement is inhibited or reduced (e.g., to levels of about 100%, 90%, 80%, 70%, 60%, 50%, 40%, or less relative to control levels) for about 2 hours to about 336 hours after administration.

[0004] In another aspect, the disclosure features a method of treating a subject in need of treatment for a complement-mediated disorder, the method including intravenously administering to a subject in need thereof about 100 mg to about 2500 mg of a PEGylated compstatin analog comprising about 40 kD PEG, thereby treating the complement-mediated disorder.

[0005] In some embodiments, the methods include administering a single dose of a PEGylated compstatin analog intravenously. In some embodiments, the methods include administering two or more doses of a PEGylated compstatin analog.

[0006] In some embodiments, the single dose is an injection.

[0007] In some embodiments, the method comprises intravenously administering about 200 mg, about 600 mg, about 1500 mg, or about 2300 mg of a PEGylated compstatin analog.In some embodiments, the method comprises intravenously administering about 200 mg, about 600 mg, about 1500 mg, or about 2300 mg of a PEGylated compstatin analog over about 30 minutes.

[0008] In some embodiments, the methods include administering the infusion at a rate of about 6.5 mg / min to about 80 mg / min, hi some embodiments, the methods include administering the infusion at a rate of about 6.5 mg / min, about 20 mg / min, about 50 mg / min, or about 75 mg / min.

[0009] In some embodiments, the methods include administering the infusion over a period of about 15 minutes to about 1 hour.

[0010] In some embodiments, complement inhibition is assessed by measuring the level of complement activity in a serum sample of the subject.

[0011] In some embodiments, the level of complement activity is measured using an alternative pathway assay, a classical pathway assay, or both.

[0012] In some embodiments, the subject has or is at risk of having a complement-mediated disorder.In some embodiments, the complement-mediated disorder is hemolytic anemia, warm antibody autoimmune hemolytic anemia, cold agglutinin disease, C3 glomerulopathy, paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis, glomerulonephritis, neuromyelitis optica (NMO), amyotrophic lateral sclerosis (ALS), polyneuropathy, nephropathy, or vasculitis.

[0013] In some embodiments, the method optionally further comprises, after the intravenous administration step, subcutaneously administering a PEGylated compstatin analog to the subject.

[0014] In some embodiments, after the administration step, complement in the subject is inhibited or reduced (e.g., to levels that are about 100%, 90%, 80%, 70%, 60%, 50%, 40%, or less relative to control levels) for about 2 hours to about 336 hours after administration.

[0015] In some embodiments, the subject is in need of treatment for an exacerbation of the disorder.

[0016] In another aspect, the disclosure features a method of treating acute hemolysis in a subject, e.g., a subject suffering from a complement-mediated disorder, e.g., a subject suffering from PNH, the method including administering intensive therapy to the subject, the intensive therapy including (i) administering to the subject about 540 to about 2160 mg of a PEGylated compstatin analog comprising about 40 kD PEG, intravenously, or (ii) administering to the subject about 540 to about 2160 mg of a PEGylated compstatin analog comprising about 40 kD PEG, subcutaneously, each day for three consecutive days.

[0017] In some embodiments, the intensive therapy comprises intravenously administering to the subject about 540 mg to about 2160 mg of a PEGylated compstatin analog comprising about 40 kD PEG. In some embodiments, the intensive therapy comprises intravenously administering to the subject about 1080 mg of a PEGylated compstatin analog comprising about 40 kD PEG. In some embodiments, the intensive therapy comprises subcutaneously administering to the subject about 540 mg to about 2160 mg of a PEGylated compstatin analog comprising about 40 kD PEG each day for three consecutive days. In some embodiments, the intensive therapy comprises subcutaneously administering to the subject about 1080 mg of a PEGylated compstatin analog comprising about 40 kD PEG each day for three consecutive days.

[0018] In some embodiments, prior to acute hemolysis, the subject is treated with about 1080 mg of a PEGylated compstatin analog comprising about 40 kD PEG administered subcutaneously twice a week, and after intensive therapy, the subject is treated with about 1080 mg of a PEGylated compstatin analog comprising about 40 kD PEG administered subcutaneously every 3 days. In some embodiments, prior to acute hemolysis, the subject is treated with about 1080 mg of a PEGylated compstatin analog comprising about 40 kD PEG administered subcutaneously every 3 days, and after intensive therapy, the subject is treated with about 1080 mg of a PEGylated compstatin analog comprising about 40 kD PEG administered subcutaneously three times a week. In some embodiments, prior to acute hemolysis, the subject is treated with a C5 inhibitor, and after intensive therapy, the subject is treated with about 1080 mg of a PEGylated compstatin analog comprising about 40 kD PEG administered subcutaneously twice a week. In some embodiments, prior to acute hemolysis, the subject is treated with a C5 inhibitor, and after intensive therapy, the subject is treated with about 1080 mg of a PEGylated compstatin analog comprising about 40 kD PEG administered subcutaneously twice a week. In some embodiments, prior to acute hemolysis, the subject is not treated with a complement inhibitor, and after intensive therapy, the subject is treated with about 1080 mg of a PEGylated compstatin analog comprising about 40 kD PEG administered subcutaneously twice a week. In some embodiments, prior to acute hemolysis, the subject is not treated with a complement inhibitor, and following intensive therapy, the subject is treated with about 1080 mg of a PEGylated compstatin analog comprising about 40 kD PEG administered subcutaneously twice weekly.

[0019] In some embodiments, the subject continues treatment with the C5 inhibitor for four weeks after receiving the intensive therapy, and then discontinues treatment with the C5 inhibitor.

[0020] In some embodiments, prior to intensive therapy, the subject had an LDH level of at least 2x the ULN.

[0021] In some embodiments, the method optionally further includes determining that the subject is experiencing acute hemolysis by a method comprising detecting an LDH level of at least twice the ULN in a blood sample obtained from the subject prior to administration of the intensive therapy.

[0022] In some embodiments, the method optionally further comprises measuring LDH in a blood sample obtained from the subject within two weeks of the intensive therapy.

[0023] In some embodiments, the PEGylated compstatin analog comprises a PEG having at least two compstatin analog moieties attached thereto. In some embodiments, the PEGylated compstatin analog comprises a linear PEG having a compstatin analog moiety attached to each end. In some embodiments, each compstatin analog moiety comprises a cyclic peptide comprising the amino acid sequence of one of SEQ ID NOs: 3-36, 37, 69, 70, 71, and 72.

[0024] In some embodiments, a PEGylated compstatin analog comprises one or more PEG moieties attached to one or more compstatin analog moieties, each compstatin analog moiety comprising a cyclic peptide having an amino acid sequence set forth in any of SEQ ID NOs: 3-36 extended at the N-terminus, C-terminus, or both, by one or more terminal amino acids, one or more of which have a side chain comprising a primary or secondary amine and are separated from the cyclic peptide by a rigid or flexible spacer, optionally comprising an oligo(ethylene glycol) moiety, each PEG being covalently attached to one or more compstatin analog moieties via a linking moiety, the linking moiety comprising an unsaturated alkyl moiety, a moiety comprising a non-aromatic ring system, an aromatic moiety, an ether moiety, an amide moiety, an ester moiety, a carbonyl moiety, an imine moiety, a thioether moiety, and / or an amino acid residue.

[0025] In some embodiments, each compstatin analog moiety comprises a cyclic peptide extended at the N-terminus, C-terminus, or both by one or more amino acids, and the one or more amino acids are separated from the cyclic portion of the peptide by a rigid or flexible spacer comprising 8-amino-3,6-dioxaoctanoic acid (AEEAc) or 11-amino-3,6,9-trioxaundecanoic acid.

[0026] In some embodiments, the cyclic peptide comprises the amino acid sequence of SEQ ID NO: 28 and the spacer comprises AEEAc.In some embodiments, the PEGylated compstatin analog comprises the structure shown in FIG.

[0027] The present teachings described herein will be more fully understood from the following description of various exemplary embodiments when read in conjunction with the accompanying drawings, in which it is understood that the drawings described below are for illustrative purposes only and are not intended to limit the scope of the present teachings in any manner. [Brief description of the drawings]

[0028] [Figure 1] 1 shows structures of exemplary PEGylated compstatin analogs. [Diagram 2] 1 shows the mean serum levels of the PEGylated compstatin analog of FIG. 1 having a PEG of about 40 kilodaltons (kD) for the cohort. The PEGylated compstatin analog is referred to as PEG in the figure. [Diagram 3] 1 shows the mean AH50 (U / mL) levels of the PEGylated compstatin analog cohort. The PEGylated compstatin analog is referred to as PEG in the figures. [Figure 4]FIG. 2 shows a diagram of an exemplary treatment regimen for intensive therapy of patients with acute hemolysis (AH) using the PEGylated compstatin analog (pegcetacoplan) of FIG. 1, having a PEG of about 40 kilodaltons (kD). Patients received either intravenous (IV) (upper route) or intensive subcutaneous (SC) (lower route) administration of pegcetacoplan. LDH=lactate dehydrogenase, Q3D=every 3 days, TIW=three times a week, ULN=upper limit of normal. [Diagram 5] 1 shows the percent change in lactate dehydrogenase (LDH) from day 1 of intensive therapy in patients with acute hemolysis. Patients received intensive subcutaneous (SC) (dashed line) or intravenous (IV) (solid line) administration of the PEGylated compstatin analog of FIG. 1 having a PEG of about 40 kilodaltons (kD). The PEGylated compstatin analog is referred to as PEG in the figures. [Figure 6] Average hemoglobin (Hb(g / L)) levels from day 1 of intensive therapy in patients with acute hemolysis. Patients received an intensive dose of the PEGylated compstatin analog of FIG. 1 with a PEG of approximately 40 kilodaltons (kD). The top data line (squares) represents patients who did not receive red blood cell (RBC) transfusions (N=9), and the bottom data line (circles) represents patients who received at least one RBC transfusion (N=4). The number of patients for whom Hb level measurements were collected for each time point is indicated by the bottom number just above the x-axis (top row=no transfusion (Tx), bottom row=transfusion (Tx)). Dashed horizontal lines represent the lower limit of normal (LLN) for men (top) and women (bottom). W1=week 1, W2=week 2, W3=week 3, W4=week 4.

[0029] definition Antibody: As used herein, the term "antibody" refers to an immunoglobulin or derivative thereof that contains an immunoglobulin domain capable of binding to an antigen. The antibody may be of any species, e.g., human, rodent, rabbit, goat, chicken, etc. The antibody may be a member of any immunoglobulin class, including any of the human classes: IgG, IgM, IgA, IgD, and IgE, or subclasses thereof, such as IgG1, IgG2, etc. In various embodiments of the invention, the antibody may be any of the Fab', F(ab') and / or F(ab') fragments that retain the antigen-binding site. 2 , fragments such as scFv (single chain variable) or other fragments, or recombinantly produced scFv fragments, including recombinantly produced fragments. See, for example, Allen, T., Nature Reviews Cancer, Vol. 2, 750-765, 2002, and references therein. Antibodies can be monovalent, bivalent, or multivalent. Antibodies can be, for example, chimeric or "humanized" antibodies in which variable domains of rodent origin are fused to constant domains of human origin, thus retaining the specificity of rodent antibodies. The domain of human origin need not be directly derived from a human, in the sense that it is first synthesized in a human. Instead, the "human" domain may be generated in a rodent that has integrated human immunoglobulin genes into its genome. See, for example, Vaughan, et al., (1998), Nature Biotechnology, 16:535-539. Antibodies can be partially or fully humanized. Antibodies can be polyclonal or monoclonal, but for the purpose of the present invention, monoclonal antibodies are generally preferred.Methods for producing antibodies that specifically bind to virtually any molecule of interest are known in the art.For example, monoclonal or polyclonal antibodies can be purified from the blood or ascites of animals that produce antibodies (e.g., following natural exposure to or immunization with the molecule or its antigenic fragment), can be produced using recombinant technology in cell culture or transgenic organisms, or can be made at least in part by chemical synthesis.

[0030] Approximately: As used herein, the terms "approximately" or "about" in reference to numbers are generally interpreted to include numbers within 5%, 10%, 15%, or 20% in either direction (greater or less) of the number unless specifically stated otherwise or otherwise clear from the context (except where such number is less than 0% or greater than 100% of a possible value).

[0031] Combination therapy: As used herein, the term "combination therapy" refers to a situation in which two or more different pharmaceutical agents are administered in an overlapping regimen such that a subject is exposed to both agents at the same time. When used in combination therapy, the two or more different agents may be administered simultaneously or separately. This administration in combination can include simultaneous administration of two or more agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, two or more agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, two or more agents can be administered simultaneously, where the agents are in separate formulations. In another alternative, the first agent can be administered followed by one or more additional agents. In separate administration protocols, the two or more agents can be administered minutes apart, or hours apart, days apart, or weeks apart. In some embodiments, the two or more agents can be administered 1-2 weeks apart.

[0032] Complement components: As used herein, the term "complement components" or "complement proteins" refers to molecules involved in the activation of the complement system or involved in one or more complement-mediated activities. Components of the classical complement pathway include, for example, C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, C9, and the C5b-9 complex, also referred to as the membrane attack complex (MAC), as well as active fragments or enzymatic cleavage products of any of the foregoing (e.g., C3a, C3b, C4a, C4b, C5a, etc.). Components of the alternative pathway include, for example, factors B, D, H, and I, and properdin, with factor H being a negative regulator of the pathway. Components of the lectin pathway include, for example, MBL2, MASP-1, and MASP-2. Complement components also include cell-bound receptors for soluble complement components. Such receptors include, for example, C5a receptor (C5aR), C3a receptor (C3aR), complement receptor 1 (CR1), complement receptor 2 (CR2), complement receptor 3 (CR3), etc. The term "complement components" is not intended to include molecules and molecular structures that act as "triggers" for complement activation, such as antigen-antibody complexes, foreign structures found on microorganisms or artificial surfaces, etc.

[0033] Co-administration: As used herein, the term "co-administration" with respect to two or more agents, e.g., therapeutic agents, is administration that is performed using doses and time intervals such that the administered agents are present together in the body, e.g., at one or more sites of action in the body, in non-negligible amounts over a period of time. The time intervals can be minutes (e.g., at least 1 minute, 1-30 minutes, 30-60 minutes), hours (e.g., at least 1 hour, 1-2 hours, 2-6 hours, 6-12 hours, 12-24 hours), days (e.g., at least 1 day, 1-2 days, 2-4 days, 4-7 days, etc.), weeks (e.g., at least 1 week, 2 weeks, or 3 weeks, etc.). Thus, the agents can be, but are not necessarily, administered together as part of a single composition. In addition, the agents can be, but are not necessarily, administered essentially simultaneously (e.g., less than 5 minutes, or less than 1 minute apart) or within a short time of each other (e.g., less than 1 hour, less than 30 minutes, less than 10 minutes, about 5 minutes apart). According to various embodiments of the present disclosure, agents administered within such a time interval may be considered to be administered at substantially the same time. In certain embodiments of the present disclosure, the co-administered agents are present in the body (e.g., in the blood and / or at the site of local complement activation) at effective concentrations over the time interval. When administered simultaneously, the effective concentration of each of the agents required to induce a particular biological response may be lower than the effective concentration of each agent when administered alone, thereby allowing for a reduction in the dose of one or more agents compared to the dose required when the agent is administered as a single agent. The effect of multiple agents may be, but is not necessarily, additive or synergistic. Agents may be administered multiple times. A non-negligible concentration of an agent may be, for example, less than about 5% of the concentration required to induce a particular biological response, e.g., a desired biological response.

[0034] Linked: As used herein, the term "linked" when used in reference to two or more moieties means that the moieties are physically bound or connected to each other to form a molecular structure that is sufficiently stable so that the moieties remain linked under the conditions under which the bond is formed, preferably under the conditions under which the new molecular structure is used, e.g., physiological conditions. In certain preferred embodiments of the invention, the link is a covalent link. In other embodiments, the link is non-covalent. The moieties may be linked directly or indirectly. When two moieties are directly linked, they are either covalently bound to each other or in sufficient proximity that intermolecular forces between the two moieties maintain their association. When two moieties are indirectly linked, they are each linked, either covalently or non-covalently, to a third moiety, which maintains the association between the two moieties. In general, when two moieties are referred to as being linked by a "linker" or "linking moiety" or "linking portion," the link between the two linking moieties is indirect, and typically each of the linking moieties is covalently bound to the linker. The linker can be any suitable moiety that will react with the two moieties being linked in sufficient quantity and within a reasonable period of time to produce a reasonable yield, under conditions consistent with the stability of the moieties (which can be appropriately protected depending on the conditions).

[0035] Sequential administration: As used herein, the term "sequential administration" of two or more agents refers to administering two or more agents to a subject such that the agents are not present together in the subject's body or at relevant sites of activity within the body at more than negligible concentrations. The administration of the agents can be, but is not necessarily, alternated. Each agent can be administered multiple times.

[0036] Subject: As used herein, the term "subject" or "subject" refers to any organism to which a provided compound or composition is administered in accordance with the present invention, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mice, rats, rabbits, non-human primates, and humans, insects, worms, etc.). In some embodiments, a subject may be suffering from and / or susceptible to a disease, disorder, and / or condition.

[0037] Substantially: As used herein, the term "substantially" refers to a qualitative condition that indicates the entire or nearly entire extent or degree of a characteristic or property of interest. Those skilled in the art of biology will understand that biological and chemical phenomena, if they exist at all, rarely go to completion and / or rarely proceed completely or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and / or chemical phenomena.

[0038] Suffering from: An individual who is "suffering from" a disease, disorder, and / or condition has been diagnosed with and / or displays one or more symptoms of the disease, disorder, and / or condition.

[0039] Systemic: As used herein, the term "systemic" with respect to complement components refers to complement proteins that are synthesized by liver hepatocytes and enter the bloodstream, or synthesized by circulating macrophages or monocytes or other cells and secreted into the bloodstream.

[0040] Therapeutic Agent: As used herein, the phrase "therapeutic agent" refers to any agent that has a therapeutic effect and / or induces a desired biological and / or pharmacological effect when administered to a subject. In some embodiments, a therapeutic agent can be an agent that can prevent undesirable side effects, such as an immune response to the viral vectors described herein, when administered to a subject. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay the onset of, reduce the severity, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition.

[0041] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" refers to an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that induces a desired biological response when administered as part of a treatment regimen. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent, and / or delay the onset of a disease, disorder, and / or condition when administered to a subject suffering from or susceptible to the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, prevent, and / or delay the onset of an undesirable side effect, such as an immune response to a viral vector described herein, when administered to a subject suffering from or susceptible to the disease, disorder, and / or condition. As will be appreciated by one of skill in the art, the effective amount of a substance may vary depending on factors such as the desired biological endpoint, the substance delivered, the target cell or tissue, etc. For example, an effective amount of a compound in a formulation for treating a disease, disorder, and / or condition is an amount that alleviates, ameliorates, alleviates, inhibits, prevents, delays the onset of, reduces the severity of, and / or reduces the occurrence of one or more symptoms or signs of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose, and in some embodiments, multiple unit doses are required to deliver the therapeutically effective amount.

[0042] Treating: As used herein, the term "treating" refers to providing therapy, i.e., providing any type of medical or surgical management of a subject. Treatment may be provided to reverse, alleviate, inhibit, prevent or reduce the progression of a disease, disorder, or condition, or to reverse, alleviate, prevent the progression of, or reduce the likelihood of, one or more symptoms or signs of a disease, disorder, or condition. "Preventing" refers to preventing the occurrence of such a disease, disorder, condition, or symptom or sign in at least some individuals, at least for a period of time. Treating can include administering an agent to a subject after the onset of one or more symptoms or signs indicative of a complement-mediated condition, for example, to reverse, alleviate, reduce the severity, and / or inhibit or prevent the progression of the condition, and / or to reverse, alleviate, reduce the severity, and / or inhibit one or more symptoms or signs of the condition. The compositions of the present disclosure can be administered to subjects who have developed a complement-mediated disorder or who are at high risk of developing such a disorder compared to members of the general population. The compositions of the present disclosure can be administered prophylactically, i.e., before the onset of a symptom or sign of a condition. In this case, the subject will typically be at risk of developing the condition.

[0043] Nucleic acid: The term "nucleic acid" includes any nucleotide, its analogs, and polymers thereof. As used herein, the term "polynucleotide" refers to a polymeric form of nucleotides of any length, either ribonucleotides (RNA) or deoxyribonucleotides (DNA). These terms refer to the primary structure of the molecule, and thus include double- and single-stranded DNA, double- and single-stranded RNA. These terms include, as equivalents, analogs of RNA or DNA made from nucleotide analogs and modified polynucleotides, such as, but not limited to, methylated, protected, and / or capped nucleotides or polynucleotides. The term includes poly- or oligoribonucleotides (RNA) and poly- or oligodeoxyribonucleotides (DNA), RNA or DNA derived from N- or C-glycosides of nucleobases and / or modified nucleobases, nucleic acids derived from sugars and / or modified sugars, and nucleic acids derived from phosphate bridges and / or modified phosphorus atom bridges (also referred to herein as "internucleotide linkages"). The term includes nucleic acids containing any combination of nucleobases, modified nucleobases, sugars, modified sugars, phosphate bridges or modified phosphorus atom bridges. Examples include, but are not limited to, nucleic acids containing a ribose moiety, nucleic acids containing a deoxyribose moiety, nucleic acids containing both a ribose moiety and a deoxyribose moiety, nucleic acids containing a ribose moiety, and modified ribose moieties. In some embodiments, the prefix "poly" refers to a nucleic acid that contains from 2 to about 10,000, 2 to about 50,000, or 2 to about 100,000 nucleotide monomer units. In some embodiments, the prefix "oligo" refers to a nucleic acid that contains from 2 to about 200 nucleotide monomer units.

[0044] Vector: As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it is linked. One type of vector is a "plasmid," which refers to a circular double-stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, which allows additional DNA segments to be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors, etc.). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and are thereby replicated along with the host genome. In addition, certain vectors can induce the expression of a gene to which the vector is operably linked. Such vectors are referred to herein as "expression vectors." One skilled in the art will appreciate that the "viral vectors" described herein include viral components in addition to the transgenes, e.g., capsid proteins, described herein.

[0045] Standard techniques of recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation are used (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques can be performed according to manufacturer's specifications or as commonly practiced in the art or as described herein. The techniques and procedures described above can generally be performed according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification. See, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989)), which is incorporated herein by reference for any purpose. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0046] The present disclosure provides methods and compositions for inhibiting complement over a period of time, where the level of complement inhibition declines relatively quickly following the initiation of administration of a PEGylated compstatin analog described herein.

[0047] I. Complement system Complement is a system of numerous plasma and cell-bound proteins that play an important role in both innate and adaptive immunity. The proteins of the complement system act in a series of enzymatic cascades through various protein interactions and cleavage events. To facilitate understanding of this disclosure, this section provides an overview of complement and its activation pathways, without intending to limit the invention in any way. Further details can be found in, for example, Kuby Immunology, 6 th ed., 2006, Paul, WE, Fundamental Immunology, Lippincott Williams & Wilkins;6 th ed., 2008, and Walport MJ., Complement. First of two parts. N Engl J Med., 344(14):1058-66, 2001.

[0048] Complement is a weapon of the innate immune system that plays a key role in defending the body against infectious pathogens. The complement system is composed of more than 30 serum and cellular proteins that participate in three major pathways, known as the classical, alternative, and lectin pathways. The classical pathway is usually triggered by the binding of a complex of antigen and IgM or IgG antibodies to C1 (although certain other activators can also initiate the pathway). Activated C1 cleaves C4 and C2 to generate C4a and C4b, in addition to C2a and C2b. C4b and C2a combine to form C3 convertase, which cleaves C3 to form C3a and C3b. Binding of C3b to C3 convertase generates C5 convertase, which cleaves C5 to C5a and C5b. C3a, C4a, and C5a are anaphylatoxins that mediate multiple responses in acute inflammatory responses. C3a and C5a are also chemotactic factors that attract immune system cells such as neutrophils. It will be appreciated that the earlier designations "C2a" and "C2b" have later been reversed in the scientific literature.

[0049] The alternative pathway is initiated and amplified, for example, by microbial surfaces and various complex polysaccharides. This pathway involves the spontaneous production of C3 to C3(H 2Hydrolysis of C3 to C3a (O) results in the binding of factor B, which is cleaved by factor D, generating the fluid-phase C3 convertase that activates complement by cleaving C3 into C3a and C3b. C3b binds to targets such as cell surfaces and forms a complex with factor B, which is subsequently cleaved by factor D to become the C3 convertase. The surface-bound C3 convertase cleaves and activates additional C3 molecules, leading to rapid deposition of C3b in close proximity to the activation site, forming additional C3 convertase, which in turn generates additional C3b. This process results in a cycle of C3 cleavage and C3 convertase formation, greatly amplifying the response. Cleavage of C3 and binding of another molecule of C3b to the C3 convertase gives rise to the C5 convertase. The C3 and C5 convertases in this pathway are regulated by the cellular molecules CR1, DAF, MCP, CD59, and fH. The mode of action of these proteins involves either decay-accelerating activity (i.e., the ability to dissociate convertases), the ability to function as a cofactor in the degradation of C3b or C4b by factor I, or both. Normally, the presence of complement regulatory proteins on cell surfaces prevents significant complement activation from occurring thereon.

[0050] C5 convertases generated by both pathways cleave C5 to generate C5a and C5b. C5b then binds to C6, C7, and C8 to form C5b-8 and catalyzes the polymerization of C9 to form the C5b-9 membrane attack complex (MAC). The MAC inserts itself into the target cell membrane, causing cell lysis. Small amounts of MAC on the cell membrane can have various consequences other than cell death. If TCC does not insert into the membrane, it can circulate in the blood as soluble sC5b-9 (sC5b-9). The level of sC5b-9 in the blood can serve as an indicator of complement activation.

[0051] The lectin complement pathway is initiated by the binding of mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs) to carbohydrates. The MB1-1 gene (known as LMAN-1 in humans) encodes a type I integral membrane protein that is localized in the intermediate region between the endoplasmic reticulum and the Golgi apparatus. The MBL-2 gene encodes a soluble mannose-binding protein found in serum. In the human lectin pathway, MASP-1 and MASP-2 are involved in the proteolysis of C4 and C2, leading to the C3 convertases mentioned above.

[0052] Complement activity is regulated by a variety of mammalian proteins termed complement control proteins (CCPs) or regulators of complement activation (RCA) proteins (US Pat. No. 6,897,290). These proteins differ with respect to their ligand specificity and mechanism(s) of complement inhibition. They may accelerate the normal decay of convertases and / or function as cofactors for factor I, enzymatically cleaving C3b and / or C4b into smaller fragments. CCPs are characterized by the presence of multiple (usually 4-56) homologous motifs of approximately 50-70 amino acids in length, including a conserved motif containing four disulfide-linked cysteines (two disulfide bonds), proline, tryptophan, and many hydrophobic residues, known as short consensus repeats (SCRs), complement control protein (CCP) modules, or SUSHI domains. The CCP family includes complement receptor type 1 (CR1, C3b:C4b receptor), complement receptor type 2 (CR2), membrane complement protein (MCP, CD46), decay accelerating factor (DAF), complement factor H (fH), and C4b binding protein (C4bp). CD59 is a membrane-bound complement regulatory protein that is structurally unrelated to the CCPs. Complement regulatory proteins normally act to limit complement activation that can occur in mammalian cells or tissues, such as the human host. Thus, "self" cells are normally protected from the deleterious effects that would result from complement activation proceeding on these cells. Deficiencies or defects in complement regulatory protein(s) have been implicated in the pathogenesis of various complement-mediated disorders.

[0053] II. Compstatin Analogs The disclosed method includes administration of a compstatin analog. Compstatin is a cyclic peptide that binds to C3 and inhibits complement activation. U.S. Pat. No. 6,319,897 describes a peptide having the sequence Ile-[Cys-Val-Val-Gln-Asp-Trp-Gly-His-His-Arg-Cys]-Thr (SEQ ID NO: 1), with a disulfide bond between the two cysteines shown in brackets. It is understood that the name "compstatin" was not used in U.S. Pat. No. 6,319,897, but it was subsequently adopted in the scientific and patent literature (see, e.g., Morikis, et al., Protein Sci., 7(3):619-27, 1998) and applied to refer to a peptide having the same sequence as SEQ ID NO: 2 disclosed in U.S. Pat. No. 6,319,897, but amidated at the C-terminus as shown in Table 1 (SEQ ID NO: 8). The term "compstatin" is used herein in accordance with such usage (i.e., referring to SEQ ID NO: 8). Compstatin analogs have been developed that have greater complement inhibitory activity than compstatin. See, e.g., WO2004 / 026328 (PCT / US2003 / 029653), Morikis, D., et al., Biochem Soc Trans. 32 (Pt 1): 28-32, 2004, Mallik, B., et al., J. Med. Chem., 274-286, 2005, Katragadda, M., et al. al. J. Med. Chem., 49:4616-4622, 2006, WO2007062249 (PCT / US2006 / 045539), WO2007044668 (PCT / US2006 / 039397), WO / 2009 / 046198 (PCT / US2008 / 078593), WO / 2010 / 127336 (PCT / US2010 / 033345), and the discussion below.

[0054] As used herein, the term "compstatin analog" includes compstatin and any complement inhibitory analogs thereof. The term "compstatin analog" encompasses compstatin as well as other compounds designed or identified based on compstatin, whose complement inhibitory activity is at least 50% as great as that of compstatin, e.g., when measured using any art-recognized complement activation assay or a substantially similar or equivalent assay. Certain suitable assays are described in U.S. Patent No. 6,319,897, WO 2004 / 026328, Morikis, supra, Mallik, supra, Katragadda 2006, supra, WO 2007062249 (PCT / US2006 / 045539), WO 2007044668 (PCT / US2006 / 039397), WO / 2009 / 046198 (PCT / US2008 / 078593), and / or WO / 2010 / 127336 (PCT / US2010 / 033345). The assay may, for example, measure red blood cell lysis mediated by the alternative or classical pathway, or may be an ELISA assay. In some embodiments, the assays described in WO / 2010 / 135717 (PCT / US2010 / 035871) are used.

[0055] Table 1 provides a non-limiting list of compstatin analogs useful in the present disclosure. The analogs are referred to by abbreviations in the left column by indicating the specific modifications at the designated positions (1-13) compared to the parent peptide compstatin. Consistent with usage in the art, "compstatin" as used herein, and the activities of the compstatin analogs described herein compared to the activity of compstatin, refer to the compstatin peptide amidated at the C-terminus. Unless otherwise indicated, the peptides in Table 1 are amidated at the C-terminus. Bold text is used to indicate the specific modifications. Activity compared to compstatin is based on published data and assays described therein (WO2004 / 026328, WO2007044668, Mallik, 2005, Katragadda, 2006). In certain embodiments, the peptides listed in Table 1, when used in the therapeutic compositions and methods of the present disclosure, are cyclized via a disulfide bond between two Cys residues. Alternative means for cyclizing peptides are also within the scope of this disclosure. [Table 1-1] [Table 1-2]

[0056] In certain embodiments of the compositions and methods of the present disclosure, the compstatin analog has a sequence selected from sequences 9-36. In some embodiments, the compstatin analog has the sequence of SEQ ID NO: 28. As used herein, "L-amino acid" refers to either the naturally occurring levorotatory alpha-amino acids normally found in proteins or the alkyl esters of those alpha-amino acids. The term "D-amino acid" refers to dextrorotatory alpha-amino acids. Unless otherwise specified, all amino acids referred to herein are L-amino acids.

[0057] In some embodiments, one or more amino acid(s) of a compstatin analog (e.g., any of the compstatin analogs disclosed herein) can be an N-alkyl amino acid (e.g., an N-methyl amino acid). For example, without limitation, at least one amino acid within the cyclic portion of the peptide, at least one amino acid at the N-terminus of the cyclic portion, and / or at least one amino acid at the C-terminus of the cyclic portion can be an N-alkyl amino acid, e.g., an N-methyl amino acid. In some embodiments, for example, a compstatin analog includes an N-methyl glycine, e.g., at a position corresponding to position 8 of compstatin and / or at a position corresponding to position 13 of compstatin. In some embodiments, one or more of the compstatin analogs of Table 1 include at least one N-methyl glycine, e.g., at a position corresponding to position 8 of compstatin and / or at a position corresponding to position 13 of compstatin. In some embodiments, one or more of the compstatin analogs of Table 1 include at least one N-methyl isoleucine, e.g., at a position corresponding to position 13 of compstatin. For example, the Thr at or near the C-terminus of a peptide whose sequence is listed in Table 1, or any other compstatin analog sequence, can be replaced with N-methyl Ile. As will be appreciated, in some embodiments, the N-methylated amino acid includes an N-methyl Gly at position 8 and an N-methyl Ile at position 13.

[0058] Compstatin analogs can be prepared by various synthetic methods of peptide synthesis known in the art through condensation of amino acid residues, for example, from an appropriate nucleic acid sequence encoding the compstatin analog, by expression in vitro according to conventional peptide synthesis methods, or in living cells using methods known in the art. For example, peptides can be synthesized using standard solid-phase methods, as described in Malik, supra, Katragadda, supra, WO2004026328, and / or WO2007062249. Potentially reactive moieties, such as amino and carboxyl groups, reactive functional groups, etc., can be protected and subsequently deprotected using various protecting groups and methodologies known in the art. For example, see "Protective Groups in Organic Synthesis", 3 rd See, ed. Greene, TW and Wuts, PG, Eds., John Wiley & Sons, New York: 1999. Peptides can be purified using standard approaches such as reversed-phase HPLC. Separation of diastereomeric peptides can be performed, if desired, using known methods such as reversed-phase HPLC. Preparations can be lyophilized, if desired, and then dissolved in a suitable solvent, e.g., water. The pH of the resulting solution can be adjusted to physiological pH, e.g., using a base such as NaOH. Peptide preparations can be characterized, if desired, e.g., by mass spectrometry to confirm mass and / or disulfide bond formation. See, e.g., Mallik, 2005, and Katragadda, 2006.

[0059] Compstatin analogs can be modified by the addition of molecules such as polyethylene glycol (PEG) to stabilize the compound, reduce its immunogenicity, extend its lifetime in the body, increase and decrease its solubility, and / or increase its resistance to degradation. Methods of pegylation are well known in the art (Veronese, FM & Harris, Adv. Drug Deliv. Rev. 54, 453-456, 2002; Davis, FF, Adv. Drug Deliv. Rev. 54, 457-458, 2002); Hinds, KD & Kim, SW Adv. Drug Deliv. Rev. 54, 505-530 (2002); Roberts, MJ, Bentley, MD & Harris, JMAdv. Drug Deliv. Rev. 54, 459-476; 2002); Wang, YSet al. Adv. Drug Deliv. Rev. 54, 547-570, 2002). A wide variety of polymers, such as PEG and modified PEG, including derivatized PEG, to which polypeptides can be conveniently attached are described in the Nektar Advanced Pegylation 2005-2006 Product Catalog, Nektar Therapeutics, San Carlos, Calif., which also provides details of suitable conjugation procedures.

[0060] In some embodiments, a compstatin analog of any of SEQ ID NOs: 9-36 is extended at the N-terminus, C-terminus, or both, by one or more amino acids, where at least one of the amino acids has a side chain that includes a reactive functional group, such as a primary or secondary amine, a sulfhydryl group, a carboxyl group (which may be present as a carboxylate group), a guanidino group, a phenol group, an indole ring, a thioether, or an imidazole ring, that facilitates conjugation with a reactive functional group for attaching PEG to the compstatin analog. In some embodiments, a compstatin analog includes an amino acid that has a side chain that includes a primary or secondary amine, e.g., a Lys residue. For example, a Lys residue, or a sequence that includes a Lys residue, is added to the N-terminus and / or C-terminus of a compstatin analog described herein (e.g., a compstatin analog including any one of SEQ ID NOs: 9-36).

[0061] In some embodiments, the Lys residue is separated from the cyclic portion of the compstatin analog by a rigid or flexible spacer. The spacer may include, for example, a substituted or unsubstituted, saturated or unsaturated alkyl chain, an oligo(ethylene glycol) chain, and / or other moieties, for example, as described herein with respect to the linker. The length of the chain may be, for example, 2-20 carbon atoms. In other embodiments, the spacer is a peptide. A peptide spacer may be, for example, 1-20 amino acids in length, for example, 4-20 amino acids in length. A suitable spacer may, for example, comprise or consist of multiple Gly residues, Ser residues, or both. Optionally, the amino acid having a side chain containing a primary or secondary amine and / or at least one amino acid in the spacer is a D-amino acid. Any of a variety of polymer backbones or scaffolds could be used. For example, the polymer backbone or scaffold may be a polyamide, polysaccharide, polyanhydride, polyacrylamide, polymethacrylate, polypeptide, polyethylene oxide, or dendrimer. Suitable methods and polymer backbones are described, for example, in WO98 / 46270 (PCT / US98 / 07171) or WO98 / 47002 (PCT / US98 / 06963). In some embodiments, the polymer backbone or scaffold contains multiple reactive functional groups, such as carboxylic acid, anhydride, or succinimide groups. The polymer backbone or scaffold is reacted with a compstatin analog. In some embodiments, the compstatin analog contains any of several different reactive functional groups, such as carboxylic acid, anhydride, or succinimide groups, that react with appropriate groups on the polymer backbone. Alternatively, monomer units that can be linked together to form a polymer backbone or scaffold are first reacted with a compstatin analog, and the resulting monomers are polymerized. In some embodiments, short chains are prepolymerized and functionalized, and then a mixture of short chains of different compositions is assembled into a longer polymer.

[0062] In some embodiments, a compstatin analog moiety is attached to each end of a linear PEG. Bifunctional PEGs with reactive functional groups at each end of the chain may be used, for example, as described herein. In some embodiments, the reactive functional groups are the same, while in some embodiments, different reactive functional groups are present at each end.

[0063] Generally, and for the compounds depicted herein, the polyethylene glycol moieties are depicted with the oxygen atom on the right side of the repeat unit or the left side of the repeat unit. Where only one orientation is depicted, the present disclosure contemplates both orientations of the polyethylene glycol moiety of a given compound or genus (i.e., (CH 2 CH 2 O) n and (OCH 2 CH 2 ) n ), or if a compound or genus contains multiple polyethylene glycol moieties, all combinations of orientations are encompassed in the disclosure.

[0064] In some embodiments, a bifunctional linear PEG comprises a moiety that contains a reactive functional group at each of its termini. The reactive functional groups can be the same (homobifunctional) or different (heterobifunctional). In some embodiments, the structure of a bifunctional PEG can be symmetrical, with the same moiety bearing the reactive functional group as -(CH 2 CH 2 O) n It is used to connect to the oxygen atom at each end of the chain. In some embodiments, different moieties are used to connect the two reactive functional groups to the PEG portion of the molecule. An exemplary bifunctional PEG structure is shown below. For illustration purposes, a formula is shown in which the reactive functional group includes an NHS ester, although other reactive functional group(s) could be used.

[0065] In some embodiments, the bifunctional linear PEG is of formula A: [ka] wherein each T and “reactive functional group” is independently defined below and described in classes and subclasses herein, and n is defined above and described in classes and subclasses herein. Each T is independently a covalent bond or C 1-12 wherein one or more carbon units of T are optionally and independently selected from -O-, -S-, -N(R x )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R x )C(O)-, -C(O)N(R x )-, -S(O)-, -S(O) 2 -, -N(R x )SO 2 - or -SO 2 N(R x )- and each R x are independently hydrogen or C 1-6 It is aliphatic. The reactive functional group has the structure -COO-NHS.

[0066] Exemplary bifunctional PEGs of Formula A include the following: [ka]

[0067] In some embodiments, a functional group on a compstatin analog (e.g., an amine, hydroxyl, or thiol group) can be reacted with a PEG-containing compound having a "reactive functional group" as described herein to produce such a conjugate. As an example, Formula I can form a compstatin analog conjugate having the following structure: [ka] During the ceremony, [ka] represents the point of attachment of an amine group on a compstatin analog. In certain embodiments, the amine group is a lysine side chain group.

[0068] In certain embodiments, the PEG component of such conjugates has an average molecular weight of about 5 kD, about 10 kD, about 15 kD, about 20 kD, about 30 kD, or about 40 kD. In certain embodiments, the PEG component of such conjugates has an average molecular weight of about 40 kD.

[0069] The term "bifunctional" or "bifunctionalized" may be used herein to refer to a compound that includes two compstatin analog moieties linked to PEG. Such compounds may be abbreviated as "BF". In some embodiments, the bifunctionalized compound is symmetrical. In some embodiments, the bond between the PEG and each compstatin analog moiety of the bifunctionalized compound is the same. In some embodiments, each bond between the PEG and the compstatin analog of the bifunctionalized compound includes a carbamate. In some embodiments, each bond between the PEG and the compstatin analog of the bifunctionalized compound includes a carbamate and does not include an ester. In some embodiments, each compstatin analog of the bifunctionalized compound is directly linked to the PEG via a carbamate. In some embodiments, each compstatin analog of the bifunctionalized compound is directly linked to the PEG via a carbamate, and the bifunctionalized compound has the following structure: [ka]

[0070] In some embodiments of the formulas and embodiments described herein, [ka] represents the point of attachment of the lysine side chain group in a compstatin analog having the following structure: [ka] In the formula, the symbol " [ka] " represents the point of attachment of the chemical moiety to the remainder of the molecule or chemical formula.

[0071] PEG containing one or more reactive functional groups may in some embodiments be obtained from NOF America Corp. White Plains, NY or BOC Sciences 45-16 Ramsey Road Shirley, NY 11967, USA, among others, or may be prepared using methods known in the art.

[0072] In some embodiments, a linker is used to connect the compstatin analog described herein to the PEG described herein. Suitable linkers for connecting the compstatin analog to the PEG are broadly described above and in the classes and subclasses herein. In some embodiments, the linker has multiple functional groups, one functional group connected to the compstatin analog and another functional group connected to the PEG moiety. In some embodiments, the linker is a bifunctional compound. In some embodiments, the linker is an NH 2 (CH 2 CH 2 O)nCH 2 The linker has the structure: C(=O)OH, where n is 1 to 1000. In some embodiments, the linker is 8-amino-3,6-dioxaoctanoic acid (AEEAc). In some embodiments, the linker is activated for conjugation with a polymer moiety or functional group of a compstatin analog. For example, in some embodiments, the carboxyl group of AEEAc is activated prior to conjugation with the amine group of the side chain of a lysine group.

[0073] In some embodiments, a suitable functional group on the compstatin analog (e.g., an amine, hydroxyl, thiol, or carboxylic acid group) is used for conjugation to the PEG moiety, either directly or via a linker. In some embodiments, the compstatin analog is conjugated to the PEG moiety through a linker via an amine group. In some embodiments, the amine group is the α-amino group of an amino acid residue. In some embodiments, the amine group is an amine group of a lysine side chain. In some embodiments, the compstatin analog is an NH 2 (CH 2 CH 2 O)nCH 2 The compstatin analog is conjugated to the PEG moiety through the amino group of the lysine side chain (ε-amino group) via a linker having the structure C(═O)OH, where n is 1 to 1000. In some embodiments, the compstatin analog is conjugated to the PEG moiety through the amino group of the lysine side chain via an AEEAc linker. In some embodiments, the NH 2 (CH 2 CH 2 O)nCH 2 The C(=O)OH linker is attached to the lysine side chain of compstatin after conjugation by -NH(CH 2 CH 2 O)nCH 2 In some embodiments, the AEEAc linker introduces a -NH(CH)- moiety onto the lysine side chain of compstatin after conjugation. 2 CH 2 O) 2 CH 2 Introducing the C(=O)-moiety.

[0074] In some embodiments, the compstatin analog is conjugated to the PEG moiety via a linker, the linker comprising an AEEAc moiety and an amino acid residue. In some embodiments, the compstatin analog is conjugated to the PEG moiety via a linker, the linker comprising an AEEAc moiety and a lysine residue. In some embodiments, the C-terminus of the compstatin analog is connected to the amino group of AEEAc, and the C-terminus of AEEAc is connected to a lysine residue. In some embodiments, the C-terminus of the compstatin analog is connected to the amino group of AEEAc, and the C-terminus of AEEAc is connected to the α-amino acid of a lysine residue. In some embodiments, the C-terminus of the compstatin analog is connected to the amino group of AEEAc, and the C-terminus of AEEAc is connected to the α-amino group of a lysine residue, and the PEG moiety is conjugated through the ε-amino group of the lysine residue. In some embodiments, the C-terminus of the lysine residue is modified. In some embodiments, the C-terminus of the lysine residue is modified by amidation. In some embodiments, the N-terminus of the compstatin analog is modified. In some embodiments, the N-terminus of a compstatin analog is acetylated.

[0075] In certain embodiments, the compstatin analog is M-AEEAc-Lys-B 2 where B 2 is a blocking moiety, e.g., NH 2 M represents any one of SEQ ID NOs: 9 to 36, provided that the C-terminal amino acid of any one of SEQ ID NOs: 9 to 36 is linked via a peptide bond to AEEAc-Lys-B 2The NHS moiety of a mono- or polyfunctional (e.g., bifunctional) PEG can be reacted with the free amine of a lysine side chain to produce a mono-functionalized (one compstatin analog moiety) or poly-functionalized (multiple compstatin analog moieties) PEGylated compstatin analog. In various embodiments, any amino acid containing a side chain that contains a reactive functional group can be used in place of (or in addition to) Lys. Mono- or polyfunctional PEGs containing suitable reactive functional groups can be reacted with such side chains in a manner similar to the reaction of NHS-ester activated PEG with Lys.

[0076] With respect to any of the above formulas and structures, it should be understood that embodiments are expressly disclosed in which the compstatin analog component comprises any of the compstatin analogs described herein, e.g., any of SEQ ID NOS: 9-36. For example, without limitation, the compstatin analog may comprise the amino acid sequence of SEQ ID NO: 28. An exemplary PEGylated compstatin analog in which the compstatin analog component comprises the amino acid sequence of SEQ ID NO: 28 is shown in FIG. 1. It will be understood that the PEG moiety may have a variety of different molecular weights or average molecular weights in various embodiments described herein. In certain embodiments of particular interest, the compstatin analog is pegcetacoplan ("APL-2") having the structure of the compound of FIG. 1, n is about 800 to about 1100, and the PEG has an average molecular weight of about 40 kD. Pegcetacoplan is a compound consisting of poly(oxy-1,2-ethanediyl), α-hydro-ω-hydroxy-, N-acetyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-α-aspartyl-L-tryptophyl-glycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-L-threonyl-2-[2-(2-aminoethoxy)ethoxy]acetyl-N 6 -Carboxy-L-lysine amide cyclic (2-->12)-(disulfide) 15,15'-diester or O,O'-bis[(S 2 ,S 12-Cyclo{N-acetyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-α-aspartyl-L-tryptophyl-glycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteine-L-threonyl-2-[2-(2-aminoethoxy)ethoxy]acetyl-L-lysineamide})-N 6.15 -carbonyl]polyethylene glycol (n=800-1100). Additional compstatin analogs are described, for example, in WO2012 / 155107, WO2014 / 078731, and WO2019 / 166411.

[0077] III. Method of Administration In some embodiments, a compstatin analog described herein, such as a PEGylated compstatin analog described herein, such as pegcetacoplan, is administered intravenously to a subject. In some embodiments, the subject requires relatively rapid complement inhibition (e.g., within about 15 minutes, 30 minutes, 45 minutes, 1 hour, or 2 hours of administration) and / or complement inhibition over a defined period of time (e.g., at least about 4 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 144 hours, 168 hours, or more after administration begins). In any of the embodiments described herein relating to administration of a PEGylated compstatin analog, the PEGylated compstatin analog can be pegcetacoplan.

[0078] In some embodiments, a PEGylated compstatin analog, e.g., pegcetacoplan, is administered to a subject in need thereof at a dose of about 100 mg to about 2500 mg (e.g., about 100 mg to about 600 mg, about 600 mg to about 1500 mg, about 1500 mg to about 2500 mg, about 200 mg to about 2300 mg, about 100 to 120 mg, about 120 to 140 mg, about 140 to 160 mg, about 160 to 180 mg, about 180 to 200 mg, about 200 to 220 mg, about 220 to 240 mg, about 240 to 260 mg, about 260 to 280 mg, about 280 to 300 mg, about 300 to 400 mg, about 400 to 500 mg, about 500 to 600 mg, about 600 to 700 mg, about 700 to 800 mg, about 800 to 900 mg, about 900 to 1000 mg, about 1000 to 1200 mg, about 1200 to 140 mg, about 1400 to 160 mg, about 160 20mg, about 320-340mg, about 340-360mg, about 360-380mg, about 380-400mg, about 400-420mg, about 420-440mg, about 440-460mg, about 460-480mg, about 480-500mg, about 500-520mg, about 520-540m g, about 540-560 mg, about 560-580 mg, about 580-600 mg, about 600-620 mg, about 620-640 mg, about 640-660 mg, about 660-680 mg, about 680-700 mg, about 700-720 mg, about 720-740 mg, about 740-760 mg, about 760-780mg, about 780-800mg, about 800-820mg, about 820-840mg, about 840-860mg, about 860-880mg, about 880-900mg, about 900-920mg, about 920-940mg, about 940-960mg, about 960-980mg, about 980 ~1000mg, approximately 1000~1020mg, approximately 1020~1040mg, approximately 1040~1060mg, approximately 1060~1080mg, approximately 1080~1100mg, approximately 1100~1120mg, approximately 1120~1140mg, approximately 1140~1160mg, approximately 1160~1180mg , about 1180-1200mg, about 1200-1250mg, about 1250-1300mg, about 1300-1350mg, about 1350-1400mg, about 1400-1450mg, about 1450-1500mg, about 1500-1550mg, about 1550-1600mg, about 1600- 1650mg, about 1650-1700mg, about 1700-about 1750mg, about 1750-1800mg, about 1800-1850mg, about 1850-1900mg, about 1900-1950mg, about 1950-2000mg, about 2000-2050mg, about 2050-2100mg,About 2100-2150 mg, about 2150-2200 mg, about 2200-2250 mg, about 2250-2300 mg, about 2300-2350 mg, about 2350-2400 mg, about 2400-2450 mg, about 2450-2500 mg), or more is administered. In some embodiments, the PEGylated compstatin analog, e.g., pegcetacoplan, is administered intravenously to the subject at about 200 mg. In some embodiments, the PEGylated compstatin analog, e.g., pegcetacoplan, is administered intravenously to the subject at about 600 mg. In some embodiments, the PEGylated compstatin analog, e.g., pegcetacoplan, is administered intravenously to the subject at about 1500 mg. In some embodiments, the PEGylated compstatin analog is administered intravenously to the subject at about 2300 mg. In some embodiments, complement is inhibited for at least about 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, 28 hours, 32 hours, 36 hours, 48 ​​hours, 72 hours, 144 hours, 168 hours, 192 hours, 216 hours, 240 hours, 264 hours, 288 hours, 312 hours, 336 hours, or more, after the start of intravenous administration. In some embodiments, complement is inhibited or reduced (e.g., to levels of about 100%, 90%, 80%, 70%, 60%, 50%, 40%, or less relative to control levels) after intravenous administration of a PEGylated compstatin analog. In some embodiments, AH50 and / or CH50 are inhibited or reduced (e.g., to levels of about 100%, 90%, 80%, 70%, 60%, 50%, 40%, or less relative to control levels) after intravenous administration of a PEGylated compstatin analog. In some embodiments, following intravenous administration of a PEGylated compstatin analog, complement is not inhibited or reduced after about 168 hours, 192 hours, 216 hours, 240 hours, 264 hours, 288 hours, 312 hours, 336 hours, 360 hours, 408 hours, 456 hours, 504 hours, or more after administration. In some embodiments, a PEGylated compstatin analog is administered intravenously for a sustained period of time, e.g., as an infusion as described herein, and complement is inhibited or reduced (e.g., by about 100%, 90%, 80%, 70%, 60%, 50%, relative to control levels) within about 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, or 4 hours of the start of administration.40% or less). In some embodiments, the control level is a level detected or measured in the same subject prior to intravenous administration of the PEGylated compstatin analog. In some embodiments, the control level is a reference level.

[0079] In some embodiments, the PEGylated compstatin analog is administered intravenously as a single dose.In some embodiments, the single dose is a bolus.In some embodiments, the bolus is the amount of PEGylated compstatin analog administered over about 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes or less, for example, by IV infusion.

[0080] In some embodiments, the PEGylated compstatin analog is administered as an infusion at a rate of about 0.25 mg / min to about 85 mg / min, e.g., about 6.5 mg / min to about 80 mg / min, about 20 mg / min to about 50 mg / min. In some embodiments, the infusion rate is about 5 mg / min, about 6 mg / min, about 6.5 mg / min, about 7 mg / min, about 20 mg / min, about 50 mg / min, about 70 mg / min, about 75 mg / min, or about 80 mg / min. In some embodiments, the infusion is administered over a period of about 15 minutes to about 2 hours, e.g., about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, or about 2 hours.

[0081] In some embodiments, the PEGylated compstatin analog is administered intravenously as two or more doses. For example, any of the above amounts can be administered as two doses administered intravenously close in time, for example, up to 30 minutes apart, up to 60 minutes apart, up to 2 hours apart, or up to 12 hours apart. For example, in some embodiments, an amount of about 2160 mg can be administered as two doses of about 1080 mg each, up to about 12 hours apart. In some embodiments, the first dose (e.g., a loading dose) and the second dose (e.g., a maintenance dose) are administered intravenously. In some embodiments, the first dose and the second dose contain the same amount of the PEGylated compstatin analog. In some embodiments, the first dose and the second dose contain different amounts of the PEGylated compstatin analog.

[0082] In some embodiments, the subject is an adult (i.e., the subject is at least 18 years old). In some embodiments, the subject is less than 18 years old. In some embodiments, the subject is at least 12 years old. In some embodiments, the subject is 12-18 years old (e.g., 12-17 years old). In some embodiments, the subject is 6-12 years old. In some embodiments, the subject is 1-12 years old.

[0083] In some embodiments, the method of treating a complement-mediated disorder includes administering multiple doses of a PEGylated compstatin analog, e.g., pegcetacoplan, described herein, where a dose of 500 mg to 2500 mg is administered intravenously and an additional dose is administered subcutaneously, with the first subcutaneous (SC) dose being administered within 3 days of the intravenous (IV) dose, e.g., within 3 days after administration of the IV dose. The first dose can function as a loading dose to rapidly achieve a target serum concentration of the compstatin analog (e.g., within 1 hour after administration) and rapidly reduce complement activation. Subsequent doses, which may be referred to as maintenance therapy, can be administered to maintain a therapeutically effective level of the PEGylated compstatin analog, e.g., pegcetacoplan. In some embodiments, the loading dose of pegcetacoplan is sufficient to result in a pegcetacoplan serum concentration of about 500 μg / mL to about 800 μg / mL, e.g., about 500 μg / mL to about 625 μg / mL, or about 625 μg / mL to about 750 μg / mL, within 1 hour after administration. In some embodiments, complement-mediated disorders may be treated by administering an IV loading dose of a PEGylated compstatin analog, e.g., pegcetacoplan, followed by maintenance therapy administered subcutaneously. In certain embodiments, a subject in need of treatment for a complement-mediated disorder receives an IV dose(s) of a PEGylated compstatin analog, e.g., pegcetacoplan, on a given day, which may be referred to as day 1, then receives a first SC dose of pegcetacoplan on day 2, day 3, or day 4, and thereafter continues treatment with SC administration of a PEGylated compstatin analog, e.g., pegcetacoplan, according to any of the SC dosing regimens described herein. For example, as described in PCT / US2018 / 026753 (WO2018187813) and U.S. Pat. No. 11,040,107, pegcetacoplan may be administered subcutaneously twice weekly, every 3 days, three times weekly, or once weekly at a dose of 990 mg to 1215 mg per dose, e.g., about 1080 mg per dose. In some embodiments, the SC dose is administered in a volume of about 20 mL at a concentration of about 54 mg / mL. In some embodiments, the SC dose (e.g., 1080 mg in a volume of 20 mL) is administered using a syringe pump or an internal delivery device.In some embodiments, the patient may self-administer the SC dose.

[0084] In some embodiments, a compstatin analog, e.g., a PEGylated compstatin analog, e.g., pegcetacoplan, is administered intravenously to a subject suffering from a complement-mediated disorder experiencing an exacerbation of the disease, as described herein. An "exacerbation," which may also be referred to as an "attack," "attack," or similar term, refers to a relatively sudden deterioration of a chronic condition from a previous state, e.g., the subject's usual state of health, e.g., a stable state. Exacerbations are a common feature of many chronic diseases. Exacerbations usually manifest over a period of up to several hours, up to a day, up to a week, or up to two weeks. An exacerbation is typically characterized by a marked increase in one or more symptoms of the disorder and / or a marked change (indicating a worsening) in one or more physiological parameters compared to the patient's usual state in a healthy individual and / or compared to the normal range of the parameter in a healthy individual. An exacerbation of a complement-mediated disorder may be at least partially due to and / or associated with an increased level of complement activation compared to the level of complement activation that is typical for the subject or that is typical for a healthy individual. In some embodiments, the subject experiencing the exacerbation of complement-mediated disorder may not have been previously treated with a complement inhibitor, such as pegcetacoplan.In some embodiments, the subject experiencing the exacerbation of complement-mediated disorder may have already been treated with a complement inhibitor, such as pegcetacoplan administered subcutaneously.Although the disorder can usually be adequately controlled by pegcetacoplan administered subcutaneously, in the case of exacerbation, the subject may benefit from the rapid reduction of complement achieved by IV administration of pegcetacoplan as described herein.

[0085] In some embodiments, the method includes determining that the subject is experiencing an exacerbation of a complement-mediated disorder (e.g., any of the complement-mediated disorders described herein) and administering to the subject one or more intravenous doses of a PEGylated compstatin analog, e.g., pegcetacoplan, of 500 mg to 2500 mg, e.g., 1100 mg to 2500 mg, e.g., 1500 mg to 2500 mg, e.g., about 1500 mg or about 2300 mg. In some embodiments, a dose of about 2160 mg may be administered. In some embodiments, a dose of 990 mg to 1215 mg, e.g., 1080 mg, may be administered. In some embodiments, a dose of 1215 mg to 2000 mg, e.g., 1500 mg, may be administered. In some embodiments, a dose of 2000 mg to 2500 mg, e.g., 2160 mg or 2300 mg, may be administered. In some embodiments, the dose may be selected based at least in part on the duration of complement inhibition desired. For example, in some embodiments, a dose of 1500 mg may be selected, for example, to inhibit alternative pathway complement activation nearly completely or completely (e.g., to undetectable levels) for about 24-36 hours. In some embodiments, a dose of about 2300 mg may be selected, for example, to inhibit alternative pathway complement activation nearly completely or completely (e.g., to undetectable levels) for about 72-96 hours. In some embodiments, for example, if a longer period of complement inhibition is desired for treatment of an exacerbation, the subject may be treated with two or more IV doses, for example, 2, 3, 4, or 5 doses, administered on consecutive days, or every other day, or every third day. A subject who has received IV administration of a PEGylated compstatin analog, for example, IV pegcetacoplan, for treatment of an exacerbation may receive subsequent treatment with a PEGylated compstatin analog, for example, IV pegcetacoplan, administered intravenously, for a subsequent exacerbation.

[0086] In some embodiments, a compstatin analog, e.g., a PEGylated compstatin analog, e.g., pegcetacoplan, is administered to a subject using an intensive dosing regimen prior to an event potentially associated with complement activation (e.g., surgery, vaccination). In some embodiments, prior to such an event (e.g., surgery or vaccination), the subject is treated with an intensive dosing regimen comprising intravenous administration of about 500 mg to about 2500 mg, e.g., about 540 mg to about 2160 mg, e.g., about 1100 mg to about 2500 mg, e.g., about 1500 mg to about 2500 mg, e.g., about 1500 mg or about 2300 mg, of pegcetacoplan. In some embodiments, the intensive dosing regimen comprises intravenous administration of about 1080 mg of pegcetacoplan. In some embodiments, the intensive dosing regimen comprises intravenous administration of about 2160 mg of pegcetacoplan. In some embodiments, pegcetacoplan is administered intravenously to a subject about 1, 2, 3, 4, 5, 6, or 7 days or more prior to an event potentially associated with complement activation (e.g., surgery, vaccination). In some embodiments, pegcetacoplan is administered intravenously to a subject about 1, 2, 3, 4, 5, 6, or 7 days or less prior to an event potentially associated with complement activation (e.g., surgery, vaccination). In some embodiments, the intensive dosing regimen comprises daily subcutaneous administration of about 500 mg to about 2500 mg, e.g., about 540 mg to about 2160 mg, e.g., about 1100 mg to about 2500 mg, e.g., about 1500 mg to about 2500 mg, e.g., about 1500 mg to about 2300 mg of pegcetacoplan for three consecutive days. In some embodiments, the intensive dosing regimen comprises subcutaneous administration of about 1080 mg of pegcetacoplan daily for three consecutive days. In some embodiments, the intensive dosing regimen comprises subcutaneous administration of about 2160 mg of pegcetacoplan daily for three consecutive days. In some embodiments, pegcetacoplan is subcutaneously administered to the subject daily for three consecutive days, the third of the consecutive days being about 1, 2, 3, 4, 5, 6, or 7 or more days prior to an event potentially associated with complement activation (e.g., surgery, vaccination).In some embodiments, pegcetacoplan is administered subcutaneously to a subject daily for three consecutive days, with the third consecutive day being no more than about 1, 2, 3, 4, 5, 6, or 7 days prior to an event potentially associated with complement activation (e.g., surgery, vaccination).

[0087] In some embodiments, a subject suffering from a complement-mediated disorder exhibits acute hemolysis while already undergoing treatment, e.g., treatment with a complement inhibitor that normally controls hemolysis in the subject. In some embodiments, the method includes determining that a subject having a complement-mediated disorder is exhibiting acute hemolysis (i.e., identifying the subject as exhibiting acute hemolysis) and administering pegcetacoplan to the subject using an intensive dosing regimen. In some embodiments, the subject is treated with an intensive dosing regimen that includes intravenously administering to the subject about 500 mg to about 2500 mg, e.g., about 540 mg to about 2160 mg, e.g., about 1100 mg to about 2500 mg, e.g., about 1500 mg to about 2500 mg, e.g., about 1500 mg or about 2300 mg of pegcetacoplan. In some embodiments, the intensive dosing regimen includes intravenously administering about 1080 mg of pegcetacoplan. In some embodiments, the intensive dosing regimen comprises administering about 2160 mg of pegcetacoplan intravenously. In some embodiments, the intensive dosing regimen comprises administering about 500 mg to about 2500 mg, e.g., about 540 mg to about 2160 mg, e.g., about 1100 mg to about 2500 mg, e.g., about 1500 mg to about 2500 mg, e.g., about 1500 mg to about 2300 mg of pegcetacoplan subcutaneously to the subject daily for three consecutive days. In some embodiments, the intensive dosing regimen comprises administering about 1080 mg of pegcetacoplan subcutaneously daily for three consecutive days. In some embodiments, the intensive dosing regimen comprises administering about 2160 mg of pegcetacoplan subcutaneously daily for three consecutive days. In some embodiments, the subject has already been treated with a therapy, e.g., a complement inhibitor therapy, prior to the acute hemolytic event and continues such therapy after administration of the intensive dosing regimen.

[0088] In some embodiments, the complement-mediated disorder is PNH and the subject exhibits acute hemolysis during subcutaneous treatment with a complement inhibitor, e.g., pegcetacoplan, that normally controls hemolysis in the subject. In some embodiments, the method includes determining that a subject with PNH is exhibiting acute hemolysis (i.e., identifying the subject as exhibiting acute hemolysis) and treating the subject with an intensive dosing regimen of pegcetacoplan. In some embodiments, the intensive dosing regimen includes intravenously administering to the subject about 500 mg to about 2500 mg, e.g., about 540 mg to about 2160 mg, e.g., about 1100 mg to about 2500 mg, e.g., about 1500 mg to about 2500 mg, e.g., about 1500 mg or about 2300 mg of pegcetacoplan. In some embodiments, the intensive dosing regimen includes intravenously administering to the subject about 1080 mg of pegcetacoplan. In some embodiments, the intensive dosing regimen comprises administering about 2160 mg of pegcetacoplan intravenously. In some embodiments, the intensive dosing regimen comprises administering about 500 mg to about 2500 mg, e.g., about 540 mg to about 2160 mg, e.g., about 1100 mg to about 2500 mg, e.g., about 1500 mg to about 2500 mg, e.g., about 1500 mg to about 2300 mg of pegcetacoplan subcutaneously to a subject daily for three consecutive days. In some embodiments, the intensive dosing regimen comprises administering about 1080 mg of pegcetacoplan subcutaneously daily for three consecutive days. In some embodiments, the intensive dosing regimen comprises administering about 2160 mg of pegcetacoplan subcutaneously daily for three consecutive days. In some embodiments, the subject is already treated with SC pegcetacoplan at a dose of 1080 mg administered twice weekly prior to the acute hemolytic event and continues such treatment after administration of the intensive dosing regimen. In some embodiments, the subject is already treated with SC pegcetacoplan at a dose of 1080 mg administered twice weekly prior to the acute hemolytic event and is treated with pegcetacoplan every 3 days after administration of the intensive dosing regimen.In some embodiments, the subject is already treated with SC pegcetacoplan at a dose of 1080 mg administered twice a week prior to the acute hemolytic event, and is treated with pegcetacoplan three times a week (i.e., 3 times per week) after administration of the intensive dosing regimen. In some embodiments, the subject is already treated with SC pegcetacoplan at a dose of 1080 mg administered every 3 days prior to the acute hemolytic event, and continues such treatment after administration of the intensive dosing regimen. In some embodiments, the subject is already treated with SC pegcetacoplan at a dose of 1080 mg administered every 3 days prior to the acute hemolytic event, and is treated with pegcetacoplan three times a week (i.e., 3 times per week) after administration of the intensive dosing regimen. In some embodiments, the subject is already treated with SC pegcetacoplan at a dose of 1080 mg administered three times a week (i.e., 3 times per week) prior to the acute hemolytic event, and continues such therapy after administration of the intensive dosing regimen, optionally with more frequent SC administration than prior to the event. In some embodiments, the last dose of the intensive dosing regimen is the first dose of the resumed maintenance dose. For example, in some embodiments, the subject is treated with an intensive dosing regimen including intravenous administration of pegcetacoplan on day 1, with day 1 being the first day of a subsequent dosing regimen once a week, twice a week, every 3 days, 3 times a week, etc. In some embodiments, the subject begins treatment on day 1 with an intensive dosing regimen including subcutaneous administration of pegcetacoplan for three consecutive days (e.g., on days 1, 2, and 3), with day 3 being the first day of a subsequent dosing regimen once a week, twice a week, every 3 days, 3 times a week, etc. In some embodiments, a subject may be determined to be experiencing (e.g., identified as exhibiting) hemolysis (e.g., acute hemolysis) if the subject exhibits a measured LDH level that is at least twice the upper limit of normal (ULN), i.e., at least twice the ULN. In some embodiments, the upper limit of normal is about 225 U / L, e.g., in some embodiments, 225 U / L.In some embodiments, a subject may be identified as exhibiting hemolysis (e.g., acute hemolysis) if the subject additionally exhibits at least one additional sign or symptom of hemolysis (e.g., decreased hemoglobin (e.g., a decrease of at least 1 g / dL or at least 2 g / dL, or a decrease in Hb to less than 10 g / dL), hemoglobinuria, or increased fatigue (e.g., a decrease of at least 3 points on the FACIT, with higher values ​​indicating less fatigue). In some embodiments, a subject may be identified as exhibiting hemolysis (e.g., acute hemolysis) if such ... acute hemolysis) in the presence of LDH greater than 2 times the upper limit of normal (ULN). For example, a subject may be identified as exhibiting hemolysis (e.g., acute hemolysis) if the subject exhibits at least one new or worsening symptom or sign of fatigue, hemoglobinuria, abdominal pain, dysphagia, dyspnea, anemia (e.g., hemoglobin <10 grams (g) / deciliter (dL)), a major adverse vascular event (including thrombosis), or erectile dysfunction. In some embodiments, a subject may have LDH below a predetermined level, e.g., below 1.5×ULN, for a period of time, e.g., at least 4 weeks, at least 8 weeks, at least 12 weeks, after which such subject has at least 2×ULN LDH. Subjects may be identified as exhibiting hemolysis (e.g., acute hemolysis) if they exhibit LN LDH. Subjects so identified may be treated with IV pegcetacoplan as described herein, followed by SC pegcetacoplan. In some embodiments, treatment with subcutaneously administered pegcetacoplan may be continued for one year or more, e.g., indefinitely, for the treatment of PNH. In some embodiments, subjects exhibit a decrease in LDH levels after treatment with an intensive dosing regimen as described herein. In some embodiments, subjects exhibit a decrease in LDH levels after treatment with an intensive dosing regimen as described herein. In some embodiments, the subject exhibits a decrease in LDH levels at about day 2 after completion of the intensive dosing regimen. In some embodiments, the subject exhibits a decrease in LDH levels of about 10%, about 20%, about 30%, about 40%, about 50%, about 60% at about day 2 after completion of the intensive dosing regimen. In some embodiments, the subject exhibits a decrease in LDH levels of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% at about day 8 after completion of the intensive dosing regimen.In some embodiments, the subject exhibits a decrease in LDH levels of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% about 15 days after completion of the intensive dose regimen. In some embodiments, the subject exhibits a decrease in LDH levels after three consecutive days of daily SC administration of pegcetacoplan. In some embodiments, the subject exhibits a decrease in LDH levels 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, and / or 15 days after three consecutive days of daily SC administration of pegcetacoplan. In some embodiments, the subject exhibits a decrease in LDH levels about 2 days after three consecutive days of daily SC administration of pegcetacoplan. In some embodiments, the subject exhibits a reduction of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% after about 8 days of daily SC administration of pegcetacoplan for 3 consecutive days. In some embodiments, the subject exhibits a reduction of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% after about 15 days of daily SC administration of pegcetacoplan for 3 consecutive days. In some embodiments, the subject exhibits a reduction in LDH after IV administration of pegcetacoplan. In some embodiments, the subject exhibits a reduction in LDH after 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, and / or 15 days after IV administration of pegcetacoplan. In some embodiments, the subject exhibits about a 10%, about 20%, about 30%, about 40%, about 50%, about 60% reduction about 2 days after IV administration of pegcetacoplan. In some embodiments, the subject exhibits about a 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% reduction about 8 days after IV administration of pegcetacoplan. In some embodiments, the subject exhibits about a 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% reduction about 15 days after IV administration of pegcetacoplan.

[0089] In some embodiments, a subject suffering from a complement-mediated disorder treated intravenously with a PEGylated compstatin analog, e.g., IV pegcetacoplan, as described herein, is not already treated with SC pegcetacoplan, and the subject may then begin treatment with SC pegcetacoplan, where the first dose of SC pegcetacoplan is administered on the same day as the IV administration. In some embodiments, if the subject is not already treated with SC pegcetacoplan, the subject may begin treatment with SC pegcetacoplan, where the first dose of SC pegcetacoplan is administered the day after the IV administration. In some embodiments, if the subject is not already treated with SC pegcetacoplan, the subject may begin treatment with SC pegcetacoplan, where the first dose of SC pegcetacoplan is administered the day after the IV administration. In some embodiments, if the subject is not already treated with SC pegcetacoplan, the subject may begin treatment with SC pegcetacoplan, where the first dose of SC pegcetacoplan is administered at an interval of one day after the IV dose.

[0090] In some embodiments, if a subject being treated with a PEGylated compstatin analog, e.g., pegcetacoplan by IV administration, as described herein, is already being treated with SC pegcetacoplan (e.g., at a dose of 1080 mg administered twice a week, every 3 days, 3 times a week, or once a week), and if the subject's next dose of SC pegcetacoplan is normally administered on the same day as the administration of the IV dose, the subject may receive the SC dose according to his or her usual schedule (i.e., on the same day as the IV dose). In some embodiments, if a subject is already being treated with SC pegcetacoplan and the subject's next dose of SC pegcetacoplan is normally administered on the same day as the administration of the IV dose, the next dose of SC pegcetacoplan may instead be administered the following day. In some embodiments, if the subject is already treated with SC pegcetacoplan and the subject's next dose of SC pegcetacoplan is normally administered on the same day as the administration of the IV dose, the next dose of SC pegcetacoplan may instead be administered at an interval of one day after the IV dose. In some embodiments, if the subject is already treated with SC pegcetacoplan and the subject's next dose of SC pegcetacoplan is normally administered the day after the administration of the IV dose, the next dose of SC pegcetacoplan may be delayed by one day. In some embodiments, treatment with subcutaneously administered pegcetacoplan may continue for one year or more, for example indefinitely, for the treatment of chronic complement-mediated disorders.

[0091] In some embodiments, a subject who experiences an acute event that induces complement activation, e.g., stroke, myocardial infarction, surgical procedure, trauma, or administration of an agent such as a gene therapy vector or other exposure to a foreign substance that induces complement activation, may be treated intravenously with a PEGylated compstatin analog described herein, e.g., IV pegcetacoplan, and such treatment is not followed by further administration of a complement inhibitor, e.g., pegcetacoplan, unless the subject receives a new diagnosis of a complement-mediated disorder or experiences another triggering event for complement activation. In some embodiments, a subject who experiences an acute event that induces complement activation, e.g., stroke, myocardial infarction, surgical procedure, trauma, or administration of an agent such as a gene therapy vector, or other exposure to a foreign substance that induces complement activation, may be treated with IV pegcetacoplan as described herein, and following such treatment, a complement inhibitor, e.g., pegcetacoplan (e.g., administered subcutaneously), may be further administered for a limited period of time, e.g., up to 1, 2, 3, or 4 weeks, e.g., up to 1 month.

[0092] IV. Pharmaceutical Compositions The complement inhibitors described herein, e.g., PEGylated compstatin analogs, can be incorporated into pharmaceutical compositions. Such pharmaceutical compositions are useful, inter alia, for administration and delivery to a subject in vivo or ex vivo. In some embodiments, the pharmaceutical composition comprises a pharma- ceutically acceptable carrier or excipient. Such excipients include any pharmaceutical agent, e.g., a pharmaceutical agent that does not itself induce a harmful immune response in an individual to whom the composition is administered, and that can be administered without undue toxicity. As used herein, the terms "pharmaceutical acceptable" and "physiologically acceptable" refer to a biologically acceptable formulation, gas, liquid, or solid, or mixture thereof, that is suitable for one or more routes of administration, in vivo delivery, or contact. Pharmaceutically acceptable excipients include, but are not limited to, liquids such as water, saline, glycerol, sugar, and ethanol. Pharmaceutically acceptable salts, e.g., mineral acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, and the like, salts of organic acids such as acetate, propionate, malonate, benzoate, and the like, can also be included therein. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present in such vehicles.

[0093] The pharmaceutical compositions may be provided as salts, which may be formed with a number of acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, etc. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. In some embodiments, the pharmaceutical compositions may be lyophilized powders.

[0094] Pharmaceutical compositions may include solvents (aqueous or non-aqueous), solutions (aqueous or non-aqueous), emulsions (e.g., oil-in-water or water-in-oil), suspensions, syrups, elixirs, dispersions and suspension media, coatings, isotonicity and absorption enhancing or delaying agents that are compatible with pharmaceutical administration or in vivo contact or delivery. Aqueous and non-aqueous solvents, solutions and suspensions may include suspending agents and thickening agents. Such pharma-ceutically acceptable carriers include tablets (coated or uncoated), capsules (hard or soft), microbeads, powders, granules and crystals. Supplementary active compounds (e.g., preservatives, antibacterial agents, antiviral agents and antifungal agents) may also be incorporated into the compositions.

[0095] Pharmaceutical compositions can be formulated to be compatible with a particular route of administration or delivery as described herein or known to those of skill in the art. Thus, pharmaceutical compositions include carriers, diluents, or excipients suitable for administration by various routes.

[0096] Compositions suitable for parenteral administration can include aqueous and non-aqueous solutions, suspensions or emulsions of the active compound, which preparations are typically sterile and can be isotonic with the blood of the intended recipient. Non-limiting illustrative examples include water, buffered saline, Hank's solution, Ringer's solution, dextrose, fructose, ethanol, animal oils, vegetable oils, or synthetic oils. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, mannitol, or dextran. Additionally, suspensions of the active compound can be prepared as suitable oil injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Optionally, such suspensions can also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agent, allowing for the preparation of highly concentrated solutions. In some embodiments, the pharmaceutical composition comprises sodium acetate (e.g., about 5 mM to about 30 mM, e.g., about 10 mM), NaCl (e.g., about 0.5% to about 2%, e.g., about 0.9%), and water, and has a pH of about 4 to about 7, e.g., about 5. In some embodiments, such pharmaceutical compositions are diluted in isotonic saline prior to IV administration.

[0097] Cosolvents and adjuvants can be added to the formulation.Non-limiting examples of cosolvents include alcohols with hydroxyl groups or other polar groups, such as isopropyl alcohol; glycols such as propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether; glycerol; polyoxyethylene alcohols and polyoxyethylene fatty acid esters.Adjuvants include surfactants such as soybean lecithin and oleic acid, sorbitan esters such as sorbitan trioleate, and polyvinylpyrrolidone.

[0098] After pharmaceutical compositions have been prepared, they can be placed in an appropriate container and labeled for treatment, such labeling can include dosage, frequency of administration, and method of administration.

[0099] Pharmaceutical compositions and delivery systems suitable for the compositions, methods and uses of the present disclosure are known in the art (see, e.g., Remington: The Science and Practice of Pharmacy. 21st Edition. Philadelphia, PA. Lippincott Williams & Wilkins, 2005).

[0100] In some aspects, a unit dose of a compstatin analog, e.g., a PEGylated compstatin analog (e.g., pegcetacoplan), may contain any of the amounts described herein. In some embodiments, the unit dose is greater than 540 mg, e.g., at least 541 mg, e.g., at least 545 mg. In some embodiments, the unit dose is greater than 1080 mg, e.g., at least 1081 mg, e.g., at least 1085 mg. In some embodiments, the unit dose is greater than 2160 mg, e.g., at least 2161 mg, e.g., at least 2165 mg. In some embodiments, the unit dose is less than 540 mg, e.g., up to 539 mg, e.g., up to 535 mg. In some embodiments, the unit dose is less than 1080 mg, e.g., up to 1079 mg, e.g., up to 1075 mg. In some embodiments, the unit dose is less than 2160 mg, e.g., up to 2159 mg, e.g., up to 2155 mg. In some embodiments, the unit dose is about 540 mg to about 2500 mg, about 545 mg to about 1690 mg, about 630 mg to about 930 mg, about 795 mg to about 885 mg, about 585 mg to about 2510 mg, about 900 mg to about 1395 mg, about 990 mg to about 1215 mg, about 1215 mg to about 1395 mg, about 1080 mg to about 1500 mg, about 1500 mg to about 2160 mg, about 2160 mg to about 2520 mg, about 1500 mg to about 2500 mg, or about 1080 mg to about 2160 mg. In some embodiments, the unit dose is about 540 mg. In some embodiments, the unit dose is about 1080 mg. In some embodiments, the unit dose is about 2160 mg. In some embodiments, the unit dose is about 1500 mg. In some embodiments, the unit dose is about 2300 mg. The unit dose can include an amount within any of the ranges described herein, or any specific value within said ranges.

[0101] In some embodiments, the present specification describes a container, cartridge, syringe, or drug delivery device that contains such a unit dose.Those skilled in the art who read this disclosure will understand that a container that contains a specific volume described herein can contain additional volume sufficient to allow a specified specific volume (e.g., a unit dose) to be withdrawn from the container for administration, according to standard practices in the art.

[0102] The pegylated compstatin analogs described herein can be administered by any suitable route. The route and / or mode of administration can vary depending on the desired outcome. The methods and uses of the present disclosure include delivery and administration systemically, locally, or topically, or by any route, such as injection or infusion. The method of administration is left to the discretion of the practitioner. Delivery of pharmaceutical compositions in vivo can generally be achieved via injection using a conventional syringe, although other delivery methods such as convection-enhanced delivery can also be used (see, for example, U.S. Pat. No. 5,720,720). For example, the compositions can be delivered subcutaneously, epidermally, epidurally, intracerebrally, intradermally, intranasally, intrathecally, intraorbitally, intramucosally, intraperitoneally, intravenously, intrapleurally, subretinally, intraarterially, sublingually, intrahepatically, via the portal vein, and intramuscularly. In some embodiments, administration is via intravenous infusion, e.g., central or peripheral intravenous infusion. The clinician can determine the optimal route for administration.

[0103] V. Diseases, Disorders, and Conditions The provided technology is useful for preventing or treating various conditions, disorders, or diseases, such as those described herein. In some embodiments, the disclosure provides a method for preventing a condition, disorder, or disease, comprising administering to a subject susceptible to the condition, disorder, or disease an effective amount of a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) using a dose and / or administration regimen described herein. In some embodiments, the disclosure provides a method for treating a condition, disorder, or disease, comprising administering to a subject suffering from the condition, disorder, or disease an effective amount of a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) using a dose and / or administration regimen described herein. In some embodiments, the disclosure provides a method of reducing C3 activation comprising contacting C3 with a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) using a dose and / or administration regimen described herein. In some embodiments, the disclosure provides a method of reducing C3 convertase activity comprising contacting C3 with a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) using a dose and / or administration regimen described herein. In some embodiments, the disclosure provides a method for reducing complement activation in a system comprising administering to the system a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) using a dose and / or administration regimen described herein. In some embodiments, the disclosure provides methods for reducing C3 activation in a system comprising administering to the system a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) using the doses and / or administration regimens described herein.In some embodiments, the disclosure provides a method for decreasing C3 convertase activity in a system comprising administering to the system a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) using a dose and / or administration regimen described herein. In some embodiments, the disclosure provides a method for reducing the generation of C3a in a system comprising administering to the system a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) using a dose and / or administration regimen described herein. In some embodiments, the system is a plurality of cells, tissues, or organs in a subject. In some embodiments, the system is or includes blood. In some embodiments, the system is an animal. In some embodiments, the system is a human. In some embodiments, the subject is a human.

[0104] In some embodiments, the condition, disorder, or disease is a complement-mediated condition, disorder, or disease. In some embodiments, the condition, disorder, or disease is or includes complement-mediated damage to an organ, tissue, or cell. In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered in combination with another therapeutic agent, e.g., a different complement inhibitor.

[0105] A. Blood-related disorders In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan), alone or in combination with one or more additional complement inhibitors described herein, is administered using the doses and / or dosing regimens described herein to a subject suffering from or at risk for a complement-mediated blood-related disorder, such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), autoimmune hemolytic anemia, chronic cold agglutinin disease, HELLP syndrome, and / or warm autoimmune hemolytic anemia. In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan), alone or in combination with one or more additional complement inhibitors described herein, is administered using the doses and / or dosing regimens described herein to a subject suffering from or at risk for a complement-mediated disorder affecting the circulatory system. For example, in some embodiments, the disorder is thrombotic microangiopathy (TMA) or vasculitis (e.g., IgA vasculitis) or other disorders associated with vascular inflammation, e.g., vascular and / or lymphatic inflammation. In some embodiments, the vasculitis is polyarteritis nodosa, hypocomplementary urticarial vasculitis, pulmonary vasculitis, Wegener's granulomatosis, giant cell arteritis, Tuerck-Strauss syndrome, microscopic polyangiitis, Porcine immune vasculitis, Henoch-Schonlein purpura, Takayasu's arteritis, Kawasaki disease, or Behcet's disease. In some embodiments, the disorder is TMA secondary to atypical hemolytic uremic syndrome. In some embodiments, the subject is positive for antineutrophil cytoplasmic antibodies (ANCA).

[0106] B. Eye disorders In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered to a subject for the treatment of a complement-mediated eye disorder, such as macular degeneration (e.g., age-related macular degeneration (AMD) and Stargardt's macular dystrophy), diabetic retinopathy, glaucoma, or uveitis (e.g., posterior uveitis or anterior uveitis), using a dose and / or administration regimen described herein. In some embodiments, the subject is afflicted with or at risk for AMD. In some embodiments, the AMD is neovascular (wet) AMD. In some embodiments, the AMD is dry AMD. As will be appreciated by those skilled in the art, dry AMD includes geographic atrophy (GA), intermediate AMD, and early AMD. In some embodiments, a subject with GA is treated to slow or stop the progression of the disease. For example, in some embodiments, treating a subject with GA reduces the rate of retinal cell death. A reduction in the rate of retinal cell death may be evidenced by a reduction in the rate of GA lesion growth in patients treated with a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) compared to controls (e.g., patients receiving a sham dose). In some embodiments, the subject has intermediate AMD. In some embodiments, the subject has early AMD. In some embodiments, a subject with intermediate or early AMD is treated to slow or stop disease progression. For example, in some embodiments, treating a subject with intermediate AMD may slow or prevent progression to advanced AMD (neovascular AMD or GA). In some embodiments, treating a subject with early AMD may slow or prevent progression to intermediate AMD. In some embodiments, the eye has both GA and neovascular AMD. In some embodiments, the eye has GA but not wet AMD.

[0107] In some embodiments, the subject has an ocular disorder characterized by macular degeneration, choroidal neovascularization (CNV), retinal neovascularization (RNV), ocular inflammation, or any combination of the above. Macular degeneration, CNV, RNV, and / or ocular inflammation may be the defining and / or diagnostic features of the disorder. Exemplary disorders characterized by one or more of these features include, but are not limited to, macular degeneration-related conditions, diabetic retinopathy, retinopathy of prematurity, proliferative vitreoretinopathy, uveitis, keratitis, conjunctivitis, and scleritis. In some embodiments, the subject is in need of treatment for ocular inflammation. Ocular inflammation may occur in many ocular structures, such as the conjunctiva (conjunctivitis), cornea (keratitis), episclera, sclera (scleritis), uveal tract, retina, vasculature, and / or optic nerve. Evidence of ocular inflammation may include one or more symptoms such as the presence of inflammation-related cells, such as white blood cells (e.g., neutrophils, macrophages) in the eye, the presence of endogenous inflammatory mediator(s), eye pain, redness, light sensitivity, blurred vision, and floaters. Uveitis is a general term that refers to inflammation in the uvea of ​​the eye, such as any of the uveal structures, including the iris, ciliary body, or choroid. Specific types of uveitis include iritis, iridocyclitis, cyclitis, pars planitis, and choroiditis. In some embodiments, the ocular disorder is Behcet's disease. In some embodiments, the ocular disorder is an ocular disorder characterized by optic nerve damage (e.g., optic nerve degeneration), such as glaucoma. Additional ocular disorders include, for example, retinitis pigmentosa, macular edema, Vogt-Koyangi-Harada syndrome, bird shot retinochoriocytitis, sympathetic ophthalmia, ocular bifocal pemphigoid pemphigus, ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, and retinal vein occlusion.

[0108] C. Nervous system disorders In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is used to treat a subject suffering from or at risk for a complement-mediated disorder affecting the nervous system, e.g., the central nervous system (CNS) and / or peripheral nervous system (PNS). In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered to a subject suffering from or at risk for a complement-mediated disorder affecting the nervous system, e.g., the central nervous system (CNS) and / or peripheral nervous system (PNS), using a dose and / or administration regimen described herein. Examples of such disorders include, for example, neurodegenerative disorders such as multiple sclerosis, other demyelinating diseases (e.g., neuromyelitis optica or chronic inflammatory demyelinating polyneuropathy (CIDP)), amyotrophic lateral sclerosis, chronic pain, fibromyalgia, stroke, intracerebral hemorrhage, allergic neuritis, diabetic neuropathy, Huntington's disease, schizophrenia, Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, Ruby body dementia (i.e., dementia with Ruby bodies or Parkinson's disease dementia), frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome, Pick's disease, mild cognitive impairment, traumatic brain injury, traumatic spinal cord injury, multiple system atrophy, chronic traumatic encephalitis, Kurtzert-Jacob disease, Gill-In-Barre syndrome, autoimmune neuroencephalitis, and encephalomyelitis. In some embodiments, the subject suffers from neuropathic pain, for example, resulting from a pathology involving somatosensory pathways with damage to small fibers of peripheral nerves and / or the spino-thalamocortical system of the CNS.

[0109] In certain embodiments, the disorder is stroke, and the method includes administering a PEGylated compstatin analog (e.g., pegcetacoplan) using a dose and / or dosing regimen described herein to a subject who has experienced a stroke shortly after the onset of one or more stroke symptoms, for example, within about 5, 10, 15, 30, 1, 2, 3, or 4 hours of the onset of one or more stroke symptoms (e.g., sudden onset of weakness, blurred or otherwise impaired vision, malaria or otherwise impaired speech). In certain embodiments, the disorder has an acute onset, and symptoms appear over a period of minutes or hours (e.g., over a period of 24 hours or less, or over a period of 48 hours or less). In some embodiments, the method includes administering a PEGylated compstatin analog using a dose and / or dosing regimen described herein to a subject who has experienced a stroke shortly after (e.g., within about 5, 10, 15, 30, 1, 2, 3, or 4 hours) after diagnosis of stroke.

[0110] D. Kidney problems In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is used to treat a subject suffering from or at risk of a complement-mediated kidney disorder. In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered to a subject suffering from or at risk of a complement-mediated kidney disorder using a dose and / or administration regimen described herein. Such disorders include, for example, nephritis, e.g., glomerulonephritis, e.g., membranoproliferative glomerulonephritis (MPGN) (e.g., MPGN type I, MPGN type II, or MPGN type III), e.g., immune complex membranoproliferative glomerulonephritis (IC-MPGN). In some embodiments, the disorder is IgA nephropathy (IgAN), primary membranous nephropathy, or diabetic nephropathy. In some embodiments, the disorder is polycystic kidney disease (PKD). In some embodiments, the disorder is C3 glomerulopathy. In some embodiments, the disorder is characterized by glomerular deposits in the kidney that contain one or more complement activation products, such as C3b. In some embodiments, the treatments described herein reduce the levels of such deposits. In some embodiments, subjects suffering from complement-mediated kidney disorders have proteinuria (abnormally high levels of protein in the urine) and / or abnormally low glomerular filtration rate (GFR). In some embodiments, the treatments described herein result in a reduction in proteinuria and / or an increase or stabilization of GFR.

[0111] E. Respiratory disorders In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is used to treat a subject suffering from or at risk for complement-mediated kidney damage. In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered to a subject suffering from or at risk for complement-mediated kidney damage using a dose and / or administration regimen described herein. In some embodiments, the subject suffers from or is at risk for acute respiratory distress syndrome. In some embodiments, the respiratory disease is, for example, asthma (e.g., allergic asthma), emphysema, chronic inflammation, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), radiation-induced lung injury, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis (also known as allergic pneumonitis), eosinophilic pneumonia, interstitial pneumonia, sarcoid, Wegener's granulomatosis, pulmonary embolism and infarction, dyspnea, hemoptysis, bronchoconstriction, or obstructive bronchitis.

[0112] F. Musculoskeletal disorders In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is used to treat a subject suffering from or at risk of a complement-mediated disorder affecting the musculoskeletal system. In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered to a subject suffering from or at risk of a complement-mediated disorder affecting the musculoskeletal system using a dose and / or administration regimen described herein. Examples of such disorders include inflammatory joint conditions (e.g., arthritis such as rheumatoid arthritis or psoriatic arthritis, juvenile chronic arthritis, spondyloarthropathy, Reiter's syndrome, gout). In some embodiments, musculoskeletal disorders result in symptoms such as pain, stiffness and / or limited movement of the affected body part(s). Inflammatory muscle disorders include dermatomyositis, polymyositis, and various other disorders of chronic muscle inflammation of unknown etiology that cause muscle weakness. In some embodiments, the complement-mediated musculoskeletal disorder is myasthenia gravis.

[0113] G.Transplantation In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is used to protect a graft from complement-mediated damage. The graft can be contacted with a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) before, during, and / or after transplantation in various embodiments of the present disclosure. In another embodiment, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered to the donor prior to removal of the graft (e.g., using a dose and / or administration regimen described herein). In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered to the recipient during and / or after introduction of the graft (e.g., using a dose and / or administration regimen described herein). In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered to the recipient prior to introduction of the graft (e.g., using a dose and / or administration regimen described herein). In some embodiments, the subject receives a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) after receiving the graft (e.g., using a dose and / or administration regimen described herein).

[0114] In some embodiments, the graft is or includes a solid organ, such as a kidney, liver, lung, pancreas, or heart. In some embodiments, the graft is or includes bone, cartilage, fascia, tendon, ligament, cornea, sclera, pericardium, skin, heart valve, blood vessel, amniotic membrane, or dura mater. In some embodiments, the graft includes multiple organs, such as a heart-lung graft or a pancreatic-kidney graft. In some embodiments, the graft includes less than a complete organ or tissue. For example, the graft may include a portion of an organ or tissue, such as a liver lobe, a portion of a blood vessel, a skin flap, or a heart valve. In some embodiments, the graft includes a preparation that includes isolated cells or tissue fragments that have been isolated from the original tissue but retain at least some tissue structure, such as pancreatic islets. In some embodiments, the preparation includes isolated cells that are not attached to each other via connective tissue, such as hematopoietic stem or progenitor cells derived from peripheral blood and / or umbilical cord blood, or whole blood, or any cell-containing blood product, such as red blood cells (RBCs) or platelets.

[0115] In some embodiments, the graft is a xenograft (i.e., the donor and recipient are different species), an autograft (i.e., a graft from one part of the body to another part of the body in the same individual), a homograft (i.e., the donor and recipient are genetically identical), or an allograft (i.e., the donor and recipient are members of the same species who are not genetically identical).

[0116] H. Ischemia / reperfusion injury Ischemia-reperfusion (I / R) injury is a contributing factor in tissue damage after trauma, as well as in other conditions involving temporary interruption of blood flow, such as myocardial infarction, stroke, severe infection, vascular disease, aneurysm repair, cardiopulmonary bypass, and transplantation. In the setting of trauma, ischemia is caused by systemic hypoxemia, hypotension, contusion, compartment syndrome, and interruption of local blood supply due to vascular injury, resulting in injury to metabolically active tissues. Restoration of blood supply triggers a potent systemic inflammatory response. After reperfusion, all three major complement pathways are activated and, acting either coordinately or independently, are involved in I / R-related adverse events affecting multiple organ systems.

[0117] In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered (e.g., using a dose and / or dosing regimen described herein) to a subject who has recently (e.g., within the previous 2, 4, 8, 12, 24, or 48 hours) experienced a trauma, e.g., a trauma that places the subject at risk for I / R injury, e.g., due to systemic hypoxemia, hypotension, and / or local interruption of blood supply. In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) may be administered intravascularly (e.g., using a dose and / or dosing regimen described herein), optionally into a blood vessel supplying the injured body part, or directly to the body part. In some embodiments, the subject has a spinal cord injury, traumatic brain injury, burn injury, and / or hemorrhagic shock.

[0118] In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered to a subject prior to (e.g., within 1, 2, 4, 8, 12, 24, or 48 hours prior to) or after (e.g., within 1, 2, 4, 8, 12, 24, or 48 hours after) a surgical procedure, e.g., a surgical procedure that is expected to temporarily interrupt, e.g., blood flow to a tissue, organ, or body part, using a dose and / or administration regimen described herein. Examples of such procedures include cardiopulmonary bypass, angioplasty, heart valve repair / replacement, aneurysm repair, or other vascular surgery. A compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) can be administered (e.g., using the dosages and / or dosing regimens described herein) before, after, and / or during a period overlapping with a surgical procedure.

[0119] In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered to a subject suffering from an MI, thromboembolic stroke, deep vein thrombosis, or pulmonary embolism using the doses and / or dosing regimens described herein. In some embodiments, the compstatin analog is administered within 1, 2, 4, 8, 12, 24, or 48 hours after the event. A compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) may be administered in combination with a thrombolytic agent, such as tissue plasminogen activator (tPA) (e.g., alteplase (activase), reteplase (retabase), tenecteplase (TNKase)), anistreplase (eminase), streptokinase (fungal kinase, streptocase), or urokinase (abokinase). In some embodiments, a compstatin analog described herein (eg, a PEGylated compstatin analog, e.g., pegcetacoplan) can be administered before, after, and / or during an overlapping period with the thrombolytic agent.

[0120] I. Other Disabilities In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is used to treat a subject suffering from or at risk of a complement-mediated disorder affecting the integumentary system. In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered to a subject suffering from or at risk of a complement-mediated disorder affecting the integumentary system using a dose and / or administration regimen described herein. Examples of such disorders include, for example, atopic dermatitis, psoriasis, pemphigoid, pemphigus, systemic lupus erythematosus, dermatomyositis, scleroderma, sclerodermomyositis, Sjogren's syndrome, and chronic urticaria.

[0121] In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is used to treat a subject suffering from or at risk for a complement-mediated disorder affecting the gastrointestinal system, e.g., inflammatory bowel disease, e.g., Crohn's disease or ulcerative colitis. In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered to a subject suffering from or at risk for a complement-mediated disorder affecting the gastrointestinal system, e.g., inflammatory bowel disease, e.g., Crohn's disease or ulcerative colitis, using the doses and / or administration regimens described herein.

[0122] In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is used to treat a subject suffering from or at risk for a complement-mediated inflammatory disorder, such as rhinosinusitis or myocarditis. In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered to a subject suffering from or at risk for a complement-mediated inflammatory disorder, such as rhinosinusitis or myocarditis, using the doses and / or dosing regimens described herein.

[0123] In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is used to treat a subject suffering from or at risk for thyroiditis (e.g., Hashimoto's thyroiditis, Graves' disease, postpartum thyroiditis), hepatitis (e.g., hepatitis C), pancreatitis, pancreatitis, or a MYH9-associated disorder. In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is administered using the doses and / or dosing regimens described herein to a subject suffering from or at risk for thyroiditis (e.g., Hashimoto's thyroiditis, Graves' disease, postpartum thyroiditis), hepatitis (e.g., hepatitis C), pancreatitis, tonsillitis, or a MYH9-associated disorder.

[0124] In some embodiments, a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) is used to treat (e.g., using the doses and / or dosing regimens described herein) interleukin-2 induced toxicity during IL-2 therapy, myocardial infarction, post-pump syndrome in cardiopulmonary or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis, immune complex disorders and autoimmune diseases, hepatic fibrosis, fibrous dust disease, nasal polyposis, parasitic diseases, Goodpasture's syndrome, immune complex-associated inflammation, antiphospholipid syndrome, cancer, periodontitis, gingivitis, or obesity.

[0125] In some embodiments, the complement-mediated condition, disorder, or disease is complement activation secondary to administration of another therapeutic or diagnostic agent. For example, in some embodiments, the complement-mediated condition, disorder, or disease is complement activation secondary to gene therapy (e.g., gene therapy with a viral vector, such as an adeno-associated virus (AAV), adenovirus, or lentivirus vector) or complement activation secondary to cell therapy. In some embodiments, the subject is suffering from TMA secondary to hematopoietic stem cell transplant (HSCT-TMA). In some embodiments, the subject is suffering from drug-induced TMA. In some embodiments, administration of a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) before and / or after administration of another therapeutic agent may enhance the efficacy and / or safety of such therapeutic agent.

[0126] In some embodiments, the complement-mediated condition, disorder, or disease is complement activation secondary to exposure of blood to foreign bodies, such as occurs during hemodialysis or extracorporeal membrane oxygenation (ECMO). In some embodiments, the method comprises administering a PEGylated compstatin analog to the subject (i) prior to the initiation of a dialysis procedure (e.g., about 2 hours, 1 hour, 30 minutes, or 15 minutes prior to the initiation of dialysis), and / or (ii) during the dialysis procedure, and / or (iii) after completion of the dialysis procedure (e.g., about 15 minutes, 30 minutes, 1 hour, or 2 hours after completion of the dialysis procedure). In some embodiments, the method comprises administering a PEGylated compstatin analog to the subject (i) prior to the initiation of ECMO (e.g., about 2 hours, 1 hour, 30 minutes, or 15 minutes prior to the initiation of ECMO), and / or (ii) during ECMO, and / or (iii) after completion of ECMO (e.g., about 15 minutes, 30 minutes, 1 hour, or 2 hours after completion of the dialysis procedure). In some embodiments, a method of inhibiting complement activation in a subject whose blood is exposed to one or more components (e.g., tubing, membrane) of a dialysis or ECMO circuit comprises intravenously administering a PEGylated compstatin analog to a subject described herein (e.g., using the doses and / or dosing regimens described herein).

[0127] VI. Combination Therapy In some aspects, the methods of the disclosure include administering a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan), alone or in combination with one or more additional therapies. In some embodiments, the one or more additional therapies modulate the immune response. In some embodiments, a compstatin analog described herein (e.g., pegcetacoplan) is administered to a subject already undergoing therapy with another immunomodulatory therapy. In some embodiments, the other immunomodulatory therapy is administered to a subject receiving a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan). In some embodiments, both a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) and another immunomodulatory therapy are administered to the subject.

[0128] Examples of immunomodulatory therapies include cancer vaccines, adoptive T cell or antibody therapy, immune checkpoint blockade, or a combination thereof. In some embodiments, the immunomodulatory therapy includes drugs such as interleukins (e.g., IL-2, IL-7, IL-12); cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interferons; various chemokines such as CXCL13, CCL26, CXCL7; antagonists of immune checkpoint blockade such as anti-CTLA-4, anti-PD-1, anti-PD-Ll, anti-LAG3, and anti-B7-H3; modulators of regulatory T cells (Tregs) such as synthetic cytosine phosphate-guanosine (CpG), oligodeoxynucleotides, glucans, cyclophosphamide, or other immunomodulatory agents. In one embodiment, the immunomodulatory therapy includes an agonist antibody against 4-IBB (CD137). In some embodiments, the immunomodulatory therapy is a macrophage modulator, such as bindarit. In some embodiments, the immunomodulatory therapy is a TNFα inhibitor, such as Humira. In some embodiments, administration of a compstatin analog described herein (e.g., a PEGylated compstatin analog, e.g., pegcetacoplan) may allow for administration of a reduced dosing regimen of the second therapy (e.g., with smaller individual doses, less frequent dosing, reduced doses, and / or reduced overall exposure) compared to administration of such second therapy alone. Without wishing to be bound by theory, in some embodiments, a reduced dosing regimen of the second therapy may avoid one or more undesirable adverse effects that may otherwise occur.

[0129] In some embodiments, such reduced doses may be administered in smaller volumes, or using lower concentrations, or using longer dosing intervals, or any combination of the foregoing, compared to administration of a compstatin analog (e.g., pegcetacoplan) described herein or the second therapy alone.

[0130] All publications, patent applications, patents, and other references mentioned herein, including GenBank accession numbers, are incorporated by reference in their entirety. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described herein.

[0131] The present disclosure is further illustrated by the following examples. The examples are provided for illustrative purposes only. They should not be construed as limiting the scope or content of the present disclosure in any way. EXAMPLES

[0132] Example 1 - Dose Escalation Study of Exemplary PEGylated Compstatin Analogs method Healthy human volunteers were divided into four cohorts, with each cohort containing four subjects receiving a PEGylated compstatin analog having about 40 kD PEG ("PEG") as shown in Figure 1, and each cohort containing one subject receiving a placebo. The PEGylated compstatin analog is referred to as PEG in the figures. The PEGylated compstatin analog (i.e., PEG) was formulated in acetate buffered saline (10 mM NaOAc in 0.9% NaCl, pH 5.0) and administered by a single IV bolus injection administered over approximately 30 minutes using a syringe pump according to the following dosing schedule: [Table 2]

[0133] Time point of analysis Blood samples for pharmacokinetic analysis of PEGylated compstatin analog ("PEG") concentrations, and alternative complement pathway hemolytic activity (AH50), total complement hemolytic activity (CH50), C3 and C3a levels were collected at 15, 30, and 60 minutes, 4, 8, 12, and 24 hours post-dose, and on days 3, 4, 5, 6, 7, 8, 15, 22, 29, and 43. Subjects were monitored during the safety period from days 2 to 8 for physical exam, ECG, hematology, serum chemistry, monitoring of injection site reactions, and treatment-emergent adverse events (TEAEs). Follow-up safety assessments were conducted on days 15, 22, 29, and 43.

[0134] Analysis method AH50 Method: AH50 was measured by a hemolytic assay based on the lysis of rabbit red blood cells (RA) due to the activation of complement on the cell surface. AH50 (50% alternative complement hemolytic dose) was determined for each component by adding limiting amounts of test serum or plasma. In this assay, a buffer is created that blocks the activity of the classical pathway, which requires calcium. Serial dilutions of the test specimen were mixed with an equal volume of RA. This functional assay measures the amount of hemoglobin released when target cells are lysed by the action of complement, from which the percentage of lysed cells was calculated. The main peak of the hemoglobin spectrum was read at a wavelength of 415 nm. For each assay, the run was verified with 5-point standards and 5-point characterized QC controls.

[0135] Calculation of AH50: For verifiable continuity between assay runs, the AH50 assay was performed using a human serum standard with known AH50 activity. Serial dilutions of the standard were used to establish its 50% lysis point (the point at which the best-fit line formed from percent lysis (Y) against the inverse of the dilution of serum (X) reaches 50%). If the dilution series produced lysis that straddled the 50% point, the three points closest to the 50% point were used to determine the slope and intercept of the line by linear regression. If the percent lysis was so low that none of the dilutions produced 50% lysis, the two highest points of the series were used because the slope changes dramatically as the sigmoid curve reaches its lower limit. Each specimen from the study was diluted in the same manner, and individual 50% lysis points were determined by linear regression.

[0136] Testing for C3a cleavage products: C3a was measured by ELISA (BD Pharmingen optEIA) using microtiter plates precoated with a specific monoclonal antibody against C3a. Standards, controls and test samples were diluted, placed in duplicate in wells and incubated to allow the cleavage products to bind to the antibody in the wells. After washing away unbound protein, an anti-cleavage product secondary antibody conjugated to an enzyme (horseradish peroxidase) was reacted with the cleavage products bound to the primary antibody on the plate. After appropriate incubation times and washing, a chromogenic substrate for the enzyme was added to the wells and the intensity of the color developed was determined spectrophotometrically. Triplicate runs of QC samples were performed for each assay.

[0137] C3a ELISA calculation: The optical density (OD) of each well containing the standards for the assay was entered as the dependent variable (Y) in a linear regression calculation (Microsoft Excel) where the concentration of the standard (provided by the kit manufacturer, BD Pharmingen) was the independent variable (X). The slope (m) and intercept (b) obtained from the log-log regression analysis were then used to calculate the concentrations of the unknowns (control and test specimens). The equation of the line was used to calculate the unknown values ​​using a log / log solution: LnY=mLnX+b, for X: X=exp(LnY-b) / m*dilution.

[0138] C3: C3 levels were measured with the BindingSite SPA Plus. The SPA Plus measures protein concentration by turbidimetric immunoassay. The specimen to be tested is mixed with a fixed concentration of excess polyclonal antibody against the analyte of interest. This results in the formation of large antigen-antibody immune complexes. The specimen is diluted to reach a point where the antigen concentration is close to that of the antibody. As light passes through the suspension, some is transmitted and focused by an optical lens system onto a photodiode. The amount of transmitted light is indirectly proportional to the specific protein concentration in the sample. The concentration is automatically calculated by reference to a calibration curve. Thus, the amount of analyte (C3 causing agglutination) in the sample can be easily determined. C3 concentration is expressed as g / L.

[0139] Calculation of C3: In the case of turbidimetric assays, the change in the amount of light absorbed (the inverse of the amount transmitted) depends on the amount of agglutination between the analyte and a specific antibody, thereby determining the amount of analyte (C3 causing agglutination) in the sample.

[0140] result Twenty subjects were enrolled and assigned 4:1 per cohort to receive PEG or placebo (PEG-200 mg, n=4; PEG-600 mg, n=4; PEG-1500 mg, n=4; PEG-2300 mg, n=4; pooled placebo, n=4). After a single IV administration, peak PEG concentrations (C max) were observed (mean serum concentrations: PEG-200 mg, 61 μg / mL; PEG-600 mg, 193 μg / mL; PEG-2300 mg, 708 μg / mL) except for PEG-1500 mg (542 μg / mL at 4 hours). PEG concentrations at the end of the infusion were significantly higher than the observed C max PEG concentrations declined monoexponentially, with terminal elimination half-lives ranging from 200 to 222 hours in cohorts 1–3 and increasing to 285 hours in cohort 4 (Figure 2). Systemic clearance of PEG after IV administration was similar between cohorts.

[0141] In all PEG cohorts, an early, immediate decrease in mean AH50 values ​​was detected within 1 hour, with the 1500 mg and 2300 mg doses reducing AH50 to undetectable levels starting 1 hour after dosing initiation (Figure 3). Reductions in mean AH50 values ​​were maintained for at least 12, 72, 144, and 168 hours after single doses of 200, 600, 1500, and 2300 mg PEG, respectively. All PEG groups demonstrated statistically significantly greater mean maximum decreases in AH50 compared to placebo (p<0.0001).

[0142] Mean CH50 decreased immediately upon dosing in all cohorts (data not shown). The maximum mean decrease from baseline (-71.3 U / mL, -28.23%) occurred in the PEG-2 300 mg group 1 hour after dosing initiation and returned to baseline by 24 hours after dosing initiation. The decrease in mean CH50 in the PEG-1 500 mg group (maximum mean decrease -59.8 U / mL, -23.80%) was maintained for at least 48 hours. Only the PEG-1 500 mg dose group had a statistically significant (p<0.05) greater mean maximum decrease in mean CH50 compared to placebo, although this result may have been skewed by one subject in this group who had a much larger decrease in CH50 at 336 hours after dosing.

[0143] After a delay, mean C3 increased in all PEG groups, peaking at 168 hours after initiation of dosing in all PEG groups except the PEG-600mg group, which peaked at 120 hours after initiation of dosing (data not shown). Mean C3 levels remained elevated well beyond week 4. The greatest mean increase in C3 levels occurred in the PEG-2300mg group (+1.0923mg / mL, +90.33%). The mean maximum increase in C3 increased with dose. The PEG-600mg, PEG-1500mg and PEG-2300mg groups all achieved statistically significantly greater mean maximum increases in C3 compared to placebo (p<0.05).

[0144] All PEG groups had an initial rapid decline in mean C3a levels within 1 hour, and all dose groups had trough mean C3a levels within 24 hours of dosing (data not shown). No dose-related decline in mean C3a was observed, with all doses recording a maximum mean decline of 47% to 57%, with the greatest mean C3a decline from baseline in the PEG-1500mg group (a 57% decline) 4 hours after dosing began. No change in C3a levels was seen with placebo, and all PEG groups showed a statistically significant mean maximum decline in C3a compared to placebo (p<0.05).

[0145] Of the 20 subjects enrolled in the study, 11 (55.0%) experienced treatment-related adverse events (TEAEs). The most common TEAEs in the PEG group were headache (n=6, 37.5%), upper respiratory tract infection due to seasonal viral infection (n=2, 12.5%), and diarrhea (n=2, 12.5%). No serious adverse events, deaths, or serious TEAEs occurred. One subject (5.0%) in the PEG-2 300 mg cohort experienced a moderate TEAE (infusion-related reaction, dizziness, sliminess, nausea) that led to discontinuation of the study.

[0146] These results suggest that administration of IV PEG in sodium acetate solution has a good safety profile and effectively increases PEG serum concentrations while reducing complement activity within 1 hour after administration in healthy subjects.

[0147] Example 2 - Mass dosing study of exemplary PEGylated compstatin analogs method Patients enrolled in PNH open-label extension studies of pegcetacoplan (including the PEGASUS (NCT03500549), PADDOCK (NCT02588833), and PRINCE (NCT04085601) trials) who experienced acute hemolysis warranting acute intervention were offered the opportunity to receive intensive subcutaneous (SC) or intensive intravenous (IV) dosing of a PEGylated compstatin analog ("PEG"), shown in Figure 1, with a PEG of approximately 40 kD, at the investigator's discretion. Eligibility criteria for the intensive dosing regimen included lactate dehydrogenase (LDH) >2x the upper limit of normal (ULN) and one new or worsening sign or symptom of hemolysis (e.g., decreased hemoglobin (Hb), hemoglobinuria, or fatigue).

[0148] The intensive dosing regimen is shown in Figure 4. Patients who received 1080 mg PEG SC twice weekly and showed acute hemolysis received a single dose of 1080 mg IV PEG, or 1080 mg SC PEG for three doses every 24 hours (intensive PEG treatment), followed by an increased maintenance regimen of 1080 mg SC PEG every 3 days. Patients who received 1080 mg SC PEG every 3 days or three times weekly and showed acute hemolysis received intensive PEG treatment, followed by a maintenance dose of 1080 mg SC PEG three times weekly. Patients who experienced additional acute hemolytic events after receiving intensive PEG treatment received additional doses of intensive SC PEG or intensive IV PEG. Additionally, 4 of 13 patients (3 of 9 intensive SC PEG and 1 of 4 intensive IV PEG-treated patients) received at least one red blood cell (RBC) transfusion during the management of the acute hemolytic event (between days 1 and 19). The data analyzed relates to the first of multiple acute hemolytic events in which the patient experienced multiple events.

[0149] Hb (day 1) and LDH (days 1, 2, 7-12, 14-19) levels were measured during acute hemolytic events. For measurements on days 7-12 and 14-19, the first available measurements ≥7 and ≥14 days after intensive PEG treatment were used, respectively. For each patient, at least 6 days were between measurements on days 7-12 and 14-19. Safety was assessed by the incidence and severity of adverse events.

[0150] result In total, 13 of 137 patients aged 20–72 years who participated in the open-label extension study underwent intensive PEG treatment. At the time of participation in the open-label extension study, these 13 patients had a mean LDH level of 249 U / L (5 patients >ULN, 11 patients <1.5 times ULN) and a mean Hb level of 12.0 g / dL (range: 8–15 g / dL).

[0151] From before intensive PEG treatment to day 1, Hb fell by less than 2 g / dL in six patients and by more than 2 g / dL in seven patients. The maximum fall in one patient was 4.9 g / dL (from 11.4 g / dL to 6.5 g / dL). Additionally, as shown in Figure 6, mean Hb increased in patients who received at least one RBC transfusion and in patients who did not receive an RBC transfusion. LDH levels were determined by a series of local and central laboratories, and local lab values ​​were standardized to the central lab based on normal ranges from the respective laboratories. On day 1, nine patients had LDH <10x ULN and four patients had LDH >10x ULN (two patients treated with intensive SCPEG and two patients treated with intensive IVPEG). Management of acute hemolytic events included intensive SCPEG administration in nine patients and a single intensive IVPEG administration in four patients. As shown in Figure 5 , LDH levels decreased from day 1 to day 2 in 8 of 12 evaluable patients (4 of 8 patients treated with intensive SCPEG and 4 of 4 patients treated with intensive IVPEG) and in all 13 patients from days 7 to 12. LDH levels further decreased from days 7 to 12 to days 14 to 19 in 11 of 13 patients (7 of 9 patients treated with intensive SCPEG and 3 of 4 patients treated with intensive IVPEG).

[0152] The incidence and severity of adverse events were similar to those seen in the overall open-label extension study. Nine of 13 patients (69%) experienced a treatment-emergent adverse event, and four of 13 patients (31%) experienced a serious adverse event. The majority of treatment-emergent adverse events (76%) were mild. No meningitis or thrombotic adverse events occurred. Of the four patients who experienced a serious adverse event, three experienced a second hemolytic event leading to another round of intensive therapy. None of the adverse events led to treatment discontinuation.

[0153] These results suggest that intensive SC or intensive IV administration regimens of PEG may provide effective management of acute hemolytic events and potentially rapid control of LDH levels. Moreover, intensive treatment with PEG demonstrated a favorable safety and tolerability profile.

[0154] Equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The scope of the invention is not intended to be limited to the above Description, but is as set forth in the following claims.

Claims

1. 1. A pharmaceutical for use in a method for treating acute hemolysis in a subject suffering from PNH, said method comprising administering intensive therapy to the subject, said intensive therapy comprising (i) intravenously administering to said subject about 540 mg to about 2160 mg of a PEGylated compstatin analog comprising about 40 kDa PEG, or (ii) subcutaneously administering to said subject about 540 mg to about 2160 mg of a PEGylated compstatin analog comprising about 40 kDa PEG each day for three consecutive days.

2. The intensive therapy comprises: a) administering to the subject about 540 mg to about 2160 mg of a PEGylated compstatin analog comprising about 40 kD PEG intravenously, preferably about 1080 mg of a PEGylated compstatin analog comprising about 40 kD PEG intravenously; or b) administering to said subject about 540 mg to about 2160 mg of a PEGylated compstatin analog comprising about 40 kD PEG subcutaneously each day for three consecutive days, preferably about 1080 mg of a PEGylated compstatin analog comprising about 40 kD PEG subcutaneously each day for three consecutive days; The pharmaceutical composition according to claim 1,

3. Prior to the acute hemolysis, a) the subject is being treated with about 1080 mg of a PEGylated compstatin analog comprising about 40 kD of PEG administered subcutaneously twice weekly, and after the intensive therapy, the subject receives treatment with about 1080 mg of a PEGylated compstatin analog comprising about 40 kD of PEG administered subcutaneously every three days; or b) the subject is being treated with about 1080 mg of a PEGylated compstatin analog comprising about 40 kDa PEG administered subcutaneously every three days, and after the intensive therapy, the subject receives treatment with about 1080 mg of a PEGylated compstatin analog comprising about 40 kDa PEG administered subcutaneously three times per week; or c) prior to said acute hemolysis, said subject was treated with a C5 inhibitor, and after said intensive therapy, said subject was treated with about 1080 mg of a PEGylated compstatin analog comprising about 40 kDa PEG administered subcutaneously twice a week, every three days, or three times a week; Optionally, the subject continues treatment with the C5 inhibitor for 4 weeks after receiving the intensive therapy, and then discontinues treatment with the C5 inhibitor; or d) prior to said acute hemolysis, said subject has not been treated with a complement inhibitor, and after said intensive therapy, said subject is treated with about 1080 mg of a PEGylated compstatin analog comprising about 40 kDa PEG administered subcutaneously twice a week, every three days, or three times a week, preferably twice a week. The pharmaceutical composition according to claim 1,

4. a) prior to said intensive therapy, said subject had an LDH level of at least 2 times the ULN; and / or b) the method further comprises determining that the subject is experiencing acute hemolysis by a method comprising detecting an LDH level of at least 2 times the ULN in a blood sample obtained from the subject; and / or c) measuring LDH in a blood sample obtained from the subject within two weeks after the intensive therapy; The pharmaceutical composition according to claim 1,

5. 1. A medicament for use in a method of inhibiting complement in a subject, comprising intravenously administering to a subject in need thereof about 100 mg to about 2500 mg of a PEGylated compstatin analog comprising about 40 kDa PEG, wherein complement is inhibited or reduced (e.g., to levels of about 100%, 90%, 80%, 70%, 60%, 50%, 40%, or less relative to control levels) for about 2 hours to about 336 hours after administration.

6. The method comprises: a) about 200 mg, about 600 mg, about 1500 mg, or about 2300 mg of a PEGylated compstatin analog; or b) administering a single dose of a PEGylated compstatin analog intravenously; optionally about 200 mg, about 600 mg, about 1500 mg, or about 2300 mg of a PEGylated compstatin analog; or c) Two or more doses of a PEGylated compstatin analog The pharmaceutical composition according to claim 5, which comprises intravenously administering

7. The single dose is an infusion and further optionally comprises: a) administering the infusion at a rate of about 6.5 mg / min to about 80 mg / min, preferably at a rate of about 6.5 mg / min, about 20 mg / min, about 50 mg / min, or about 75 mg / min; and / or b) administering said infusion over a period of about 15 minutes to about 1 hour c) intravenously administering about 200 mg, about 600 mg, about 1500 mg, or about 2300 mg of the PEGylated compstatin analog over about 30 minutes; The pharmaceutical composition according to claim 6, comprising:

8. a) complement inhibition is assessed by measuring the level of complement activity in a serum sample of said subject, optionally wherein the level of complement activity is measured using an alternative pathway assay, a classical pathway assay, or both; and / or 6. The pharmaceutical composition of claim 5, wherein the subject has or is at risk of having a complement-mediated disorder, and optionally the complement-mediated disorder is hemolytic anemia, warm antibody autoimmune hemolytic anemia, cold agglutinin disease, C3 glomerulopathy, paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis, glomerulonephritis, neuromyelitis optica (NMO), amyotrophic lateral sclerosis (ALS), polyneuropathy, nephropathy, or vasculitis, and optionally further comprises subcutaneously administering the PEGylated compstatin analog to the subject after the intravenous administration step.

9. 1. A pharmaceutical for use in a method of treating a subject in need of treatment for a complement-mediated disorder, said method comprising intravenously administering to a subject in need thereof about 100 mg to about 2500 mg of a PEGylated compstatin analog comprising about 40 kD PEG, thereby treating said complement-mediated disorder.

10. 10. The method of claim 9, wherein the method comprises administering two or more doses of the PEGylated compstatin analog.

11. a) the complement-mediated disorder is hemolytic anemia, warm antibody autoimmune hemolytic anemia, cold agglutinin disease, C3 glomerulopathy, paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis, glomerulonephritis, neuromyelitis optica (NMO), amyotrophic lateral sclerosis (ALS), polyneuropathy, nephropathy, or vasculitis; and / or b) after the administering step, complement in said subject is inhibited or reduced (e.g., to a level of about 100%, 90%, 80%, 70%, 60%, 50%, 40%, or less relative to control levels) for about 2 hours to about 336 hours after administration; and / or c) a single dose of said PEGylated compstatin analog is administered intravenously, optionally wherein said single dose is an infusion; and / or d) intravenously administering about 200 mg, about 600 mg, about 1500 mg, or about 2300 mg of the PEGylated compstatin analog; e) complement inhibition is assessed by measuring the level of complement activity in a serum sample from said subject, optionally measured using an alternative pathway assay, a classical pathway assay, or both; and / or f) the subject is in need of treatment for an exacerbation of the disorder. The pharmaceutical composition according to claim 9,

12. the single dose is an infusion, and the method comprises administering the infusion at a rate of about 6.5 mg / min to about 80 mg / min; optionally, administering the infusion at a rate of about 6.5 mg / min, about 20 mg / min, about 50 mg / min, or about 75 mg / min; and / or the method comprising administering the infusion over a period of about 15 minutes to about 1 hour; The pharmaceutical composition according to claim 11,

13. 10. The method of claim 9, wherein the method comprises intravenously administering about 200 mg, about 600 mg, about 1500 mg, or about 2300 mg of the PEGylated compstatin analog over about 30 minutes.

14. The PEGylated compstatin analog comprises a PEG having at least two compstatin analog moieties attached thereto, and optionally a) the PEGylated compstatin analog comprises a linear PEG having a compstatin analog moiety attached to each end; and / or b) each compstatin analog moiety comprises a cyclic peptide comprising the amino acid sequence of one of SEQ ID NOs: 3-36, 37, 69, 70, 71, and 72; and / or c) the PEGylated compstatin analog comprises one or more PEG moieties attached to one or more compstatin analog moieties, each compstatin analog moiety comprising a cyclic peptide having the amino acid sequence set forth in any of SEQ ID NOs: 3-36 extended at the N-terminus, C-terminus, or both, by one or more terminal amino acids, one or more of which have a side chain comprising a primary or secondary amine and are separated from the cyclic peptide by a rigid or flexible spacer optionally comprising an oligo(ethylene glycol) moiety, each PEG covalently attached to one or more compstatin analog moieties via a linking moiety, the linking moiety comprising an unsaturated alkyl moiety, a moiety comprising a non-aromatic ring system, an aromatic moiety, an ether moiety, an amide moiety, an ester moiety, a carbonyl moiety, an imine moiety, a thioether moiety, and / or an amino acid residue; and / or d) each compstatin analog moiety comprises a cyclic peptide extended at the N-terminus, C-terminus, or both, by one or more amino acids, said one or more amino acids being separated from the cyclic portion of the peptide by a rigid or flexible spacer comprising 8-amino-3,6-dioxaoctanoic acid (AEEAc) or 11-amino-3,6,9-trioxaundecanoic acid; and / or e) The pharmaceutical according to any one of claims 1 to 13, wherein the cyclic peptide comprises the amino acid sequence of SEQ ID NO: 28 and the spacer comprises AEEAc.

15. The PEGylated compstatin analog comprises a PEG having at least two compstatin analog moieties attached thereto, optionally comprising: a) the PEGylated compstatin analog comprises a linear PEG having a compstatin analog moiety attached to each end; and / or b) each compstatin analog moiety comprises a cyclic peptide comprising the amino acid sequence of one of SEQ ID NOs: 3-36, 37, 69, 70, 71, and 72; and / or c) the PEGylated compstatin analog comprises one or more PEG moieties attached to one or more compstatin analog moieties, each compstatin analog moiety comprising a cyclic peptide having the amino acid sequence set forth in any of SEQ ID NOs: 3-36 extended at the N-terminus, C-terminus, or both, by one or more terminal amino acids, one or more of which have a side chain comprising a primary or secondary amine and are separated from the cyclic peptide by a rigid or flexible spacer optionally comprising an oligo(ethylene glycol) moiety, each PEG covalently attached to one or more compstatin analog moieties via a linking moiety, the linking moiety comprising an unsaturated alkyl moiety, a moiety comprising a non-aromatic ring system, an aromatic moiety, an ether moiety, an amide moiety, an ester moiety, a carbonyl moiety, an imine moiety, a thioether moiety, and / or an amino acid residue; and / or d) each compstatin analog moiety comprises a cyclic peptide extended at the N-terminus, C-terminus, or both, by one or more amino acids, said one or more amino acids being separated from the cyclic portion of the peptide by a rigid or flexible spacer comprising 8-amino-3,6-dioxaoctanoic acid (AEEAc) or 11-amino-3,6,9-trioxaundecanoic acid; and / or e) The pharmaceutical according to any one of claims 1 to 13, wherein the cyclic peptide comprises the amino acid sequence of SEQ ID NO: 28 and the spacer comprises AEEAc.

16. The PEGylated compstatin analog has the following structure: 【Chemistry 1】 The pharmaceutical composition according to any one of claims 1 to 13, comprising:

Images